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DIMERCAPROL 301 Dimenhydrinate may also be known as: chloranautine, dimen-hydrinatum, diphenhydramine teoclate, and diphenhydramine theoclate; many trade names are available. Storage/Stability/Compatibility Dimenhydrinate products should be stored at room temperature; avoid freezing the oral solution and injectable products. The oral solution should be stored in tight containers; tablets stored in well-closed containers. Dimenhydrinate injection is reportedly physically compatible with all commonly used intravenous replenishment solutions and the following drugs: amikacin sulfate, atropine sulfate, calcium gluconate, chloramphenicol sodium succinate, corticotropin, dia-trizoate meglumine and sodium, diphenhydramine HCl, droperi-dol, fentanyl citrate, heparin sodium, iothalamate meglumine and sodium, meperidine HCl, methicillin sodium, metoclopramide, morphine sulfate, norepinephrine bitartrate, oxytetracycline HCl, penicillin G potassium, pentazocine lactate, perphenazine, pheno-barbital sodium, potassium chloride, scopolamine HBr, vancomy-cin HCl and vitamin B-complex with vitamin C. The following drugs are either physically incompatible or com-patible only in certain concentrations with dimenhydrinate: amino-phylline, ammonium chloride, amobarbital sodium, butorphanol tartrate, glycopyrrolate, hydrocortisone sodium succinate, hy-DIMERCAPROL BAL (dye-mer-kap-role) BAL in Oil® ANTIDOTE Prescriber Highlights TT Chelating agent for arsenicals; sometimes used for lead, mercury, & gold compounds TT Contraindications: Patients with impaired hepatic func-tion, unless secondary to acute arsenic toxicity, & in iron, cadmium, & selenium poisoning TT Caution: Patients with impaired renal function TT Alkalinize urine TT Administer deep IM (still painful) TT Adverse Effects: Usually transient & can include vomiting & seizures with higher dosages; increased blood pressure with tachycardia possible droxyzine, iodipamide meglumine, pentobarbital sodium, prochlo-rperazine edisylate, promazine HCl, promethazine HCl, tetracy-cline HCl, and thiopental sodium. Compatibility is dependent upon factors such as p H, concentration, temperature, and diluent used; consult a hospital pharmacist or specialized references for more speciﬁc information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Dimenhydrinate Tablets: 50 mg (regular & chewable); Dramamine® (Upjohn); Calm-X® (Republic Drug); Dimetabs® (Jones Medical); Tiptone® (Del Pharmaceuticals); generic; (OTC & Rx (Dimetabs® only)) Dimenhydrinate Liquid: 12. 5 mg/4 in 90 m L, pts and gals; 12. 5 mg/5 m L in 120 m L; 15. 62 mg/5 m L in 480 m L; Dramamine® and Children's Dramamine® (Upjohn); generic; (OTC) Dimenhydrinate Injection: 50 mg/m L in 1 m L amps, 1 and 10 m L vials; Dinate® (Seatrace); Dramanate® (Pasadena); Dymenate® (Keene); Hydrate® (Hyrex); generic; (Rx) Uses/Indications The principal use of dimercaprol in veterinary medicine is in treat-ing intoxications caused by arsenical compounds. It is occasionally used for lead, mercury and gold intoxication. Pharmacology/Actions The sulfhydryl groups found on dimercaprol form heterocyclic ring complexes with heavy metals, principally arsenic, lead, mercury and gold. This binding helps prevent or reduce heavy metal binding to sulfhydryl-dependent enzymes. Different metals have differing af-ﬁnities for both dimercaprol and sulfhydryl-dependent enzymes and the drug is relatively ineffective in chelating some metals (e. g., selenium). Chelation to dimercaprol is not irreversible and met-als can dissociate from the complex as dimercaprol concentrations decrease, in an acidic environment, or if oxidized. The dimercaprol-metal complex is excreted via renal and fecal routes. Pharmacokinetics After IM injection, peak blood levels occur in 30-60 min-utes. The drug is slowly absorbed through the skin after topical administration. Dimercaprol is distributed throughout the body, including the brain. Highest tissue levels are found in the liver and kidneys. Non-metal bound drug is rapidly metabolized to inactive com-pounds and excreted in the urine, bile and feces. In humans, the duration of action is thought to be about 4 hours with the drug completely eliminated within 6-24 hours. Contraindications/Precautions/Warnings Dimercaprol is contraindicated in patients with impaired hepatic function, unless secondary to acute arsenic toxicity. The drug is also contraindicated in iron, cadmium, and selenium poisoning, as the chelated complex can be more toxic than the metal alone. Because dimercaprol is potentially nephrotoxic, it should be used cautiously in patients with impaired renal function. In order to protect the kidneys, the urine should be alkalinized to prevent the chelated drug from dissociating in the urine. Animals with di-minished renal function or who develop renal dysfunction while on therapy should either have the dosage adjusted or discontinue therapy dependent on the clinical situation.	pppbs.pdf
302 DIMERCAPROL Adverse Effects IM injections are necessary with this compound but can be very pain-ful, particularly if the drug is not administered deeply. V omiting and seizures can occur with higher dosages. Transient increases in blood pressure with concomitant tachycardia have been reported. Most ad-verse effects are transient in nature as the drug is eliminated rapidly. Dimercaprol is potentially nephrotoxic. 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. ) It is not known if dimercaprol is excreted in milk. Overdosage/Acute Toxicity Clinical signs of dimercaprol overdosage in animals include vomit-ing, seizures, tremors, coma, and death. No speciﬁc doses were lo-cated to correspond with these clinical signs, however. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dimercaprol and may be of signiﬁcance in veterinary patients: !TIRON or SELENIUM : Because dimercaprol can form a toxic com-plex with certain metals (cadmium, selenium, uranium and iron), do not administer with iron or selenium salts. At least 24 hours should pass after the last dimercaprol dose, before iron or sele-nium therapy can begin. Laboratory Considerations !TIodine I131 thyroidal uptake values may be decreased during or immediately following dimercaprol therapy as it interferes with normal iodine accumulation by the thyroid. Doses !TDOGS & CATS: For arsenic toxicity: a) Intensive supportive care is required. Give dimercaprol as early as possible after exposure at 2. 5-5 mg/kg IM. The 5 mg/ kg dose should only be used for acute cases and only for the ﬁrst day of therapy. Repeat doses at 4 hour intervals for the ﬁrst 2 days; every 8 hours on the third day, and twice daily for the next 10 days until recovery. Give with sodium thiosulfate: 40-50 mg/kg IV as a 20% solution two to three times daily until recovery. (Neiger 1989) b) Cats: If ingestion was recent, use emetics or gastric lavage to help prevent arsenic absorption. If clinical signs are pres-ent and ingestion was within 36 hours, begin dimercaprol therapy at 2. 5-5 mg/kg IM q4h for the ﬁrst 2 days, the q12h until recovery. Fluid therapy should be instituted to prevent dehydration and maintain renal function. (Reid and Oehme 1989) c) 4 mg/kg IM q4-6h; do not give for more than 4 continuous days (Grauer and Hjelle 1988c) d) Loading dose of 5 mg/kg IM (acute cases only) followed by 2. 5 mg/kg IM q3-4h for two days, then progressively lengthen the dosing interval to q12h until recovery is evident (Mount 1989) !TFOOD ANIMALS: For arsenic toxicity: a) No clinical signs after exposure: 3 mg/kg IM q8h; Clinical signs after exposure: 6 mg/kg IM q8h for 3-5 days (Post and Keller 2000) b) 4-5 mg/kg initially, then 2-3 mg/kg IM q4-6h for the ﬁrst day and 1 mg/kg for at least 2 more days. May be beneﬁcial in animals poisoned with inorganic arsenic compounds, but not organic arsenicals. (Furr and Buck 1986) For mercury toxicity: a) For bovine or swine: 3 mg/kg IM four times daily for 3 days, then twice daily for 10 days. Treatment is often unsuccessful. (Osweiler and Hook 1986) !THORSES: For arsenic toxicity: a) Dimercaprol therapy in horses is difﬁcult because of the amounts of dimercaprol that are required, the necessity to inject the drug IM and that it must be used acutely and any substantial delays in treatment signiﬁcantly decrease its effec-tiveness. If available, the dose is: 5 mg/kg IM initially, followed by 3 mg/kg IM q6h for the remainder of the ﬁrst day, then 1 mg/kg IM q6h for two or more additional days, as needed. (Oehme 1987a) b) Wash off topically absorbable arsenic and empty the digestive tract with laxatives. Administer sodium thiosulfate at 50-75 grams PO every 6-8 hours to bind unabsorbed arsenic. IV thiosulfate (25-30 grams as a 20% solution in distilled wa-ter) may counter-absorb arsenic. Dimercaprol is effective if administered within hours of ingestion. Initial treatment is: 5 mg/kg IM, followed by 3 mg/kg IM q6h for the remainder of the ﬁrst day, then 1 mg/kg IM q6h for the next 48 hours. IM injections are painful; identify source of arsenic and eliminate it. (Rees 2004) Monitoring !TLiver function !TRenal function !THemogram !THydration and perfusion status !TElectrolytes and acid/base status !TUrinary p H Client Information !TBecause of the potential toxicity of this agent and the seriousness of most heavy metal intoxications, this drug should be used with close professional supervision only. !TDimercaprol can impart a strong, unpleasant mercaptan-like odor to the animal's breath. Chemistry/Synonyms A dithiol chelating agent, dimercaprol occurs as a colorless or nearly colorless, viscous liquid that is soluble in alcohol, vegetable oils, and water, but is unstable in aqueous solutions. It has a very disagreeable mercaptan-like odor. The commercially available injection is a pea-nut oil and benzyl benzoate solution. Although the solution may be turbid or contain small amounts of ﬂocculent material or sediment, this does not mean that the solution is deteriorating. Dimercaprol may also be known as: BAL, British Anti-Lewisite, dimercaptopropanol, dithioglycerol dimercaprolum, BAL® in Oil or Sulfactin Homburg®. Storage/Stability Dimercaprol injection should be stored below 40°C; preferably at room temperature (15-30°C).	pppbs.pdf
DIMETHYL SULFOXIDE 303 Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Dimercaprol Injection: 100 mg/m L (10%) (for IM use only) in 3 m L amps; BAL® in Oil (Taylor); (Rx) DIMETHYL SULFOXIDE DMSO (dye-meth-el sul-fox-ide) Domoso® FREE RADICAL SCA VENGER Prescriber Highlights TT Free radical scavenger that has antiinﬂammatory, cryo-preservative, anti-ischemic, & radioprotective effects TT Caution: Mastocytomas, dehydration/shock; may mask existing pathology TT Handle cautiously; will be absorbed through skin & can carry toxic compounds across skin TT May cause localized “burning” when administered topically TT Administer IV to horses slowly & at concentrations of 20% or less; may occasionally cause diarrhea, tremors, & colic TT Odor may be an issue Uses/Indications Purported uses for DMSO are rampant, but the only FDA-approved veterinary indication for DMSO is: “... as a topical application to reduce acute swelling due to trauma” (Package Insert; Domoso®— Syntex). Other possible indications for DMSO include: adjunctive treatment in transient ischemic conditions, CNS trauma and cere-bral edema, skin ulcers/wounds/burns, adjunctive therapy in intes-tinal surgeries, and analgesia for post-operative or intractable pain, amyloidosis in dogs, reduction of mammary engorgement in the nursing bitch, enhancement of antibiotic penetration in mastitis in cattle, and limitation of tissue damage following extravasation in-juries secondary to chemotherapeutic agents. DMSO's effect on alcohol dehydrogenase, may make it useful in the treatment of ethylene glycol poisoning, but this has not been sufﬁciently studied as of yet. DMSO's attributes as a potential car-rier of therapeutic agents across the skin and into the systemic cir-culation and its synergistic effects with other agents are potentially exciting, but require much more study before they can be routinely recom mended. While the potential indications for DMSO are many, unfortu-nately, the lack of well-controlled studies leaves many more ques-tions than answers regarding this drug. Pharmacology/Actions The pharmacologic effects of DMSO are diverse. DMSO traps free radical hydroxide and its metabolite, dimethyl sulﬁde (DMS), traps free radical oxygen. It appears that these actions help to explain some of the antiinﬂammatory, cryopreservative, antiischemic, and radioprotective qualities of DMSO. DMSO will easily penetrate the skin. It serves as a carrier agent in promoting the percutaneous absorption of other compounds (including drugs and toxins) that normally would not penetrate. Drugs such as insulin, heparin, phenylbutazone, and sulfonamides may all be absorbed systemically when mixed with DMSO and ap-plied to the skin. DMSO has weak antibacterial activity when used clinically and possible clinical efﬁcacy when used topically as an antifungal. The mechanism for these antimicrobial effects has not been elucidated. The antiinﬂammatory/analgesic properties of DMSO have been thoroughly investigated. DMSO appears to be more effective as an antiinﬂammatory agent when used for acute inﬂammation versus chronic inﬂammatory conditions. The analgesic effects of DMSO have been compared to that produced by narcotic analgesics and is efﬁcacious for both acute and chronic musculoskeletal pain. DMSO decreases platelet aggregation but reports of its effects on coagulability have been conﬂicting, as has its effect on the myo-cardium. DMSO has diuretic activity independent of the method of administration. It provokes histamine release from mast cells, which probably contributes to the local vasodilatory effects seen af-ter topical administration. DMSO also apparently has some anticholinesterase activity and enhances prostaglandin E, but blocks the synthesis of prosta-glandins E 2, F2-alpha, H2, and G 2. It inhibits the enzyme alcohol dehydrogenase, which not only is responsible for the metabolism of alcohol, but also the metabolism of ethylene glycol into toxic me-tabolites. Pharmacokinetics DMSO is well absorbed after topical administration, especially at concentrations between 80-100%. It is extensively and rapidly dis-tributed to virtually every area of the body. After IV administration to horses, the serum half-life was approximately 9 hours. In dogs, the elimination half-life is approximately 1. 5 days. DMSO is metabo-lized to dimethyl sulﬁde (DMS) and is primarily excreted by the kid-neys, although biliary and respiratory excretion also takes place. In cattle, the drug is eliminated quite rapidly and after 20 days no detectable drug or metabolites are found in milk, urine, blood, or tissues. Contraindications/Precautions/Warnings Wear rubber gloves when applying topically, and apply with clean or sterile cotton to minimize the chances for contaminating with potentially harmful substances. Apply only to clean, dry areas to avoid carrying other chemicals into the systemic circulation. DMSO may mask existing pathology with its antiinﬂammatory and analgesic activity. Because DMSO may degranulate mast cells, animals with masto-cytomas should only receive DMSO with extreme caution. DMSO should be used cautiously in animals suffering from dehydration or shock as its diuretic and peripheral vasodilatory effects may exacer-bate these conditions. Adverse Effects When used as labeled, DMSO appears to be an extremely safe drug. Local effects (“burning”, erythema, vesiculation, dry skin, local al-lergic reactions) and garlic or oyster-like breath odor are the most likely adverse effects. They are transient and quickly resolve when therapy is discontinued. Lenticular changes, which may result in myopia, have been noted primarily in dogs and rabbits when DMSO is used chronically and at high doses. These effects are slowly re-versible after the drug is discontinued.	pppbs.pdf
304 DIMETHYL SULFOXIDE When DMSO is administered intravenously to horses it may cause hemolysis and hemoglobinuria. While older dosage references often recommended 20% or less concentrations for IV use in horses, 10% solutions are more commonly recommended today as they are probably safer. Slow administration IV may also reduce adverse ef-fects. Other adverse effects may include diarrhea, muscle tremors and colic. Reports of hepatotoxicity and renal toxicity have also been re-ported for various species and dosages. These occur fairly rarely and some clinicians actually believe DMSO has a protective effect on ischemically insulted renal tissue. Reproductive/Nursing Safety At high doses, DMSO has been shown to be teratogenic in ham-sters and chicks, but not mice, rats, or rabbits; weigh the risks versus beneﬁts when using in pregnant animals. In humans, the FDA cat-egorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ). In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the beneﬁt of therapy clearly outweighs the risks. ) It is not known whether this drug is excreted in milk; use in nurs-ing dams with caution. Overdosage/Acute Toxicity The reported LD 50's following IV dosage in dogs and cats are: Cats ≈ 4 g/kg, and Dogs ≈ 2. 5 g/kg. Signs of toxicity include: sedation and hematuria at non-lethal doses; coma, seizures, opisthotonus, dyspnea and pulmonary edema at higher dosages. Should an acute overdosage be encountered, treat supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving DMSO and may be of signiﬁcance in veterinary patients: Because of its anticholinesterase activity, avoid the use of organo-phosphates or other cholinesterase inhibitors with DMSO. A fatality secondary to mercury intoxication was reported when DMSO was mixed with a mercury salt “red blister” and applied topically to the leg of a horse. Because it inhibits alcohol dehydrogenase, DMSO may prolong the effects of alcohol. Insulin, corticosteroids, (including endogenous steroids), and atropine may be potentiated by DMSO. Doses !TDOGS: a) Liberal application should be administered topically to the skin over the affected area 3-4 times daily. T otal daily dos-age should not exceed 20 grams (or m L of liquid) and ther-apy should not exceed 14 days. (Package Insert; Domoso®—-Syntex Animal Health) b) For calcinosis cutis: Dogs may “feel bad” if large areas are treated initially, but do not become hypercalcemic. Apply topically to a small area of the body initially (if extensive areas are involved) once daily; and as these areas improve, add new treatment areas. (Merchant 2000) !THORSES: (Note : ARCI UCGFS Class 5 Drug) While older dosage references often recommended 20% or less con-centrations for IV use in horses, 10% solutions are more commonly recommended today as they are probably safer. Some recent refer-ences state unequivocally “do not exceed 10% concentrations”. a) Liberal application should be administered topically to the skin over the affected area 2-3 times daily. T otal daily dosage should not exceed 100 grams (or m L of liquid) and therapy should not exceed 30 days. (Package Insert; Domoso®—Syntex Animal Health) b) For adjunctive treatment with surgical colics: 25 mg/kg IV in-tra-operatively and continued twice daily for the ﬁrst 24-48 hours post-op. (Hassel 2005) c) For treatment of cerebral edema secondary to eastern equine encephalitis (EEE): 1 g/kg as a 20% solution in D 5W IV over 30 minutes once daily for up to 3 days (Wilson 1987) d) For spinal cord injury: 1 gm/kg IV as a 20% solution in saline once daily for 3 days, then every other day for 6 days (Robin-son 1987) e) For acute rhabdomyolysis: DMSO 1 g/kg in a 10% solution of lactated Ringer's or Multisol IV or orally. May be given in the acute stages of rhabdomyolysis once hydration status has been restored. (Hanson 1999) f) As an adjunctive treatment for laminitis: 0. 1-1 g/kg IV, 2-3 times daily (Brumbaugh, Lopez et al. 1999) g) Adjunctive treatment of equine protozoal myeloencephalitis (EPM): 1 g/kg as a 20% solution in D 5W IV over 30 minutes once to twice daily (Brewer 1987) For cantharidin poisoning: a) 0. 9 gm/kg IV as a 10% solution in polyionic ﬂuids (Schmitz and Reagor 1987) Monitoring !TEfﬁcacy !THemoglobinuria/hematocrit if indicated !TOphthalmic exams with high doses or chronic use in the dog Client Information !TDo not use non-medical grades of DMSO as they may contain harmful impurities. Wear rubber gloves when applying topically. DMSO should be applied with clean or sterile cotton to minimize the chances for contaminating with potentially harmful substanc-es. Apply only to clean, dry skin. Use in well-ventilated area; avoid inhalation and contact with eyes. May damage some fabrics. Keep lid tightly on container when not in use. Keep out of reach of chil-dren. Do not mix with any other substance without veterinarian's approval. !TSelected DMSO products are approved for use in dogs and in horses not intended for food purposes. It is a veterinary prescrip-tion (Rx) drug. Chemistry/Synonyms DMSO is a clear, colorless to straw-yellow liquid. It is dipolar, apro-tic (acts as a Lewis base) and extremely hygroscopic. It has a melting/ freezing point of 18. 5°C, boiling point of 189°C, and a molecular weight of 78. 1. It is miscible with water (heat is produced), alcohol, acetone, chloroform, ether and many organic solvents. A 2. 15% so-lution in water is isotonic with serum. Dimethylsulfoxide may also be known as: dimethyl sulphox-ide, dimethylis sulfoxidum, DMSO, methyl sulphoxide, NSC-763, SQ-9453, sulphinylbismethane, Domoso®, Kemsol®, Rheumabene®, Rimso®, or Synotic®. Storage/Stability/Compatibility Must be stored in airtight containers away from light. As DMSO may react with some plastics, it should be stored in glass or in the container provided by the manufacturer. If DMSO is allowed to contact room air it will self-dilute to a concentration of 66-67%. DMSO is apparently compatible with many compounds, but be-	pppbs.pdf
DINOPROST TROMETHAMINE 305 cause of the chances for accidental percutaneous absorption of potentially toxic compounds, the admixing of DMSO with other compounds is not to be done casually. Dosage Forms/Regulatory Status VETERINARY APPROVED PRODUCTS: Dimethyl Sulfoxide Veterinary Gel 90%: Domoso® Gel (Fort Dodge) 90% (medical grade) in 60 g, and 120 g tubes, and 425 g containers. Labeled for use in dogs and horses. Do not administer to horses that are to be slaughtered for food. Dimethyl Sulfoxide Veterinary Solution 90%: Domoso® Solution (Fort Dodge) 90% (medical grade) in 1 pint and 1 gallon bottles. Labeled for use in canines and equines. Do not administer to horses that are to be slaughtered for food. The ARCI (Racing Commissioners International) has designated this drug as a class 5 substance. See the appendix for more information. HUMAN APPROVED PRODUCTS: Dimethylsulfoxide Solution: 50 % aqueous solution in 50 m L; Rimso-50® (Research Industries); Dimethyl Sulfoxide (Bioniche); (Rx) Note : A topical otic product, Synotic® (Fort Dodge) that contains: DMSO 60% and ﬂuocinolone acetonide 0. 01% is also available for veterinary use. Supplied in 8 m L and 60 m L dropper bottles. DINOPROST TROMETHAMINE PROSTAGLANDIN F2 ALPHA TROMETHAMINE (dye-noe-prost) Lutalyse® PROSTAGLANDIN Prescriber Highlights TT (THAM) salt of the naturally occurring prostaglandin F2alpha used as a luteolytic agent for estrous synchroni-zation, pyometra treatment, & as an abortifacient TT Contraindications: Pregnancy (when abortion or induced parturition not wanted); manufacturer lists several con-traindications for horses TT Extreme caution in elderly or debilitated animals TT Do NOT administer IV TT Pregnant women should not handle; humans with asthma & women of childbearing age should handle with caution TT Adverse effects ( DOGS/CAT S): Abdominal pain, em-esis, defecation, urination, pupillary dilation followed by constriction, tachycardias, restlessness & anxiety, fever, hypersalivation, dyspnea & panting; fatalities possible (esp. dogs) TT Adverse Effects: ( CATTLE): Infection at injection site, sali-vation, & hyperthermia possible TT Adverse Effects ( SWINE): Erythema & pruritus, urination, defecation, slight ataxia, hyperpnea, dyspnea, nesting behavior, abdominal muscle spasms, tail movements, increased vocalization & salivation TT Adverse Effects ( HORSES): Body temperature changes/ sweating; seen less frequently: increased respiratory & heart rates, ataxia, abdominal pain, & lying down Uses/Indications Lutalyse® (Upjohn) is labeled for use in cattle as a luteolytic agent for estrous synchronization, unobserved (silent) estrous in lactat-ing dairy cattle, pyometra, and as an abortifacient in feedlot and non-lactating dairy cattle. It is labeled in swine to act as a parturi-ent inducing agent. The product is labeled for use in mares as a luteolytic agent to control the time of estrus in cycling mares and to assist in inducing estrus in “difﬁcult to breed mares. ” Unlabeled uses of dinoprost include its use in small animals as an abortifacient agent and as adjunctive medical therapy in pyo-metra. Although not approved, dinoprost is used also in sheep and goat reproductive medicine. Pharmacology/Actions Prostaglandin F2alpha has several pharmacologic effects on the female reproductive system, including stimulation of myometrial activity, relaxation of the cervix, and inhibition of steroidogenesis by corpora lutea; can potentially lyse corpora lutea. Pharmacokinetics In studies done in rodents, dinoprost was demonstrated to distrib-ute very rapidly to tissues after injection. In cattle, the serum half-life of dinoprost has been stated to be only “minutes” long. Contraindications/Precautions/Warnings Unless being used as an abortifacient or parturition inducer, dino-prost should not be used during pregnancy in all species. Dinoprost is contraindicated in animals with bronchoconstrictive respiratory disease (e. g., asthma, “heavey” horses). It should not be adminis-tered intravenously. According to the manufacturer, dinoprost is contraindicated in mares with acute or subacute disorders of the vascular system, GI tract, respiratory system, or reproductive tract. Dinoprost should be used with extreme caution, if at all, in dogs or cats greater than 8 years old, or with preexisting cardiopulmo-nary or other serious disease (liver, kidney, etc. ). Some clinicians regard closed-cervix pyometra as a relative contraindication to the use of dinoprost. Adverse Effects In cattle, increased temperature has been reported when adminis-tered in overdose (5-10X recommended doses) quantities. Limited salivation and bacterial infections at the injection site have been reported. If administered intravenously, increased heart rates have been noted. In mares, transient decreased body (rectal) temperature and sweating have been reported most often. Less frequently, increased respiratory and heart rates, ataxia, abdominal pain, and lying down have also been noted. These effects are generally seen within 15 minutes of administration and resolve within an hour. In swine, dinoprost has caused erythema and pruritus, urina-tion, defecation, slight ataxia, hyperpnea, dyspnea, nesting behav-ior, abdominal muscle spasms, tail movements, increased vocaliza-tion and salivation. These effects may last up to 3 hours. At doses of 10 times recommended, vomiting may be seen. In dogs and cats, dinoprost can cause abdominal pain, emesis, defecation, urination, pupillary dilation followed by constriction, tachycardias, restlessness and anxiety, fever, hypersalivation, dys-pnea, and panting. Cats may also exhibit increased vocalization and intense grooming behavior. Severity of effects is generally dose dependent. Defecation can be seen even with very low dosages. Reactions generally appear in 5-120 minutes after administration and may persist for 20-30 minutes. Fatalities have occurred (es-pecially in dogs) after use. Dogs and cats should be monitored for cardiorespiratory effects, especially after receiving higher dosages.	pppbs.pdf
306 DINOPROST TROMETHAMINE When used as an abortifacient in humans, dinoprost causes nau-sea, vomiting, or diarrhea in about 50% of patients. Reproductive/Nursing Safety Unless being used as an abortifacient or parturition inducer, dino-prost should not be used during pregnancy in all species. In swine, dinoprost should not be administered prior to 3 days of normal predicted farrowing as increased neonatal mortality may result. Overdosage/Acute Toxicity Dogs are apparently more sensitive to the toxic effects of dinoprost than other species. The LD 50 in the bitch has been reported to be 5. 13 mg/kg after SC injection, which may be only 5X greater than the recommended dose by some clinicians. In cattle, swine, and horses, dinoprost's effects when admin-istered in overdose quantities are outlined above in the Adverse Effects section. If clinical signs are severe in any species and require treatment; supportive therapy is recommended. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dinoprost and may be of signiﬁcance in veterinary patients: !TOTHER OXYTOCIC AGENTS : Activity may be enhanced by dinoprost. Reduced effect of dinoprost would be expected with concomitant administration of a progestin. Doses !TDOGS: For treatment of pyometra: a) Use is restricted to bitches 6 years of age or younger who are not critically ill, do not have signiﬁcant concurrent illness, do have an open cervix, and an owner who is adamant about saving the animal's reproductive potential. After making de-ﬁnitive diagnosis; use natural prostaglandin F2alpha (Lutal-yse®): Day 1: 0. 1 mg/kg SC once; Day 2: 0. 2 mg/kg SC once; Days 3-7: 0. 25 mg/kg SC once daily. Use antibiotics (effec-tive against E. coli) concurrent with prostaglandin treatment and for 14 days after completion. Reevaluate at 7 and 14 days after treating with prostaglandin. Re-treat at 14 days if pu-rulent discharge persists or fever, increased WBC and ﬂuid ﬁlled uterus persist. (Feldman 2000) b) 0. 025-0. 25 mg/kg every 12 hours to effect. Initially use lower dosage to determine adverse effects on patient. Dosage de-pends on adverse effects and clinical condition of animal. For small dogs and cats: Dilute 1 m L (5 mg) of dinoprost injection to 25 m L with sterile water for injection, which will yield a concentration of 0. 2 mg/m L (200 micrograms/ m L). Adjunctive therapy includes systemic antibiotics (e. g., chloramphenicol, trimethoprim/sulfa, ampicillin) and ante-rior vaginal douches with 200-500 m L warm 1% tamed io-dine (povidone iodine) solution daily during prostaglandin treatment. (Lein 1986) c) For treatment of cystic endometrial hyperplasia-pyometra: 0. 1-0. 25 mg/kg once daily until discharge stops, but not for more than 5 days; reexamine in 2 weeks. If discharge has re-curred, treat at 0. 25-0. 5 mg/kg as above. Do not give a third course of therapy. Concurrent antibiotic treatment is neces-sary. (Shille 1986) As an abortifacient: a) After day 25 or 30: SC injections must be given at least twice a day, using a maximum dosage of 80-100 mcg/kg, starting with half the dose for the ﬁrst day (or ﬁrst two administra-tions). Treatment must initially be done under the supervi-sion of a clinician, after which the bitch can be sent home (with owner administration) once side effects have been carefully (monitored) after the ﬁrst injection. Side effects include: emesis, salivation, defecation, urination and slight tachypnea. Treatment must continue (for 6 days or longer) until veriﬁcation with ultrasound or palpation. (Romagnoli 2006a) b) As an adjunctive therapy for the termination of mid-term pregnancy in the bitch: Pregnancy is conﬁrmed with ultra-sound and begun no sooner than 30 days after breeding. 1-3 mcg/kg misoprostol given intravaginally once daily concur-rently with prostaglandin F2alpha (Lutalyse®) at 0. 1 mg/kg SC three times daily for 3 days and then 0. 2 mg/kg SC three times daily to effect. Monitor efﬁcacy with ultrasound. (Cain 1999) c) All doses are quoted using the THAM salt (Lutalyse®): Dur-ing the ﬁrst half of gestation: 250 micrograms/kg every 12 hours SC for 4 days, starting at least 5 days after cytologic diestrus. After the eighth injection, draw blood sample for serum progesterone concentration. Examine several weeks post treatment to verify pregnancy termination (failures have been reported). During second half of gestation: Verify preg-nancy (palpation/ultrasound). Inject 250 micrograms/kg SC every 12 hours until abortion is complete. Treatment efﬁcacy is determined by monitoring the completeness of pregnancy termination. (Root and Johnston 1995) !TCATS: For treatment of pyometra: a) Initially 0. 1 mg/kg SC, then 0. 25 mg/kg SC once a day for 5 days. Give bactericidal antibiotics concurrently. Not rec-ommended in animals >8 yrs. old or if severely ill. Closed-cervix pyometra is a relative contraindication. Reevaluate in 2 weeks; retreat for 5 more days if necessary. (Nelson 1988), (Feldman and Nelson 1989) b) Same as for dogs above (Lein 1986) As an abortifacient: a) After day 40 of gestation: 0. 5-1 mg/kg SC initially and then 24 hours later. Abortion generally ensues in 8-24 hours. (Woody 1988) b) 2 mg (total dose) per cat IM once a day beginning at day 33. Side effects include prostration, vomiting and diarrhea. (Ro-magnoli 2006a) !TCATTLE: For estrus synchronization in beef cattle and non-lactating dairy heifers: a) 25 mg IM either once or twice at a 10-12 day interval. If using single injection method, breed at usual time relative to estrus. If using dual dose method, breed at either the usual time relative to estrus, or about 80 hours after the second injection. (Package Insert; Lutal yse®—Upjohn) For unobserved (silent) estrus in lactating dairy cattle with a corpus luteum: a) 25 mg IM. Breed cows as they are detected in estrus. If estrus not detected, breed at 80 hours post injection. If cow returns to estrus, breed at usual time relative to estrus. (Package In-sert; Lutalyse®—Upjohn) For pyometra/endometritis: a) For pyometra: 25 mg IM twice, 8 hours apart; estrus usually ensues in 3-7 days, however evaluation of the uterus using palpation and/or ultrasonography is recommended before these cows are inseminated. For endometritis if a corpus lu-teum is present: Administration of PGF2a to cows 14 days	pppbs.pdf
DINOPROST TROMETHAMINE 307 apart places 90% of cows between days 5-10 of the estrus cycle, and a conception rate of 45% to the Ovsynch protocol started 12 days after the second injection. (Archibald, Barto-lome et al. 2006) b) For pyometra: 25 mg IM. Uterus begins evacuating within 24 hours of injection (Mc Cormack 1986), (Package Insert; Lutalyse®—Upjohn) As an abortifacient: a) Between 5-150 days of gestation: 25-30 mg IM. After 150 days of gestation: 25 mg dexamethasone with 25 mg dino-prost (efﬁcacy up to 95%) (Drost 1986) b) 25 mg IM during the ﬁrst 100 days of gestation (Package In-sert; Lutalyse®—Upjohn) T o induce parturition: a) 25-30 mg IM; delivery will occur in about 72 hours (Drost 1986) !THORSES: T o induce cyclic activity in animals who are acyclic due to per-sistent corpus lutea: a) 5 mg IM; most effective in mares with corpora lutea older than 5 days, and that have progesterone levels >1 ng/m L (4 ng/m L even better) (Rossdale 1987) For difﬁcult to breed mares secondary to progesterone levels consistent with the presence of a functional corpus luteum: a) 1 mg per 45 kg body weight IM (Package Insert; Lutalyse®— Upjohn) For controlling time of estrus of estrous cycling mares: a) 1 mg per 45 kg body weight IM. When treated during diestrus, most mares return to estrus in 2-4 days and ovulate 8-12 days after treatment (Package Insert; Lutalyse®—Upjohn) As an abortifacient: a) Prior to the 12th day of pregnancy: 5 mg IM. After the 4th month of pregnancy: 1 mg per 45 kg body weight (1 mg per 100 pounds) daily until abortion takes place (Lofstedt 1986) b) From day 80-300: 2. 5 mg q12h; approximately 4 injections required on average to induce abortion (Roberts 1986a) For estrus synchronization in normally cycling mares: a) Three methods: 1) Two injection method: On day 1 give 5 mg dinoprost and again on day 16. Most (60%) mares will begin estrus 4 days after the second injection and about 90% will show estrous behavior by the 6th day after the second injection. Breed us-ing AI every second day during estrus or inseminate at prede-termined times without estrus detection. Alternatively, an IM injection of HCG (2500-3300 Units) can be added on the ﬁrst or second day (usually day 21) of estrus to hasten ovula-tion. Breed using AI on days: 20, 22, 24, and 26. This may be of more beneﬁt when used early in the breeding season. 2) Progestagen/Prostaglandin method: Give altrenogest (0. 44 mg/kg) for 8-12 days PO. On last day of altrenogest therapy (usually day 10) give dinoprost (dose not noted, but suggest using same dose as “1” above). Majority of mares will show estrus 2-5 days after last treatment. Inseminate every 2 days after detection of estrus. Synchronization may be improved by giving 2500 IU of HCG IM on ﬁrst or second day of estrus or 5-7 days after altrenogest is withdrawn. 3) On day 1, inject 150 mg progesterone and 10 mg estradi-ol-17beta daily for 10 days. On last day, also give dinoprost (dose not noted, but suggest using same dose as “1” above). Perform AI on alternate days after estrus detection or on days 19, 21, and 23. (Bristol 1987) !TSWINE: For estrus synchronization (grouping): a) At 15-55 days of gestation 15 mg dinoprost IM, followed in 12 hours by 10 mg IM. Animals will abort and return to estrus in 4-5 days. Close observation of estrus over several days is needed. (Carson 1986) As an abortifacient: a) 5-10 mg IM; abortion occurs in 24-48 hours and estrus oc-curs 4-5 days later (Drost 1986) T o induce parturition: a) 10-25 mg IM from 2-6 days before expected parturition; farrowing usually occurs 24-36 hours later (Drost 1986) !TSHEEP & GOATS: For estrus synchronization in cycling ewes and does: a) Ewes: Give 8 mg IM on day 5 of estrous cycle and repeat in 11 days. Estrus will begin approximately 2 days after last injec-tion. b) Does: Give 8 mg IM on day 4 of estrous cycle and repeat in 11 days. Estrus will begin approximately 2 days after last injec-tion. (Carson 1986) T o induce estrous in does (weighing up to 65 kg): a) 2. 5 mg on days 4-17 of estrous cycle As an abortifacient: a) Does: 5-10 mg IM throughout entire pregnancy; abortion takes place in 4-5 days. Ewes (during ﬁrst two months of pregnancy): 10-15 mg IM; abortion takes place within 72 hours (Drost 1986) T o induce parturition: a) Does: 2. 5-5 mg IM on day 144; parturition occurs in 28-57 hours (Ott 1986a) b) Does: 2. 5-20 mg on days 144-149. Higher dosage (20 mg) yields more predictable interval from injection to delivery (≈32 hours). (Ott 1986b) For chronic metritis/pyometra: a) Does: 2. 5-5 mg SC with systemic antibiotics (Franklin 1986b) Monitoring !TDepending on use, see above. Monitoring for adverse effects is especially important in small animals. Client Information !TDinoprost should be used by individuals familiar with its use and precautions. !TPregnant women, asthmatics, or other persons with bronchial diseases should handle this product with extreme caution. Any accidental exposure to skin should be washed off immediately. Chemistry/Synonyms The tromethamine (THAM) salt of the naturally occurring prosta-glandin F2alpha, dinoprost tromethamine occurs as a white to off-white, very hygroscopic, crystalline powder with a melting point of about 100°C. One gram is soluble in about 5 m L of water. 1. 3 micrograms of dinoprost tromethamine is equivalent to 1 micro-grams of dinoprost. Dinoprost and dinoprost tromethamine may also be known as: PGF(2alpha), prostaglandin F(2alpha), idinoprostum trometa-moli, PGF(2alpha) THAM, prostaglandin F(2alpha) trometamol, U-14583E, U-14583, Amtech Prostamate®, Lutalyse®, Enzaprost®, In-Synch®, Minprostin F(2)alpha®, Prostamate®, Prostin®, Prostin F2®, Prostin F2 Alpha®, Prostin F2 Alpha®, and Prostine F(2) Alpha®, Oriprost®, Glandin®, Noroprost®, Dinolytic®, and Prostarmon F®.	pppbs.pdf
308 DIPHENHYDRAMINE HCL Storage/Stability Dinoprost for injection should be stored at room temperature (15-30°C) in airtight containers. The human-approved product is recommended to be stored under refrigeration. Dinoprost is con-sidered to be relatively insensitive to heat, light, and alkalis. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Dinoprost Tromethamine for injection, equivalent to 5 mg/m L of di-noprost in 10 m L and 30 m L vials; Lutalyse® Sterile Solution (Pharma-cia and Upjohn); Amtech Prostamate® (IVX); In-Synch® (Pro Labs); Prostamate® (various); (Rx). Approved for use in beef and non-lac-tating dairy cattle, swine and mares. No preslaughter withdrawal or milk withdrawal is required when used as labeled; no speciﬁc toler-ance for dinoprost residues has been published. It is not for use in horses intended for food. HUMAN-LABELED PRODUCTS: None DIPHENHYDRAMINE HCL (dye-fen-hye-dra-meen) Benadryl® ANTIHISTAMINE Prescriber Highlights TT Antihistamine used primarily for its antihistaminic ef-fects, but with various indications (prevention of motion sickness, sedative, antiemetic, etc. ) TT Contraindications: Hypersensitive to it or others in class TT Caution: Angle closure glaucoma, GI or urinary obstruc-tion, COPD, hyperthyroidism, seizure disorders, cardiovas-cular disease or hypertension. May mask clinical signs of ototoxicity. TT Adverse Effects: CNS depression & anticholinergic ef-fects; GI effects (diarrhea, vomiting, anorexia) are less common Uses/Indications In veterinary medicine, diphenhydramine is used principally for its antihistaminic effects, but also for other pharmacologic actions. Its sedative effects can be of beneﬁt in treating the agitation (pruritus, etc. ) associated with allergic responses. It has also been used for treatment and prevention of motion sickness and as an antiemetic in small animals. It has been suggested for use as adjunctive treat-ment of aseptic laminitis in cattle and it may be useful as an adjunc-tive treatment for feline pancreatitis. For other suggested uses, refer to the Dosage section below. Pharmacology/Actions Like other antihistamines, diphenhydramine competitively inhib-its histamine at H 1 receptors. In addition, it possesses substantial sedative, anticholinergic, antitussive, and antiemetic effects. Pharmacokinetics The pharmacokinetics of this agent have apparently not been studied in domestic animals. In humans, diphenhydramine is well absorbed after oral administration, but because of a relatively high ﬁrst-pass effect, only about 40-60% reaches the systemic circulation. Following IV administration in rats, diphenhydramine reaches its highest levels in the spleen, lungs and brain. The drug is distrib-uted into milk, but has not been measured quantitatively. In hu-mans, diphenhydramine crosses the placenta and is approximately 80% bound to plasma proteins. Diphenhydramine is metabolized in the liver and the majority of the drug is excreted as metabolites into the urine. The terminal elimination half-life in adult humans ranges from 2. 4-9. 3 hours. Contraindications/Precautions/Warnings Diphenhydramine is contraindicated in patients who are hyper-sensitive to it or other antihistamines in its class. Because of their anticholinergic 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 secretions are a problem. Additionally, they should be used with caution in patients with hyperthyroidism, cardiovascular disease or hypertension. Adverse Effects The most commonly seen adverse effects are CNS depression (leth-argy, somnolence), and anticholinergic effects (dry mouth, urinary retention). The sedative effects of antihistamines may diminish with time. GI effects (diarrhea, vomiting, anorexia) are a possibility. The sedative effects of antihistamines may adversely affect the performance of working dogs. Diphenhydramine may cause paradoxical excitement in cats. The liquid formulation is very distasteful. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have un-covered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term. ) Diphenhydramine is excreted milk. Use with caution, particu-larly in neonates. Overdosage/Acute Toxicity Overdosage can cause CNS stimulation (excitement to seizures) or depression (lethargy to coma), anticholinergic effects, respiratory depression and death. Treatment consists of emptying the gut after oral ingestion using standard protocols. Induce emesis if the patient is alert and CNS status is stable. Administration of a saline cathar-tic and/or activated charcoal may be given after emesis or gastric lavage. Treatment of other clinical signs should be performed using symptomatic and supportive therapies. Phenytoin (IV) is recom-mended in the treatment of seizures caused by antihistamine over-dose in humans; barbiturates and diazepam should be avoided.	pppbs.pdf
DIPHENHYDRAMINE HCL 309 Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving diphenhydramine and may be of signiﬁcance in veterinary patients: !TANTICHOLINERGIC DRUGS (including tricyclic antidepressants ): Di-phenhydramine may potentiate anticholinergic effects !TCNS DEPRESSANT DRUGS : Increased sedation can occur Laboratory Considerations !TAntihistamines 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 !TDOGS: As an antihistamine: a) 2-4 mg/kg q8-12h PO; 1 mg/kg q8-12h IM, SC, IV (do not exceed 40 mg total dose) (Papich 2000) b) 2. 2 mg/kg PO twice daily-three times daily (Peikes 2003) c) For severe urticaria and angioedema: 2 mg/kg IM twice daily as needed (with steroids: prednisone 2 mg/kg IM twice daily and epinephrine 1:10,000: 0. 5-2 m L SC) (Giger and Werner 1988) d) For canine atopy/allergic inhalant dermatitis: 2 mg/kg PO three times daily (effectiveness is questionable, but may be tried) (Giger and Werner 1988) e) For treatment of anaphylaxis (associated with doxorubicin chemotherapy): 3-4 mg/kg IM with dexamethasone sodium phosphate (0. 5-1 mg/kg IV) wait for reaction to subside be-fore restarting infusion at slower rate. (Vail 2006) Prevention of motion sickness/antiemetic: a) 2-4 mg/kg PO, IM q8h (Washabau and Elie 1995) For treatment of extrapyramidal effects secondary to phenothi-azines: a) 2-5 mg/kg IV (Bailey 1986) For adjunctive treatment (of tremors) secondary to organophos-phate or carbamate poisoning: a) 4 mg/kg PO (Carson 1986) b) 1-4 mg/kg PO three times daily (reduces nicotinic receptor overload) (Grauer and Hjelle 1988) For prevention of allergic reactions secondary to doxorubicin therapy: a) For dogs up to 20 lbs = 10 mg IV; for dogs 20-60 lbs = 20 mg IV; for dogs over 60 lbs. = 30 mg IV; give prior to doxorubicin administration (Klausner and Bell 1988) b) 1 mg/kg IV with 5 mg/kg cimetidine before therapy (Coppoc 1988) For reduction of allergic reactions secondary to Taxol therapy: a) The night before treatment give prednisone (2 mg/kg PO); 30-60 minutes before chemotherapy give diphenhydramine (4 mg/kg IM), cimetidine (4 mg/kg IV) and dexamethasone sodium phosphate (2 mg/kg IV). Majority of patients will still have an allergic reaction. (Vail 2006) For preoperative therapy for splenic mast cell tumors: a) 2. 2 mg/kg IM twice daily (with cimetidine 5 mg/kg PO, IV three to four times daily) (Stann 1988) b) 2 mg/kg PO three times daily with famotidine (0. 5 mg/kg PO once daily) are used to prevent anaphylaxis. (Garrett 2006) For treatment of the reverse sneeze syndrome: a) 25 mg PO three to four times a day, dosage is usually de-creased to once or twice a week for maintenance (Prueter 1988a) As an antipruritic: a) 25-50 mg PO two to three times daily (Morgan 1988) !TCATS: As an antihistamine: a) 0. 5 mg/kg PO q12h; liquid formulation is distasteful (Messinger 2000) b) 2-4 mg (total dose) q12-24h (Hnilica 2003b) c) 2-4 mg/kg PO q8h (Scherk 2006) d) For severe urticaria and angioedema: 2 mg/kg IM twice daily as needed (with steroids: prednisone 2 mg/kg IM twice daily and epinephrine 1:10,000 (0. 5-2 m L SC) (Giger and Werner 1988) Prevention of motion sickness/antiemetic: a) 2-4 mg/kg PO, IM q8h (Washabau and Elie 1995) b) 2-4 mg/kg PO q8h (De Novo 1986) For adjunctive treatment of pancreatitis: a) 2-4 mg/kg PO q8h (Scherk 2005a) !TFERRETS: a) Prevaccination: 2 mg/kg PO, IM or IV 10 minutes prior to vaccination (Williams 2000) b) Pretreatment before doxorubicin: 5 mg (total dose) IM (Johnson 2006c) !TRABBITS/RODENTS/SMALL MAMMALS: a) Guinea pigs: 7. 5 mg/kg PO (Adamcak and Otten 2000) b) Rabbits: 1-2 mg/kg PO twice daily as an antihistamine (Morrisey and Antinoff 2003) !TBIRDS: For adjunctive treatment of pruritus causing feather picking in Psittacines: a) 2 mg/kg PO q12h (Siebert 2003b) !THORSES: (Note : ARCI UCGFS Class 3 Drug) As an antihistamine: a) For adjunctive therapy of anaphylaxis: 0. 25-1 mg/kg IV or IM (Evans 1996) b) For allergic skin diseases (atopy): 1-2 mg/kg twice daily (route not speciﬁed) (Miller 2005a) c) For allergic skin diseases (atopy): 0. 75-1 mg/kg PO q12h (Rees 2004) !TCATTLE: For adjunctive therapy of anaphylaxis: a) 0. 5-1 mg/kg IM or IV (used with epinephrine and steroids) (Clark 1986) For adjunctive therapy of aseptic laminitis: a) During the acute phase (with corticosteroids): 55-110 mg/100 kg body weight IV or IM (Berg 1986) Monitoring !TClinical efﬁcacy !TAdverse effects Client Information !TMost commonly diphenhydramine causes sleepiness or lethargy, but it can cause dry mucous membranes and, particularly in cats, it can cause excitement.	pppbs.pdf
310 DIPHENOXYLATE HCL + ATROPINE SULFATE Chemistry/Synonyms An ethanolamine-derivative antihistamine, diphenhydramine HCl occurs as an odorless, white, crystalline powder which will slowly darken upon exposure to light. It has a melting range of 167-172°C. One gram is soluble in about 1 m L of water or 2 m L of alcohol. Diphenhydramine HCl has a p K a of about 9; the commercially available injection has its p H adjusted to 5-6. Diphenhydramine HCl may also be known as: chloranautine, di-menhydrinatum, diphenhydramine teoclate, and diphenhydramine theoclate; many trade names are available. Storage/Stability/Compatibility Preparations containing diphenhydramine should be stored at room temperature (15-30°C) and solutions should be protected from freezing. Tablets and oral solutions should be kept in well-closed containers. Capsules and the elixir should be stored in tight containers. Diphenhydramine for injection is reportedly physically compat-ible with all commonly used IV solutions and the following drugs: amikacin sulfate, aminophylline, ascorbic acid injection, atropine sulfate, bleomycin sulfate, butorphanol tartrate, cephapirin so-dium, chlorpromazine HCl, colistimethate sodium, diatrizoate meglumine/sodium, dimenhydrinate, droperidol, erythromycin lactobionate, fentanyl citrate, glycopyrrolate, hydromorphone HCl, hydroxyzine HCl, iothalamate meglumine/sodium, lidocaine HCl, meperidine HCl, methicillin sodium, metoclopramide, methyldo-pate HCl, morphine sulfate, nafcillin sodium, netilmicin sulfate, penicillin G potassium/sodium, pentazocine lactate, perphenazine, polymyxin B sulfate, prochlorperazine edisylate, promazine HCl, promethazine HCl, scopolamine HBr, tetracycline HCl, and vita-min B complex with C. 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. Diphenhydramine is reportedly physically incompatible with the following drugs: amobarbital sodium, amphotericin B, cephalot-hin sodium, hydrocortisone sodium succinate, iodipamide meglu-mine, pentobarbital sodium, secobarbital sodium, and thiopental sodium. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: No systemic products. A shampoo, topical spray and topical liquid are available. See the topical dermatology section in the appendix for more information. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Diphenhydramine HCl Capsules and Tablets: 12. 5 mg (as hydrochlo-ride, chewable), 25 mg (as either hydrochloride or tannate, chewable), 50 mg (as hydrochloride); Banophen® (Major); Genahist® (Goldline); Benadryl® Allergy, Benadryl Allergy Kapseals, Benadryl Dye-Free Aller-gy Liqui Gels, Benadryl® Allergy Ultratabs & Aller Max® Caplets, Maxi-mum Strength (Pﬁzer); Diphenhist® & Diphenhist® Captabs (Rugby); Dytan® (Hawthorn); (OTC and Rx) Diphenhydramine Orally Disintegrating Strips: 12. 5 mg & 25 mg (as hydrochloride); Benadryl® Allergy Quick Dissolve Strips (Pﬁzer); (OTC) Diphenhydramine HCl Liquid, Oral Solution, Elixir or Syrup: 12. 5 mg/5 m L (as hydrochloride) in 30 m L, 118 m L, 120 m L, 236 m L, 237 m L, and 473 m L, and 3. 8 L; 25 mg/5 m L (as tannate) in 118 m L; Scot-Tussin Allergy Relief Formula Clear® (Scot-Tussin); Aller-Max® (Pﬁeffer); Benadryl Children's Allergy, Children's Pedia Care Nighttime Cough & Benadryl Children's Dye-Free Allergy (Pﬁzer); Diphen AF® (Morton Grove); Altaryl® Children's Allergy (Altaire); Diphenhist® (Rugby); Banophen® Allergy (Major); Siladryl® (Silarx); Tusstat® (Century); Ben-Tann® (Midlothian); Genhist® (Goldline); Hydramine Cough (various); (OTC and Rx) Diphenhydramine Injection: 50 mg/m L (as hydrochloride) in 1 m L ﬁll in 2 m L cartridges, 1 m L amps, 1 m L and 10 m L Steri-vials and 1 m L Steri-dose syringes; Benadryl® (Parke-Davis) (Rx); generic; (Rx) DIPHENOXYLATE HCL + ATROPINE SULFATE (dye-fen-ox-i-late/at-roe-peen) Lomotil® OPIATE AGONIST/ANTICHOLINERGIC Prescriber Highlights TT Opiate GI motility modiﬁer used primarily in dogs; also has antitussive properties TT Contraindications: Known hypersensitivity to narcotic analgesics, patients receiving monoamine oxidase inhibi-tors (MAOIs), diarrhea caused by a toxic ingestion until the toxin is eliminated from the GI tract TT Caution: Respiratory disease, hepatic encephalopathy, hypothyroidism, severe renal insufﬁciency, adrenocorti-cal insufﬁciency (Addison's), head injuries, or increased intracranial pressure, acute abdominal conditions, & in geriatric or severely debilitated patients TT Adverse Effects: Constipation, bloat, & sedation. Potential for: paralytic ileus, toxic megacolon, pancreatitis, & CNS effects TT Dose carefully in small dogs TT Diphenoxylate is a class-V controlled substance Uses/Indications Diphenoxylate is an opiate in combination with atropine in an-tidiarrheal products used primarily in dogs; it also has antitussive properties. Use in cats is controversial and many clinicians do not recommend its use in this species. Pharmacology/Actions Among their other actions, opiates inhibit GI motility and excessive GI propulsion. They decrease intestinal secretion induced by chol-era toxin, prostaglandin E 2 and diarrheas caused by factors where calcium is the second messenger (non-cyclic AMP/GMP mediated). Opiates may also enhance mucosal absorption. Pharmacokinetics In humans, diphenoxylate is rapidly absorbed after administration of either the tablets or oral solution; bioavailability of the tablets is approximately 90% that of the solution. Generally, onset of action occurs within 45 minutes to one hour after dosing and is sustained for 3-4 hours. Diphenoxylate is metabolized into diphenoxylic acid, an active metabolite. The serum half-lives of diphenoxylate and diphenoxylic acid are approximately 2. 5 hours and 3-14 hours, respectively.	pppbs.pdf
DIPHENOXYLATE HCL + ATROPINE SULFATE 311 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. Opiate antidiarrheals are contraindicated in cases where the patient is hy-persensitive to narcotic analgesics, in patients receiving monoamine oxidase inhibitors (MAOIs), and patients with diarrhea caused by a toxic ingestion (until the toxin is eliminated from the GI tract). Opiate antidiarrheals should be used with caution in patients with head injuries or increased intracranial pressure and acute abdominal conditions (e. g., colic), as it may obscure the diagnosis or clinical course of these conditions. It should be used with ex-treme caution in patients suffering from respiratory disease or from acute respiratory dysfunction (e. g., pulmonary edema secondary to smoke inhalation). Opiate antidiarrheals should be used with ex-treme caution in patients with hepatic disease with CNS clinical signs of hepatic encephalopathy; hepatic coma may result. Many clinicians recommend not using diphenoxylate or loper-amide in dogs weighing less than 10 kg, but this is probably a result of the potency of the tablet or capsule forms of the drugs. Dosage titration using the liquid forms of these agents should allow their safe use in dogs when indicated. Adverse Effects In dogs, constipation, bloat, and sedation are the most likely ad-verse reactions encountered when usual doses are used. Potentially, paralytic ileus, toxic megacolon, pancreatitis, and CNS effects could be seen. Use of antidiarrheal opiates in cats is controversial; this species may react with excitatory behavior. Opiates used in horses with acute diarrhea (or in any animal with a potentially bacterial-induced diarrhea) may have a detri-mental effect. Opiates may enhance bacterial proliferation, delay the disappearance of the microbe from the feces, and prolong the febrile state. Reproductive/Nursing Safety Diphenoxylate/atropine is classiﬁed 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. ) Exercise caution when administering diphenoxylate HCl with atropine to nursing patients. Diphenoxylic acid may be, and atro-pine is, excreted in maternal milk but effects on the infant may not be signiﬁcant. Overdosage/Acute Toxicity Acute overdosage of the opiate antidiarrheals could result in CNS, cardiovascular, GI, or respiratory toxicity. Because the opiates may signiﬁcantly reduce GI motility, absorption from the GI may be de-layed and prolonged. For more information, refer to the meperidine and morphine monographs found in the CNS section. Naloxone may be necessary to reverse the opiate effects. Massive overdoses of diphenoxylate/atropine sulfate may in-duce atropine toxicity. Refer to the atropine monograph for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving opiate antidiarrheals and may be of signiﬁcance in veterinary patients: !TCNS DEPRESSANT DRUGS : Other CNS depressants (e. g., anesthetic agents, antihistamines, phenothiazines, barbiturates, tranquilizers, al-cohol, etc. ) may cause increased CNS or respiratory depression when used with opiate antidiarrheal agents !TMONOAMINE OXIDASE INHIBITORS (including amitraz, and possibly selegiline ): Opiate antidiarrheal agents are contraindicated in hu-man patients receiving monoamine oxidase (MAO) inhibitors for at least 14 days after receiving MAO inhibitors Laboratory Considerations !TPlasma amylase and lipase values may be increased for up to 24 hours following administration of opiates. Doses !TDOGS: As an antidiarrheal: a) For acute colitis/irritable colon syndrome: 0. 1 mg/kg, PO three times daily (De Novo 1988) b) 0. 05 mg/kg PO three times a day; probably should not be given longer than 5 days and are potentially contraindicated when diarrhea is suspected to be caused by enteric infections (Hall and Simpson 2000) c) 0. 05-0. 2 mg/kg PO q8-12h (Willard 2003a) As an antitussive: a) Approximately 0. 25 mg/kg PO q8-12h (Church 2006) b) Diphenoxylate at 0. 2-0. 5 mg/kg PO q12h until clinical signs subside. May be used for extended periods. Constipation is an occasional problem, but stool softeners can alleviate. (Hardie and Lascelles 2004) Monitoring !TClinical efﬁcacy !TFluid and electrolyte status in severe diarrhea !TCNS effects, if using high dosages Client Information !TIf diarrhea persists or if animal appears listless or develops a high fever, contact veterinarian !TWhen used as antitussive (for cough) watch for constipation; contact veterinarian if this is a problem Chemistry/Synonyms Structurally related to meperidine, diphenoxylate HCl is a synthetic phenylpiperidine-derivative opiate agonist. It occurs as an odorless, white, crystalline powder that is slightly soluble in water and spar-ingly soluble in alcohol. Commercially available preparations also contain a small amount of atropine sulfate to discourage the abuse of the drug for its narcotic effects. At therapeutic doses, the atropine has no clinical effect. This combination may be known as co-phenotrope in the U. K. and elsewhere. Other synonyms include: R 1132, NIH 7562 or difenoxilato. A commonly used trade name is Lomotil®. Storage/Stability Diphenoxylate/atropine tablets should be stored at room tempera-ture in well-closed, light-resistant containers. Diphenoxylate/atro-pine oral solution should be stored at room temperature in tight, light-resistant containers; avoid freezing.	pppbs.pdf
312 DIRLOTAPIDE Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Diphenoxylate HCl Tablets: 2. 5 mg with 0. 025 mg Atropine Sulfate; Logen® (Goldline); Lomotil® (Searle); Lonox® (Sandoz); generic; (Rx, C-V) Diphenoxylate HCl Liquid: 2. 5 mg with 0. 025 mg Atropine Sulfate per 5 m L in 60 m L with dropper and UD 4 m L and 10 m L; Lomotil® (Searle), Lomanate® (Qualitest); generic; (Rx, C-V) Diphenylhydantoin — see Phenytoin Sodium DIRLOTAPIDE (dir-loe-ta-pyde) Slentrol® GUT MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN (GMTP) INHIBITOR Prescriber Highlights TT Indicated for the management of obesity in dogs; not for cats TT Not recommended for dogs with liver disease, unman-aged Cushing's, or receiving corticosteroids TT Primary adverse effects are GI (vomiting, diarrhea); in-creased liver enzymes possible TT Safe use not established for treatment beyond one year TT Fairly complex dosing guidelines; regular monitoring & dosage adjustment required Uses/Indications Dirlotapide oral solution is indicated for the management of obe-sity in dogs. Pharmacology/Actions Dirlotapide is a selective microsomal triglyceride transfer protein inhibitor that blocks the formation and release of lipoproteins into the systemic circulation. The mechanism of action for weight re-duction is not completely understood, but it seems to result from reduced fat absorption and a satiety signal (Peptide YY) from lipid-ﬁlled enterocytes. Dirlotapide primarily acts locally in the gut to reduce appetite, increase fecal fat and produce weight loss in the management of obesity in dogs. Although systemic blood levels do not directly cor-relate with efﬁcacy, they seem to correlate with the drug's systemic toxicity. Pharmacokinetics In dogs, dirlotapide is available systemically, but absorption is high-ly variable (22-41%). Dirlotapide in the circulation is highly pro-tein bound and the volume of distribution is 1. 3 L/kg. Systemically absorbed dirlotapide is metabolized in the liver. Dirlotapide and its metabolites are excreted in the bile and may undergo entero-hepatic circulation. Non-linear pharmacokinetics with less-than-proportional exposure, drug accumulation (at higher doses), and large inter-patient variability has been observed in multiple studies and at various doses. The mean elimination half-life in dogs ranged between 5 and 18 hours, and may increase with dosage and after repeated dosing. The fecal and biliary routes are the predominant routes of elimination. Contraindications/Precautions/Warnings The manufacturer states that dirlotapide is not recommended for use in dogs currently receiving long-term corticosteroid therapy. Do not use in dogs with liver disease. Pre-existing endocrine dis-ease, including hyperadrenocorticism (Cushing's disease), should be managed prior to use of dirlotapide. Dirlotapide should not be used in cats; increases risk of hepatic lipidosis during weight loss in obese cats. Safe use for longer than one year has not been evaluated. Adverse Effects Adverse effects most likely seen with dirlotapide in dogs include (in decreasing order of frequency): vomiting, diarrhea, lethargy, anorexia, salivation, constipation and dehydration. As additional patients receive this medication, this proﬁle could change. During ﬁeld trials, some dogs developed mild to moderate el-evation in serum hepatic transaminase activity early in treatment that decreased over time while treatment continued. Reproductive/Nursing Safety Safety in breeding, pregnant, or lactating dogs has not been established. Overdosage/Acute Toxicity Oral doses of 0. 5, 1 and 2 m L/kg (2. 5X, 5X, 10X of maximum la-beled dose) were administered to normal weight Beagles for two weeks. The drug was tolerated but vomiting, diarrhea, anorexia, lethargy, transient elevations in liver enzymes (transaminase) were noted. No histopathologic evidence of hepatic necrosis was seen. Drug Interactions Drug interactions with dirlotapide have not been reported at the time of writing, but the drug could potentially alter the oral absorp-tion (rate and extent) of many drugs. Until safe concomitant use is determined with oral drugs with narrow therapeutic indexes, it is suggested to dose these drugs at least two hours prior to adminis-tering dirlotapide; additional monitoring may be required. ! !FAT SOLUBLE VITAMINS (A, E, K ): During the ﬁrst 6 months of treat-ment, plasma vitamin A and E concentrations of treated dogs were signiﬁcantly below the vitamin A and E concentrations of the control dogs. Plasma vitamin A concentration was low after one month and the median values did not decline any further. Plasma vitamin E concentrations were lowest after 6 months of treatment but adipose tissue levels of vitamin E appeared to be increased compared to control dogs after 12 months of treat-ment. Plasma vitamin A and E concentrations appeared to in-crease during the weight stabilization phase (second 6 months of treatment) and returned to concentrations similar to the control dogs when treatment was discontinued. Prothrombin times were similar in the treated and the control dogs and there were no clinical signs of abnormal hemostasis observed during the 12-month study. Laboratory Considerations No speciﬁc alterations to laboratory tests have been noted; the drug can increase serum transaminase in some patients.	pppbs.pdf
DIRLOTAPIDE 313 Doses !TDOGS: WEIGHT LOSS PHASE: Initial assessment and dosing in ﬁrst month: Assess the dog prior to initiation of therapy to determine the desired weight and to assess the animal's general health (See Precautions). The initial dosage is 0. 01 m L/kg (0. 05 mg/kg) body weight, administered once daily, orally, for the ﬁrst 14 days. After the ﬁrst 14 days of treatment, the dose volume should be dou-bled to 0. 02 m L/kg (0. 1 mg/kg) of body weight, administered once daily for the next 14 days (days 15 to 28 of treatment). Subsequent Monthly Dose Adjustments for Weight Loss: Dogs should be weighed monthly and the dose volume adjusted ev-ery month, as necessary, to maintain a target percent weight loss of * 0. 7% per week. T o determine if a dose adjustment is necessary, compare the Actual % weight loss to the Target % weight loss and use the following guidelines. Note : All dose adjustments are based solely on volume (m L). First (or Subsequent) Dose Adjustment Section: If the dog has lost weight, determine if an adjustment in dose is required us-ing the following calculations: (Number of weeks between visits) X 0. 7 % per week = Target % weight loss. Example-in 4 weeks (28 days) the Target weight loss would be 4 X 0. 7% per week, or at least 2. 8% of the total body weight. Compare the Target % weight loss (of * 0. 7% per week) with the Ac-tual % weight loss for that dog. Monthly weight loss rate achieved. If the Actual % weight loss is the same or greater than the Target % weight loss, the dose volume (number of m L administered each day) should re-main the same for the next month of dosing until the next scheduled assessment. Monthly weight loss not achieved. If the Actual % weekly weight loss is less than the Target % weight loss of 0. 7% weekly, the following dose adjustment instructions apply: First dose adjustment: The dose volume (number of m L ad-ministered each day) should be increased by 100%, resulting in an increase of the dose volume to 2 times the dose admin-istered during the previous month of dosing. Only perform a 100% dose increase once during treatment after day 14. Subsequent dose adjustments: If additional dose increases are necessary in the following months, the dose volume (number of m L administered each day) should be increased by 50%, resulting in an increase of the dose volume to1. 5 times the dose administered the previous month of dosing. Based on the dog's current body weight a daily dose of 0. 2 m L/kg (0. 09 m L/lb) should not be exceeded. If a dog's food consumption is greatly reduced for several consecutive days, the dose may be withdrawn until the ap-petite returns (usually 1-2 days) and then resume dosing at the same volume. The monthly adjustments should continue in this way un-til the desired weight determined at the start of therapy is reached. When the desired weight is reached, begin the weight management phase. WEIGHT MANAGEMENT PHASE A 3-month weight management phase is recommended to successfully maintain the weight loss achieved with treat-ment. During the weight management phase, the veterinar-ian and the pet owner should establish the optimal level of food intake and physical activity needed. Dirlotapide admin-istration should be continued during the weight manage-ment phase until the dog owner can establish the food intake and physical activity needed to stabilize body weight at the dog's desired weight. T o dose for weight management, body weight should continue to be assessed at monthly intervals. First dose adjustment: If the dog lost *1% body weight per week in the last month of the weight loss phase, the dose volume (number of m L administered each day) should be decreased by 50% result-ing in a decrease of the dose volume to 0. 5 times the dose administered the previous month. If the dog lost between 0 and 1% the dose should remain the same. If the dog gained weight, the dose should be increased by 50% resulting in an increase of the dose volume to 1. 5 times the dose administered the previous month. Subsequent dose adjustments: In subsequent months the dose volume should be increased or decreased by 25% to maintain a constant weight. If the dog is within-5% to +5% of the body weight at the end of the weight loss phase, the dose volume (number of m L administered each day) should remain unchanged. If the dog lost >5% body weight, then the dose should be decreased by 25%. If the dog gained > 5% body weight, then the dose should be increased by 25%. Based on the dog's current body weight a daily dose of 0. 2 m L/kg (0. 09 m L/lb) should not be exceeded. When dirlotapide is discontinued, the daily amount of food offered and physical activity should be continued as estab-lished during the weight management phase. Reverting to previous food intake or physical activity levels at this point can contribute to a re-gain of some or all of the weight loss that has been achieved. (Package Insert; Slentrol®—Pﬁzer) Monitoring !TPatient weight (see dosing) !TAdverse effects !TLiver enzymes (baseline, and occasional) Client Information !TNot a cure for obesity, dirlotapide decreases the food intake of the dog by decreasing appetite and associated begging behavior. De-creased appetite seen in treated dogs is only temporary and lasts no longer than 1-2 days beyond the cessation of therapy. Weight gain will occur if the amount of food offered is not limited at the time the drug is discontinued. !TSuccessful, long-term weight management requires changes that extend beyond the period of drug therapy. T o maintain weight loss; adjustments in dietary management and physical activity that were begun as part of the overall weight loss program must be continued. !TIf total lack of appetite (inappetence or anorexia) is observed for more than one day, contact veterinarian. !TAlmost 1 in 4 of dogs placed on therapy experienced occasional episodes of vomiting and diarrhea. In most cases these episodes lasted for one or two days. Vomiting occurred most often during the ﬁrst month of treatment or within a week of a dose increase. If vomiting occurs it is recommended to continue dosing at the same dose volume, however, the time of day or method of ad-ministration (with or without food) may be changed. If vomiting is severe or lasts longer than 2 days, consult veterinarian	pppbs.pdf
314 DISOPYRAMIDE PHOSPHATE TT ! o prepare for oral administration, remove the bottle cap and insert the supplied oral dosing syringe through the membrane into the bottle. Invert the bottle and withdraw the appropriate volume required using the graduation marks on the side of the oral dosing syringe. T ! Can be administered directly into the dog's mouth or on a small amount of food; can be given with a meal or at a different time of day. T ! Wipe the oral dosing syringe clean after each use with a clean dry cloth or disposable towel; do not introduce water into the oral dosing syringe or the solution. T ! Not for use in humans. Keep this and all drugs out of reach of children. T ! If accidental eye exposure occurs, ﬂush the eyes immediately with clean water. Chemistry/Synonyms Dirlotapide has the chemical name 5-[(4'-triﬂuoromethyl-biphe-nyl-2-carbonyl)-amino]-1H-indole-2-carboxylic acid benzyl-methyl carbamoylamide. It has a molecular weight of 674. 7. The commercial product is a liquid formulation containing 5 mg/m L of dirlotapide in medium chain triglyceride (MCT) oil. Dirlotapide may also be known as CP-742,033 or by its trade name Slentrol®. Storage/Stability Dirlotapide liquid should be stored in the original container at room temperature 15-30°C (59-86°F). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Dirlotapide Oral Solution 5 mg/m L in 20, 50 and 150 m L bottles; Slentrol® (Pﬁzer); (Rx). Labeled for use in dogs. HUMAN-LABELED PRODUCTS: None DISOPYRAMIDE PHOSPHATE (dye-soe-peer-a-mide) Norpace® ANTIARRHYTHMIC AGENT Prescriber Highlights TT 2nd or 3rd line antiarrhythmic for use in the dog; nega-tive inotrope & can prolong QT interval TT Contraindications: Hypersensitivity to the drug, 2nd or 3rd degree AV block, cardiogenic shock, severe uncom-pensated or poorly compensated cardiac failure or hy-potension, glaucoma (closed-angle), urinary retention, or myasthenia gravis TT Caution: Sick sinus syndrome, bundle branch block, or Wolff-Parkinson-White (WPW) syndrome, hepatic or renal disease TT Adverse Effects most likely noted: Anticholinergic effects (dry mouth, eyes, nose; constipation; urinary hesitancy or retention) & cardiovascular effects (edema, hypotension, dyspnea, syncope, & conduction disturbances (AV block); can reduce serum glucose TT Drug interactions Uses/Indications Disopyramide may be indicated for the oral treatment or preven-tion of ventricular tachyarrhythmias in dogs. Because of its nega-tive inotropic effects and short half-life, disopyramide is generally considered to be a 2nd or 3rd line agent for veterinary (canine) use. A controlled release product is available which may prove useful, but it has not been extensively evaluated in dogs. Pharmacology/Actions Considered to be a class Ia (membrane-stabilizing) antiarrhythmic with actions similar to either quinidine or procainamide, disopyra-mide reduces myocardial excitability and conduction velocity and also possesses anticholinergic activity (150 mg of disopyramide ≈ 0. 09 mg of atropine) that may contribute to the effects of the drug. The drug's exact mechanism of action has not been established. Disopyramide's cardiac electrophysiologic effects include: 1) short-ened sinus node recovery time; 2) increased atrial and ventricular refractory times; 3) decreased conduction velocity through the atria and ventricles; 4) decreased automaticity of ectopic atrial or ven-tricular pacemakers. Disopyramide has direct negative inotropic effects. It gener-ally has minimal effects on resting heart rates or blood pressure. Systemic peripheral resistance may increase by 20%. Pharmacokinetics The half-life of the disopyramide is approximately 7 hours in hu-mans with normal renal function, but only 2-3 hours in the dog. Oral bioavailability in dogs is about 70% and it is rapidly absorbed. In humans, disopyramide is rapidly absorbed following oral ad-ministration with peak levels occurring within 2-3 hours after the conventional capsules are administered. Peak levels occur at about 6 hours post dose with the controlled-release capsules. Disopyramide is distributed throughout the body in the extra-cellular water and is not extensively bound to tissues. Binding to plasma proteins is variable and dependent on the drug's concentra-tion. At therapeutic levels it is approximately 50-65% plasma pro-tein bound (human data). Disopyramide crosses the placenta and milk concentrations may exceed those found in plasma. Disopyramide is metabolized in the liver, but 40-65% of it is excreted unchanged in the urine. Patients with renal disease may need dosage adjustments made to prevent drug accumulation. Contraindications/Precautions/Warnings Disopyramide should usually not be used in patients with glaucoma (closed-angle), urinary retention, or myasthenia gravis because of its anticholinergic effects. Disopyramide is contraindicated in 2nd or 3rd degree A V block (unless pacemaker inserted), cardiogenic shock, or if the patient is hypersensitive to the drug. Disopyramide should not be used in patients with severe un-compensated or poorly compensated cardiac failure or hypoten-sion because of its negative inotropic effects. Patients with atrial ﬁbrillation or ﬂutter must be digitalized before disopyramide ther-apy to negate increased ventricular response (beyond acceptable). Disopyramide should be used with caution in patients with sick sinus syndrome, bundle branch block, or Wolff-Parkinson-White (WPW) syndrome. Use of disopyramide with other class 1A antiarrhythmics or propranolol may cause additive negative inotropic effects (see Drug Interactions). Disopyramide should be used with caution (and possibly at a reduced dosage) in patients with hepatic or renal disease.	pppbs.pdf
DISOPYRAMIDE PHOSPHATE 315 TAdverse Effects Most common adverse reactions are secondary to disopyramide's anticholinergic effects (e. g., dry mouth, eyes, or nose; constipation; urinary hesitancy or retention) and cardiovascular effects (edema, hypotension, dyspnea, syncope, or conduction disturbances such as A V block. Other adverse effects that have been reported in humans include: GI effects (vomiting, diarrhea, etc. ), intrahepatic cholesta-sis, hypoglycemia, fatigue, headache, muscle weakness and pain. In contrast to the urinary hesitancy effects, disopyramide can also cause urinary frequency and urgency. Doses of 15 mg/kg q8h in dogs prolongs the QT interval and doses above 30 mg/kg widen the QRS complex. 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. ) Disopyramide has been detected in milk at a concentration not exceeding that found in maternal plasma. Use with caution in nurs-ing animals. Overdosage/Acute Toxicity Clinical signs of overdosage/toxicity include: anticholinergic effects, apnea, loss of consciousness, hypotension, cardiac conduction dis-turbances and arrhythmias, widening of the QRS complex and QT interval, bradycardia, congestive heart failure, seizures, asystole, and death. Treatment consists initially of prompt gastric emptying,charcoal, and cathartics. Followed by vigorous symptomatic therapy using, if necessary, cardiac glycosides, vasopressors and sympathomimetics, diuretics, mechanically assisted respiration, and endocardial pac-ing. Disopyramide can be removed with hemodialysis. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving disopyramide and may be of signiﬁcance in veterinary patients: !TANTICHOLINERGIC DRUGS : Additive anticholinergic effects may be encountered if disopyramide is used concomitantly with other anticholinergics (atropine, glycopyrrolate) !TCISAPRIDE : Additional prolongation of QT interval !TMACROLIDE ANTIBIOTICS (erythromycin, clarithromycin ): Increased disopyramide levels; prolongation of QT interval may occur !TPHENOBARBITAL : May increase disopyramide's metabolism, reduce levels !TPROCAINAMIDE, LIDOCAINE : May be used with disopyramide, but widening of QRS and prolongation of QT interval may occur !TQUINIDINE : May increase disopyramide levels; disopyramide may decrease quinidine levels !TRIFAMPIN : May increase disopyramide's metabolism and reduce serum levels !TVERAPAMIL : Because of additional negative inotropic effects, use of disopyramide within 48 hours of using verapamil is not rec-ommended Doses !TDOGS: a) When used as an antiarrhythmic (almost never used): 7-30 mg/kg PO q4h (Kittleson 2006c) b) For ventricular arrhythmias: 11-22 mg/kg q8h PO (q12h if using long-acting product). May use in conjunction with quinidine or procainamide. (Ettinger 1989) Monitoring !TECG !TBlood pressure !TClinical signs of adverse effects (see above); liver function tests if chronic therapy !TSerum levels if indicated (lack of efﬁcacy, toxicity) !Therapeutic levels in humans have been reported to be between 2-7 micrograms/m L and toxic levels are considered to above 9 micrograms/m L. Levels of up to 7 micrograms/m L may be neces-sary to treat and prevent the recurrence of refractory ventricular tachycardias. Client Information !TContact veterinarian if animal has persistent problems with dif-ﬁcult urination, dry mouth, vomiting, constipation, becomes le-thargic or depressed, or has difﬁculty breathing. Chemistry/Synonyms Structurally dissimilar from other available antiarrhythmic agents, disopyramide phosphate occurs as a white or practically white crys-talline powder with a p K a of 10. 4. It is freely soluble in water and slightly soluble in alcohol. Disopyramide Phosphate may also be known as: disopy-ramidi phosphas, SC-13957, Norpace®, Dicorantil®, Dirythmin®, Dirytmin®, Diso-Duriles®, Disomet®, Disonorm®, Durbis®, Durbis®, Isomide®, Isorythm®, Ritmodan®, Ritmoforine®, Rythmical®, Rythmodan®, and Rythmodul®. Storage/Stability Disopyramide capsules should be stored at room temperature (15-30°C) in well-closed containers. An extemporaneously pre-pared suspension of 1-10 mg/m L of disopyramide (from capsules) in cherry syrup has been shown to be stable for one month if stored in amber bottles and refrigerated (2-8°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: Disopyramide Phosphate Capsules: 100 mg & 150 mg; Norpace® (Pharmacia); generic; (Rx) Disopyramide Phosphate Capsules Extended-Release: 100 mg & 150 mg; Norpace CR® (Pharmacia); (Rx); generic; (Rx) dl-Methionine — see Methionine DMSO — see Dimethyl Sulfoxide	pppbs.pdf
316 DOBUTAMINE HCL DOBUTAMINE HCL (doe-byoo-ta-meen) Dobutrex® PARENTERAL BETA ADRENERGIC INOTROPIC Prescriber Highlights TT Parenteral, rapid acting inotropic agent TT Contraindications: Known hypersensitivity to the drug or the preservative (sodium bisulﬁte); or patients with IHSS TT Caution: Post MI TT Animals with atrial ﬁbrillation should be digitalized prior to receiving dobutamine TT Most common adverse effects: Ectopic beats, increased heart rate, increased blood pressure, chest pain TT Use only in an “ICU” setting Uses/Indications Dobutamine is used as a rapid-acting injectable positive inotropic agent for short-term treatment of heart failure. It is also useful in shock patients when ﬂuid therapy alone has not restored acceptable arterial blood pressure, cardiac output, or tissue perfusion. Pharmacology/Actions Dobutamine is considered a direct beta 1-adrenergic agonist. It also has mild beta 2-and alpha 1-adrenergic effects at therapeutic doses. These effects tend to balance one another and cause little direct ef-fect on the systemic vasculature. In contrast to dopamine, dobu-tamine does not cause the release of norepinephrine. It has rela-tively mild chronotropic, arrhythmogenic, and vasodilative effects. Increased myocardial contractility and stroke volumes result in increased cardiac output. Decreases in left ventricular ﬁlling pres-sures (wedge pressures) and total peripheral resistance occur in patients with a failing heart. Blood pressure and cardiac rate gener-ally are unaltered or slightly increased because of increased cardiac output. Increased myocardial contractility may increase myocardial oxygen demand and coronary blood ﬂow. Pharmacokinetics Because it is rapidly metabolized in the GI tract and is not available after oral administration, dobutamine is only administered intrave-nously (as a constant infusion). After intravenous administration, the onset of action generally occurs within 2 minutes and peaks after 10 minutes. Dobutamine is metabolized rapidly in the liver and other tissues and has a plasma half-life of approximately 2 minutes in humans. The drug's effects diminish rapidly after cessation of therapy. Pharmacokinetic data for domestic animals is apparently un-available. It is unknown if dobutamine crosses the placenta or into milk. Contraindications/Precautions/Warnings Dobutamine is contraindicated in patients with known hyper-sensitivity to the drug or with idiopathic hypertropic subaortic stenosis (IHSS). The injectable formu lation contains sodium bisulﬁte as a preservative that has been documented to cause al-lergic-type reactions in some human patients. Hypovolemic states must be corrected before administering dobu tamine. Because it may increase myocardial oxygen demand and increase infarct size, dobutamine should be used very cautiously after myocardial infarction. Use with extreme caution in patients with ventricular tachyar-rhythmias or atrial ﬁbrillation. Dobutamine can enhance atrioven-tricular conduction; animals with atrial ﬁbrillation should be digi-talized prior to receiving dobutamine. Adverse Effects The most commonly reported adverse effects in humans are: ecto-pic beats, increased heart rate, increased blood pressure, chest pain, and palpitations. Similar adverse effects could be expected for vet-erinary patients. At usual doses these effects are generally mild and will not necessitate halting therapy, but dosage reductions should be performed. Other, more rare, adverse effects reported include: nausea, headache, vomiting, leg cramps, paresthesias, and dyspnea. 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. ) No speciﬁc information on lactation safety for dobutamine was found. Overdosage/Acute Toxicity Clinical signs reported with excessive dosage include tachycardias, increased blood pressure, nervousness, and fatigue. Because of the drug's short duration of action, temporarily halting therapy is usu-ally all that is required to reverse these effects. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dobutamine and may be of signiﬁcance in veterinary patients: T ! ANESTHETICS, GENERAL HALOGENATED HYDROCARBON : Use of halot-hane or cyclopropane with dobutamine may result in increased incidences of ventricular arrhythmias T ! BETA-BLOCKERS (e. g., metoprolol, propranolol ): May antagonize the cardiac effects of dobutamine, and result in a preponderance of alpha-adrenergic effects and increased total peripheral resistance T ! NITROPRUSSIDE : Synergistic effects (increased cardiac output and reduced wedge pressure) can result if dobutamine is used with nitroprusside T ! OXYTOCIC DRUGS : May induce severe hypertension when used with dobutamine in obstetric patients Doses Dobutamine is administered as a constant rate intravenous infu-sion only. T ! DOGS: a) For short-term treatment of acute heart failure: 5-40 mcg/ kg/minute IV; Doses of 5-20 mcg/kg/minute are generally adequate for dogs. Infusions greater than 20 mcg/kg/minute may cause tachycardia. (Kittleson 2006a) b) For shock where ﬂuid therapy alone not adequate: 5-15 mcg/kg/minute constant rate IV infusion (Haskins 2000) c) For dilated cardiomyopathy and intractable heart failure: 2-5 mcg/kg/minute for 12 to 24 hours; repeat treatment at 2 to 6 week intervals. May improve quality of life. May have increased risk of sudden death secondary to ventricular ar-rhythmia. (Sisson 2000) d) For short-term treatment of low cardiac output and acute heart failure: 2. 5-10 mcg/kg min IV. If tachycardia and ar-rhythmias occur, reduce dose or discontinue. (Reiser 2003)	pppbs.pdf
DOCUSATE 317 Te) 5-20 mcg/kg/minute IV CRI. Increase dose rate over 48-72 hours. There is a prolonged, positive hemodynamic effect that usually lasts for weeks after therapy is discontinued. (Kramer 2003a) f) 1-10 mcg/kg/minute IV (De Francesco 2006) T ! CATS: a) For short-term treatment of acute heart failure: 5-15 mcg/ kg/minute IV (Kittleson 2006a) b) 1-3 mcg/kg/minute IV (De Francesco 2006) T ! HORSES: (Note : ARCI UCGFS Class 2 Drug) a) 1-10 micrograms/kg/minute as an IV infusion (Mogg 1999) b) Foals (after volume repletion): 2-20 mcg/kg minute CRI ( Note : another section of this reference states the dose is 3-40 mcg/kg/minute). Follow the rule of “6”: 6 times the weight of foal (in kg) = the number of mg to add to 100 m L of saline (1 m L/hr = 1 mcg/kg/minute). (Wilkins 2004b) Monitoring T ! Heart rate and rhythm, blood pressure T ! Urine ﬂow T ! Ideally, measurement of central venous or pulmonary wedge pressures and cardiac output Client Information T ! his drug should only be used by professionals familiar with its use and in a setting where adequate patient monitoring can be performed. Chemistry/Synonyms Dobutamine HCl is a synthetic inotropic agent related structurally to dopamine. It occurs as a white, to off-white, crystalline powder with a p K a of 9. 4. Dobutamine is sparingly soluble in water and alcohol. Dobutamine HCl may also be known as: 46236, compound 81929, dobutamini hydrochloridum, and LY-174008; many trade names are available. Storage/Stability/Preparation/Compatibility Dobutamine injection should be stored at room temperature (15-30°C); diluted solutions should be used within 24 hours. Preparation for Injection: The solution for injection must be further diluted to a concentration no greater than 5 mg/m L (total of at least 50 m L of diluent) before administering. Generally, it is added to D 5W, normal saline (if not severely so-dium restricted) or other compatible IV solution. The following approximate concentrations will result if 1 vial (250 mg) is added either 250, 500, or 1000 m L IV solutions: 1 vial (250 mg) in: 250 m L ≈ 1000 micrograms/m L " 500 m L ≈ 500 micrograms/m L " 1000 m L ≈ 250 micrograms/m L A mechanical ﬂuid administration control device should be used, if available, to administer dobutamine. When using a mini-drip IV administration set (60 drops ≈ 1 m L), 1 drop contains approxi-mately 8. 3 micrograms at the 500 micrograms/m L (one 250 mg vial in 500 m L IV ﬂuids) concentration. Dobutamine is physically compatible with the usually used IV solutions (D 5W, sodium chloride 0. 45% and 0. 9%, dextrose-saline combinations, lactated Ringer's) and is reported to be physically compatible with the following drugs: amiodarone HCl, atropine sul-fate, dopamine HCl, epinephrine HCl, hydralazine HCl, isoprotere-nol HCl, lidocaine HCl, meperidine HCl, metaraminol bitartrate, morphine sulfate, nitroglycerin, norepinephrine (levarterenol) bi-tartrate, phentolamine mesylate, phenylephrine HCl, procainamide HCl, propranolol HCl, and verapamil HCl. Dobutamine may be physically incompatible with the following agents: aminophylline, bretylium tosylate, bumetanide, calcium chloride or gluconate, diazepam, digoxin, furosemide, heparin (in-consistent results), regular insulin, magnesium sulfate, phenytoin sodium, potassium chloride (at high concentrations only-160 m Eq/l), potassium phosphate, and sodium bicarbonate. 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: Dobutamine HCl Injection: 12. 5 mg/m L in 20 m L (250 mg) vials (may contain sulﬁtes); generic; (Rx) DOCUSATE SODIUM DOCUSATE CALCIUM (dok-yoo-sate) Colace® SURFACTANT; STOOL SOFTENER Prescriber Highlights TT Surfactant stool softener TT Caution: Fluid/electrolyte abnormalities TT Adverse Effects: Cramping, diarrhea, & GI mucosal damage Uses/Indications Docusate is used in small animals when feces are hard or dry, or in anorectal conditions when passing ﬁrm feces would be painful or detrimental. Docusate is used alone and in combination with min-eral oil in treating fecal impactions in horses. Pharmacology/Actions Docusate salts reduce surface tension and allow water and fat to penetrate the ingesta and formed feces thereby softening the stool. Recent in vivo studies have demonstrated that docusate also in-creases c AMP concentrations in colonic mucosal cells that may increase both ion secretion and ﬂuid permeability from these cells into the colon lumen. Pharmacokinetics It is unknown how much docusate is absorbed after oral admin-istration, but it is believed that some is absorbed from the small intestine and then excreted into the bile. Contraindications/Precautions/Warnings Use with caution in patients with pre-existing ﬂuid or electrolyte abnormalities; monitor. Adverse Effects At usual doses, clinically signiﬁcant adverse effects should be very rare. Cramping, diarrhea, and intestinal mucosal damage are pos-sible. The liquid preparations may cause throat irritation if admin-istered by mouth. Docusate sodium is very bitter tasting. Overdoses in horses may be serious.	pppbs.pdf
318 DOCUSATE 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. ) It is not known whether docusate calcium, docusate potassium, or docusate sodium are excreted in milk, but it is unlikely to be of concern. Overdosage/Acute Toxicity In horses, single doses of 0. 65-1 gm/kg have caused dehydration, intestinal mucosal damage, and death. Maximum therapeutic dos-ages of up to 0. 2 g/kg have been reported. Signs of overdoses in horses can begin in 1-2 hours after dosing with initial signs in-cluding restlessness and increased intestinal sounds; increases in respiratory and cardiac rates can follow. Abdominal pain, watery diarrhea, and dehydration can occur with horses deteriorating over hours to several days to lateral recumbency and death. Because of the secretory effects that high dose docusate can produce, hydration and electrolyte status should be monitored and treated if necessary. Treatment is supportive; GI protectants, bicarbonate, corticoster-oids, and antiendotoxemic agents (NSAIDs) have been suggested as being potentially helpful. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving docusate and may be of signiﬁcance in veterinary patients: !TMINERAL OIL : Theoretically, mineral oil should not be given with docusate (DSS) as enhanced absorption of the mineral oil could occur; however, this interaction does not appear to be of signiﬁ-cant clinical concern with large animals. It is less clear whether there is a signiﬁcant problem in using this combination in small animals and the concurrent use of these agents together in dogs or cats cannot be recommended. If it is deemed necessary to use both docusate and mineral oil in small animals, separate doses by at least two hours. Doses !TDOGS: Docusate Sodium: a) 2 mg/kg PO (Davis 1985a) b) One to four 50 mg capsules PO once daily (Burrows 1986) c) 50-300 mg PO q12h (Kirk 1989) d) Small Dogs: 25 mg PO once to twice daily Medium/large Dogs: 50 mg PO once to twice daily (Morgan 1988) e) 250 mg/12 m L glycerin disposable enema syringe (Disposa-ject® P-M): Insert rectally and express contents; may repeat in one hour (Package Insert) Docusate Calcium: a) Two to three 50 mg capsules or one 240 mg capsule PO once daily (Burrows 1986) b) One or two 50 mg capsules q12-24h PO (Kirk 1989) !TCATS: Docusate Sodium: a) 50 mg PO per day; 5-10 m L of Colace® (strength not speci-ﬁed) as an enema (Sherding 1989) b) 2 mg/kg PO (Davis 1985a) c) 50 mg capsule once daily PO (Burrows 1986) d) 50-100 mg q 12-24h PO (Kirk 1989) e) 25 mg PO once to twice daily (Morgan 1988) f) 250 mg/12 m L glycerin disposable enema syringe (Disposa-ject® P-M): Insert rectally and express contents; may repeat in one hour (Package Insert) Docusate Calcium: a) 50-100 mg PO per day (Sherding 1989) b) One to two 50 mg capsules PO once daily (Burrows 1986) c) 50 mg q12-24h PO (Kirk 1989) !THORSES: a) 10-30 mg/kg PO as a 10% solution; do not give to horses with sand impaction (Moore 1999) b) 7. 5-30 grams (150-600 m L of a 5% solution) PO; or 3-5 grams (60-100 m L of 5% solution) if used with mineral oil (Sellers and Lowe 1987) c) For large colon impaction (to soften): 6-12 g/500 kg diluted in 2-4 liters of water by nasogastric tube q12-24h. (Blik-slager and Jones 2004) Monitoring !TClinical efﬁcacy !THydration and electrolyte status, if indicated Client Information !TUnless otherwise directed, give this medication to animal that has an empty stomach. !TDo not give with other laxative agents without the approval of the veterinarian. Chemistry/Synonyms Docusate is available in sodium, and calcium salts. They are an-ionic, surface-active agents and possess wetting and emulsifying properties. Docusate sodium (also known as dioctyl sodium succinate, DSS, or DOSS) occurs as a white, wax-like plastic solid with a character-istic odor. One gram is soluble in approximately 70 m L of water and it is freely soluble in alcohol and glycerin. Solutions are clear and have a bitter taste. Docusate calcium (also known as dioctyl calcium succinate) oc-curs as a white, amorphous solid with a characteristic odor (oc-tyl alcohol). It is very slightly soluble in water, but freely soluble in alcohol. Docusate sodium may also be known as: dioctyl sodium sul-phosuccinate, dioctyl sodium sulfosuccinate, docusatum natricum, DSS, and sodium dioctyl sulphosuccinate; many trade names are available. Storage/Stability/Compatibility Capsules of salts of docusate should be stored in tight containers at room temperature. T emperatures above 86°F can soften or melt soft gelatin capsules. Docusate sodium solutions should be stored in tight containers and the syrup should be stored in tight, light-re-sistant containers. Dosage Forms/Regulatory Status VETERINARY APPROVED PRODUCTS: There are several docusate products marketed for veterinary use; their approval status is unknown. Docusate products are available without prescription (OTC). Products include: Docusate Sodium Bloat Preparation: 240 mg/1 ﬂ. oz in 12 ﬂ oz con-tainers. Approved for use in ruminants. Milk Withdrawal = 96 hours. Slaughter Withdrawal = 3 days. Bloat Treatment® (Durvet); (OTC). Docusate Sodium Enema: 5% water miscible solution in 1 gal con-tainers. Approved for use in dogs, cats and horses. Dioctynate® (But-ler); (OTC).	pppbs.pdf
DOLASETRON MESYLATE 319 Docusate Sodium Enema: 250 mg in 12 m L syringes. Approved for use in dogs and cats. Disposable Enema® (Vedco) (Rx), Pet-Enema® (Phoenix), (OTC); Enema SA® (Butler), (OTC); Docu-Soft® Enema (Life Science) (OTC) Docusate sodium oral liquid 5% in gallons; various; generic. May also be called Veterinary Surfactant; (OTC) HUMAN-LABELED PRODUCTS: Docusate Sodium Tablets: 100 mg; ex-lax® Stool Softener (Novartis Consumer Health); Dioctyn® (Dixon-Shane); (OTC) Docusate Sodium Capsules & Soft-gel Capsules: 50 mg, 100 mg, & 250 mg; Docusate Sodium (UDL), Colace® (Purdue); D-S-S® (Magno-Humphries); Non-Habit Forming Stool Softener® and Stool Softener® (Rugby); Regulax SS® (Republic); D. O. S. ® and Genasoft® (Goldline Consumer); Phillips'® Liqui-Gels (Bayer Consumer); Sof-lax® (Fleet); (various); (OTC) Docusate Sodium Syrup: 20 mg/5 m L in 480 m L; 50 mg/15 m L in UD 15 and 30 m L; 60 mg/15 m L in 237 m L, 473 m L and 480 m L; 100 mg/30 m L in UD 15 and 30 m L; generic (Roxane); Docu® (Hi-T ech Pharmacal Co. ); Colace® (Purdue); Silace® (Silarx) Diocto (various); generic; (OTC) Docusate Sodium Liquid: 10 mg/m L & 150 mg/15 m L in 30 m L, 473 m L and 480 m L; Colace® (Purdue); Docu® (Hi-T ech Pharmacal Co. ), Diocto (various); Docusate Sodium (Roxane); (OTC). There are many trade names for docusate sodium; perhaps the best known is Colace®. It is also available generically. Docusate Calcium Capsules: 240 mg (regular and soft gel), Stool Soft-ener® (Apothecary), Stool Softener DC® (Rugby), Surfak® Liquigels (Pharmacia and Upjohn), DC Softgels® (Goldline); generic; (OTC). DOLASETRON MESYLATE (doe-laz-e-tron) Anzemet® ANTIEMETIC AG ENT Prescriber Highlights TT 5-HT3 receptor antagonist antiemetic particularly useful for chemo-related nausea & vomiting in small animals TT Once daily administration for IV or PO doses TT Usually well tolerated; may cause dose-related ECG changes TT Oral human tablets not easily dosed in small animals (strength) TT Expense may be an issue Uses/Indications Dolasetron may be effective in treating severe nausea and vomit-ing in dogs and cats, particularly if caused by cancer chemotherapy drugs. Because it is given once a day, the injectable form of dolas-etron is often preferred over ondansetron, a similarly effective an-tiemetic. However, for oral use in small animals, dolasetron tablets are too large (50 and 100 mg) to be practically administered. Pharmacology/Actions Dolasetron exerts its anti-nausea and antiemetic actions by se-lectively antagonizing 5-hydroxytryptamine3 (5-HT3) receptors. These receptors are found primarily in the CNS chemoreceptor trigger zone, on vagal nerve terminals and enteric neurons in the GI tract. Chemotherapy induced vomiting is believed to be caused principally by serotonin release from the mucosal enterochromafﬁn cells in the small intestine. Pharmacokinetics After dolasetron is administered IV to dogs, its half-life is only minutes long as it is rapidly reduced via carbonyl reductase to hy-drodolasetron (also called reduced dolasetron or red-dolasetron). Hydrodolasetron is primarily responsible for the drug's pharmaco-logic effect. Oral dolasetron is also rapidly absorbed and converted to hydrodolasetron. Hydrodolasetron's volume of distribution in dogs is 8. 5 L/kg; total body clearance is 25 m L/min/kg and half-life about 4 hours. In humans, dolasetron is rapidly absorbed and converted to hy-drodolasetron. Oral bioavailability is about 75%. Hydrodolasetron's half-life in humans is about 7-8 hours. The drug is partially me-tabolized in the liver, but 50-60% is excreted unchanged into the urine. Clearance may be reduced in patients with severe renal or hepatic impairment. Contraindications/Precautions/Warnings Dolasetron is contraindicated in patients hypersensitive to it, with atrioventricular block II to III, or with markedly prolonged QT c. It should be given with caution to patients with, or susceptible to, developing prolongation of cardiac conduction intervals. This includes patients with hypokalemia, hypomagnesemia, receiving anti-arrhythmic drugs or diuretics that may induce electrolyte ab-normalities, congenital QT syndrome, or a cumulative high dose of anthracycline chemotherapy. These agents are generally ineffective when used for vomiting associated with feline hepatic lipidosis or GI obstruction. Adverse Effects Dolasetron appears to be well tolerated in the limited numbers of small animal patients that have received it. In humans, it has been associated with dose-related ECG interval prolongation (PR, QT c, JT prolongation and QRS widening). Other adverse effects that have been reported in humans using the drug during chemotherapy in-clude headache and dizziness. Reproductive/Nursing Safety In pregnant humans, dolasetron is designated by the FDA as a cat-egory B drug (Animal studies have not demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal stud-ies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus during the ﬁrst tri-mester of pregnancy, and there is no evidence of risk in later trimes-ters. ) T eratogenicity studies in laboratory animals failed to demon-strate any teratogenic effects. It is unknown if the drug enters milk; the manufacturer urges caution. Overdosage/Acute Toxicity There is very limited data available. One human patient who re-ceived 13 mg/kg of dolasetron developed severe hypotension and dizziness and was treated with pressors and ﬂuids. The patient's blood pressure returned to baseline 3 hours after the dose was ad-ministered. It is suggested to manage overdoses with supportive therapy. The lethal intravenous doses in mice and rats were 160 mg/kg and 140 mg/kg respectively. This is equivalent to 6-12 times the human recommended dose when comparing equivalent body surface areas.	pppbs.pdf
320 DOMPERIDONE TDrug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dolasetron and may be of signiﬁcance in veterinary patients: T ! ATENOLOL : May reduce the clearance and increase blood levels of hydrodolasetron T ! CIMETIDINE : May reduce the clearance and increase blood levels of hydrodolasetron T ! KETOCONAZOLE : May reduce the clearance and increase blood lev-els of hydrodolasetron T ! PHENOBARBITAL : Can reduce hydrodolasetron blood levels T ! RIFAMPIN : Can reduce hydrodolasetron blood levels Laboratory Considerations No dolasetron-related laboratory interactions were noted. Doses In humans, the injection can be given as rapidly as 100 mg over 30 seconds or diluted into 50 m L of a compatible IV solution and infused over a period of up to 15 minutes. T ! DOGS: a) As an anti-emetic, particularly for patients receiving chemo-therapeutics: 0. 6 mg/kg IV once daily. (Dowling 2003a) b) For chemotherapy-associated nausea/vomiting: 0. 5 mg/kg once daily PO, SC, or IV (Bergman 2002) c) For vomiting disorders: 0. 6-1 mg/kg PO q12h (Washabau 2006a) d) For vomiting: 0. 5-1 mg/kg PO or IV once daily (Otto 2005) T ! CATS: a) As an anti-emetic, particularly for patients receiving chemo-therapeutics: 0. 6 mg/kg IV once daily. (Dowling 2003a) b) For vomiting disorders: 0. 6-1 mg/kg PO q12h (Washabau 2006a) c) For vomiting: 0. 5-1 mg/kg PO or IV once daily (Otto 2005) Monitoring T ! Efﬁcacy T ! Heart rhythm in at-risk patients Client Information T ! he injectable form of this drug is most appropriately adminis-tered at the veterinary clinic/hospital. Oral forms of the drug will most likely need to be compounded to lesser strengths; maropi-tant or ondansetron tablets may be more practical for oral dosing in small animal patients. Chemistry/Synonyms A 5-HT3 receptor antagonist antiemetic, dolasetron mesylate oc-curs as a white to off-white powder. It is freely soluble in water or propylene glycol, and slightly soluble in 0. 9% sodium chloride so-lution or alcohol. Dolasetron may also be known as Anzemet®, Anemet® or Zamanon®. Storage/Stability/Compatibility The commercially available tablets should be stored at room tem-perature 20-25°C (68-77°F) and protected from light. The com-mercially available injection should be stored at room tempera-ture (20-25°C; 68-77°F) with excursions permitted to 15-30°C (59-86° F); protect from light. Dolasetron injection is reportedly compatible with the follow-ing injectable solutions: sodium chloride 0. 9%, 5% dextrose, so-dium chloride 0. 45% with 5% dextrose, 5% dextrose and lactated Ringer's, lactated Ringer's, and mannitol 10% injection. After dilu-tion, the injectable is stable under normal lighting at room temper-atures for 24 hours; 48 hours if refrigerated. The manufacturer does not recommend mixing with other injectable drugs and states to ﬂush the infusion line before and after administering dolasetron. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Dolasetron Tablets: 50 mg & 100 mg; Anzemet® (Aventis); (Rx) Dolasetron Injection: 20 mg/m L in single use 0. 625 m L ampules, 0. 625 m L ﬁll in 2 m L Carpuject, single-use 5 m L vials & 25 m L multi-dose vials; Anzemet® (Aventis); (Rx) DOMPERIDONE (dohm-pare-i-dohne) Motilium® PROKINETIC (DOPAMINE-2 AGONIST) AGENT Prescriber Highlights TT Dopamine-2 antagonist TT Used for HORSES: Tall fescue toxicity; SMALL ANIMALS: Prokinetic agent TT No products presently approved for US market Uses/Indications Domperidone may be useful for treatment of fescue toxicosis in pregnant mares or as a prokinetic or antiemetic agent in small ani-mals. It has more effect on conditions with delayed gastric empty-ing than other GI hypomotility conditions. Via its effects on prolactin, domperidone may also be used to stimulate milk production in horses and small animals. Domperidone has been shown to increase plasma ACTH in horses with equine pituitary pars intermedia dysfunction (Equine Cushing's) and may be useful in helping diagnose this condition. Pharmacology/Actions Domperidone is a dopamine antagonist (D2-receptors) with simi-lar actions as metoclopramide. It has been stated that the drug does not cross the blood brain barrier and thus does not have CNS ef-fects as does metoclopramide, but it may be more accurate to say that it does not readily cross into the CNS, as extrapyramidal ad-verse effects have been reported in some human patients. Domperidone antagonizes dopamine in the GI tract and in the chemoreceptor trigger zone causing its prokinetic and antiemetic effects. It also is an antagonist for alpha2 and Beta2 adrenergic re-ceptors in the stomach. Domperidone's apparent efﬁcacy for the treatment of fescue toxicosis in pregnant mares is related to the fact that tall fescue toxicosis causes decreased prolactin levels. Dopamine is involved in the reduction of prolactin production and it is postulated that the alkaloids found in tall fescue act as dopamine-mimetic agents. Domperidone ostensibly blocks this effect. Pharmacokinetics Domperidone is absorbed from the GI tract, but its bioavailability in dogs is only about 20%, presumably due to a high ﬁrst pass ef-fect. Peak serum levels occur about 2 hours after oral dosing and the drug is highly bound (93%) to serum proteins. Domperidone is primarily metabolized and metabolites are excreted in the feces and urine.	pppbs.pdf
DOPAMINE HCL 321 Contraindications/Precautions/Warnings Domperidone should not be used when GI obstructions are pres-ent or suspected. Because domperidone is potentially a neurotoxic substrate of P-glycoprotein, it should be used with caution in those herding breeds (e. g., Collies) that may have the gene mutation that causes a nonfunctional protein. Also see Drug Interactions. Adverse Effects Because plasma prolactin levels may be increased, galactorrhea or gynecomastia may result. Injectable products (now withdrawn) have been associated with arrhythmias in human patients with heart disease or hypokalemia. Rarely, somnolence or dystonic reac-tions have occurred in people. Reproductive/Nursing Safety Domperidone has been shown to have teratogenic effects when used at high doses in mice, rats and rabbits. The drug's effect of causing prolactin release may impact fertility in both females and males. Domperidone has been used to increase milk supply in women. In rats, it enters milk in small amounts with approximately 1/500th of the adult dose reaching the pups. Overdosage/Acute Toxicity There is no speciﬁc antidote for domperidone overdose. Use stan-dard decontamination procedures and treat supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving domperidone and may be of signiﬁcance in veterinary patients: T ! AZOLE ANTIFUNGALS (ketoconazole, etc. ): May increase domperi-done levels T ! ANTICH OLINER GIC DRUGS : May reduce the efﬁcacy of domperidone T ! BROMOCRIPTINE/CABERGOLINE : Domperidone may antagonize ef-fects on prolactin T ! MACROLIDE ANTIBIOTICS (erythromycin, clarithromycin ): May increase domperidone levels T ! OPIOIDS : May reduce the efﬁcacy of domperidone T ! SUSTAINED-RELEASE or ENTERIC-COATED ORAL MEDICATIONS : Domp-eridone may alter the absorptive characteristics of these drugs by decreasing GI transit times Laboratory Considerations T ! Domperidone may increase serum prolactin levels T ! Domperidone may increase ALT and AST Doses T ! DOGS: As a prokinetic agent: a) 0. 05-0. 1 mg/kg PO once or twice a day. Note : Scant clinical experience; suggested dose based upon experimental data. (Hall and Washabau 1997) b) For vomiting due to gastritis: 2-5 mg (total dose) PO two to three times a day. (Bishop 2005) T ! CATS: As a prokinetic agent: a) 0. 05-0. 1 mg/kg PO once or twice a day. Note : Scant clinical experience; suggested dose based upon experimental data. (Hall and Washabau 1997) T ! HORSES : For fescue toxicity: a) 1. 1 mg/kg PO daily 30 days before foaling (Cross and Adams 2001) b) 1. 1 mg/kg PO once a day beginning at least 2 weeks prior to mare's due date (Valla 2003) Monitoring T ! Clinical efﬁcacy Client Information T ! Because there are no approved products in the USA (at time of writing), clients should understand the investigational nature of this drug. Chemistry/Synonyms Domperidone maleate occurs as a white or almost white powder that exhibits polymorphism. It is very slightly soluble in water or alcohol. Domperidone may also be known as domperidonum and R-33812. A common trade name is Motilium®, but many trade names are available internationally. Storage/Stability Domperidone tablets should be stored at room temperature and protected from light and moisture. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None An equine gel (1%) form may be available in some countries. HUMAN-LABELED PRODUCTS: None in the USA. In Canada (10 mg tablet only) and in Europe, human oral tablets of 10 mg, suppositories and oral suspension may be available. DOPAMINE HCL (doe-pa-meen) Intropin® ADRENERGIC/DOPAMINERGIC INOTROPIC AGENT Prescriber Highlights TT Catecholamine that at lower doses dilates the renal, mesenteric, coronary, & intracerebral vascular beds; at higher doses, systemic peripheral resistance is increased & hypotension treated TT Use in an “ICU” setting TT Contraindications: Pheochromocytoma, ventricular ﬁbril-lation, & uncorrected tachyarrhythmia TT Not a substitute for adequate reperfusion therapy TT Adverse Effects: Nausea/vomiting, ectopic beats, tachy-cardia, hypotension, hypertension, dyspnea, headache & vasoconstriction TT Avoid extravasation injuries Uses/Indications Dopamine should be used only in critical care settings where ad-equate monitoring can be provided. It is used to correct the hemo-dynamic imbalances present in shock after adequate ﬂuid volume replacement, and as adjunctive therapy for the treatment of acute heart failure. It has now been shown that low-dose dopamine for the treatment of oliguric renal failure is not efﬁcacious in improv-ing GFR in humans; its use for this purpose in dogs is unproven.	pppbs.pdf
322 DOPAMINE HCL Pharmacology/Actions Dopamine is a precursor to norepinephrine and acts directly and indirectly (by releasing norepinephrine) on both alpha-and beta 1-receptors. Dopamine also has dopaminergic effects. At very low IV doses, 0. 5-2 micrograms/kg/min, dopamine acts predominantly on dopaminergic receptors and dilates the re-nal, mesenteric, coronary, and intracerebral vascular beds. At doses from 2-10 micrograms/kg/min, dopamine also stimulates beta 1-adrenergic receptors. The net effect at this dosage range is to exert positive cardiac inotropic activity, increase organ perfusion, renal blood ﬂow and urine production, but GFR does not appreciably improve. At these lower doses, systemic vascular resistance remains largely unchanged. At higher doses, >10-12 micrograms/kg/min, the dopaminergic effects are overridden by alpha effects. Systemic peripheral resistance is increased and hypotension may be correct-ed in cases where systemic vascular resistance is diminished; renal and peripheral blood ﬂows are thus decreased. Pharmacokinetics Dopamine is not administered orally as it is rapidly metabolized in the GI tract. After IV administration, the onset of action is usu-ally within 5 minutes and persists for less than 10 minutes after the infusion has stopped. Dopamine is widely distributed in the body, but does not cross the blood-brain barrier in appreciable quantities. It is unknown if dopamine crosses the placenta. The plasma half-life of dopamine is approximately 2 minutes. It is metabolized in the kidney, liver, and plasma by monoamine oxi-dase (MAO) and catechol-O-methyltransferase (COMT) to inac-tive compounds. Up to 25% of a dose of dopamine is metabolized to norepinephrine in the adrenergic nerve terminals. In human pa-tients receiving monoamine oxidase inhibitors, dopamine's dura-tion of activity can be as long as one hour. Contraindications/Precautions/Warnings Dopamine is contraindicated in patients with pheochromocy-toma, ventricular ﬁbrillation, and uncorrected tachyarrhythmias. It is not a substitute for adequate ﬂuid, electrolyte or blood product replacement therapy. Dopamine should be used with caution in pa-tients with ischemic heart disease or an occlusive vascular disease. Decrease dose or discontinue the drug should clinical signs occur implicating dopamine as the cause of reduced circulation to the ex-tremities or the heart. The drug should be discontinued or dosage reduced should arrhythmias (PVC's) occur. Cats are unlikely to beneﬁt (and it may be detrimental) from low dose dopamine therapy for oliguric renal failure. Adverse Effects Most frequent adverse effects seen include: nausea and vomiting, ectopic beats, tachycardia, palpitation, hypotension, hypertension, dyspnea, headache, and vasoconstriction. Extravasation injuries with dopamine can be very serious with necrosis and sloughing of surrounding tissue. Patient's IV sites should be routinely monitored. Should extravasation occur, inﬁltrate the site (ischemic areas) with a solution of 5-10 mg phentolamine (Regitine ®) in 10-15 m L of normal saline. A syringe with a ﬁne nee-dle should be used to inﬁltrate the site with many injections. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have un-covered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term. ) It is not known whether dopamine is excreted in breast milk. Overdosage/Acute Toxicity Accidental overdosage is manifested by excessive blood pressure elevation (see adverse effects above). Treatment consists only of temporarily discontinuing therapy since dopamine's duration of activity is so brief. Should the patient's condition fail to stabilize, phentolamine has been suggested for use. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dopamine and may be of signiﬁcance in veterinary patients: !TALPHA-ADRENERGIC BLOCKERS (e. g., prazosin ): May antagonize the vasoconstrictive properties of dopamine (high-dose) !TANESTHETICS, GENERAL HALOGENATED HYDROCARBON : Use of halot-hane or cyclopropane with dopamine may result in increased in-cidences of ventricular arrhythmias !TANTIDEPRESSANTS, TRICYCLIC : May potentiate adverse cardiovas-cular effects !TBETA-BLOCKERS (e. g., metoprolol, propranolol ): May antagonize the cardiac effects of dopamine !TDIURETICS : May potentiate urine production effects of low-dose dopamine !TMONOAMINE OXIDASE INHIBITORS : Monoamine oxidase inhibitors can signiﬁcantly prolong and enhance the effects on dopamine !TOXYTOCIC DRUGS : May cause severe hypertension when used with dopamine !TPHENOTHIAZINES : In animals (species not speciﬁed), the renal and mesenteric vasodilatation effects of dopamine have been antago-nized by phenothiazines !TVASOPRESSORS/VASOCONSTRICTORS : Use with dopamine may cause severe hypertension Laboratory Considerations Dopamine may: !TSuppress serum prolactin secretion from the pituitary !TSuppress thyrotropin secretion from the pituitary !TSuppress growth hormone secretion from the pituitary Doses The dosage of dopamine is determined by its indication (for more in-formation refer to the pharmacol ogy section above). Use an IV pump or other ﬂow-controlling device to increase precision in dosing. a) For adjunctive therapy for oliguric renal failure (usually for dogs only): Low doses (0. 5-3 micrograms/kg/min) with di-uretics (furosemide) are used to attempt to convert a patient from an oliguric state to a non-oliguric one (Cowgill and El-liot 2000) b) For adjunctive therapy for acute heart failure (dogs): IV in-fusion of 1-10 mcg/kg/min (doses higher may increase pe-ripheral vascular resistance and heart rate). Initially, a dose of 2 mcg/kg/min is usually used and titrated upward to desired clinical effect (improved hemodynamics) (Kittleson 2006a) c) For treatment of severe hypotension/shock: ( Note : Dopamine is not a substitute for adequate volume replacement therapy when indicated. ) 1-3 mcg/kg/minute CRI (constant rate IV infusion); higher dosages of 3-10 mcg/kg/min CRI are in-	pppbs.pdf
DORAMECTIN 323 dicated if greater cardiotonic and BP support are indicated (Haskins 2000) Monitoring T ! Urine ﬂow T ! Cardiac rate/rhythm T ! Blood pressure T ! IV site Client Information T ! Dopamine should be used only in an intensive care setting or where adequate monitoring is possible Chemistry/Synonyms An endogenous catecholamine that is the immediate precursor to norepinephrine, dopamine (as the HCl salt) occurs as a white to off-white crystalline powder. It is freely soluble in water and soluble in alcohol. The injectable concentrated solution has a p H of 2. 5-5. 5 and may contain an antioxidant (sodium bisulfate). The p H's of the ready-to-use injectable products in dextrose range from 3-5. Dopamine HCl may also be known as: ASL-279, dopamini hy-drochloridum, and 3-hydroxytyramine hydrochloride; many trade names are available. Storage/Stability/Preparation/Compatibility Dopamine injectable products should be protected from light. Solutions that are pink, yellow, brown, or purple indicate decom-position of the drug. Solutions that are darker than a light yellow should be discarded. Dopamine solutions should be stored at room temperature (15-30°C). After dilution in a common IV solution (not 5% bicarbonate), dopamine is stable for at least 24 hours at room temperature, but it is recommended to dilute the drug just prior to use. Dopamine is stable in solutions with a p H of less than 6. 4, and most stable at p H's less than 5. It is oxidized at alkaline p H. T o prepare solution: Add contents of vial to either 250 m L, 500 m L, or 1000 m L of normal saline, D 5W, lactated Ringer's injection, or other compatible IV ﬂuid. If adding a 200 mg vial (5 m L @ 40 mg/m L) to a one-liter bag, the resultant solution will contain an ap-proximate concentration of 200 micrograms/m L. If using a mini-drip IV set (60 drops/m L), each drop will contain approximately 3. 3 micrograms. In small dogs and cats, it may be necessary to use less dopamine so the ﬁnal concentration will be less; in large ani-mals, a higher concentration may be necessary. Dopamine is reported to be physically compatible with the fol-lowing IV ﬂuids: D 5 in LRS, D 5 in half-normal saline, D 5 in normal saline, D 5W, mannitol 20% in water, lactated Ringer's, normal sa-line, and 1/6M sodium lactate. Dopamine is reported to be physi-cally compatible with the following drugs: aminophylline, bretylium tosylate, calcium chloride, carbenicillin disodium, cephalothin sodium neutral, chloramphenicol sodium succinate, dobutamine HCl, gentamicin sulfate (gentamicin potency retained for only 6 hours), heparin sodium, hydrocortisone sodium succinate, kana-mycin sulfate, lidocaine HCl, methylprednisolone sodium succi-nate, oxacillin sodium, potassium chloride, tetracycline HCl, and verapamil HCl. Dopamine is reported to be physically incompatible with: am-photericin B, ampicillin sodium, iron salts, metronidazole with sodium bicarbonate, penicillin G potassium, and sodium bicar-bonate. Compatibility is dependent upon factors such as p H, con-centration, temperature, and diluent used; it is suggested to consult specialized references for more speciﬁc information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Dopamine HCl for Injection: 40 mg/m L, 80 mg/m L and 160 mg/m L in 5 m L amps, 5, 10 and 20 m L vials & 5 m L and 10 m L syringes; Intropin® (Faulding); generic; (Rx) Dopamine HCl in 5% dextrose for Infusion: 80 mg/100 m L (0. 8 mg/ m L), 160 mg/100 m L (1. 6 mg/m L), 320 mg/100 m L (3. 2 mg/m L) in 250 m L and 500 m L; generic; (Rx) DORAMECTIN (dor-a-mek-tin) Dectomax® A VERMECTIN A NTIPARASITIC AGENT Prescriber Highlights TT Injectable (cattle, swine) & topical (cattle only) avermec-tin antiparasiticide TT Potentially useful for generalized demodicosis in small animals TT Manufacturer warns about using in other species TT IM injections may cause muscle blemishes TT Not labeled for female dairy cattle (20 months or older) TT Relatively long slaughter withdrawal times Uses/Indications Doramectin injection is indicated for the treatment and control of the following endo-and ectoparasites in cattle: roundworms (adults and some fourth stage larvae)—Ostertagia ostertagi (including in-hibited larvae), O. lyrata, Haemonchus placei, Trichostrongylus axei, T. colubriformis, T. longispicularis, Cooperia oncophora, C. pectinata, C. punctata, C. surnabada (syn. mcmasteri ), Bunostomum phle-botomum, Strongyloides papillosus, Oesophagostomum radiatum, Trichuris spp. ; lungworms (adults and fourth stage larvae)—Dic-tyocaulus viviparus; eyeworms (adults)—Thelazia spp. ; grubs (par-asitic stages)—Hypoderma bovis, H. lineatum; lice—Haematopinus eurysternus, Linognathus vituli, Solenopotes capillatus; and mange mites—Psoroptes bovis, Sarcoptes scabiei. In swine the injection is labeled for the treatment and control gastrointestinal roundworms (adults and 4th stage Ascaris suum, adults and 4th stage Oesophagostomum dentatum, Oesophagostomum quadrispinolatum adults, Strongyloides ransomi adults, and Hydrostrongylus rubidus adults), lungworms (Stephanurus den-tatus adults), mange mites (adults and immature stages Sarcoptes scabeii var. suis), and sucking lice (adults and immature stages Haematopinus suis) The manufacturer states the doramectin protects cattle against infection or reinfection with Ostertagia ostertagi for up to 21 days. Doramectin topical (pour-on) is approved for use in cattle and has a similar spectrum of action against a variety of endo-and ec-toparasites, including biting lice. Injectable doramectin has been used for treating a variety of nematode and arthropod parasites in companion animals, includ-ing generalized demodicosis in dogs and cats and spirocercosis in dogs.	pppbs.pdf
324 DORAMECTIN Pharmacology/Actions The primary mode of action of avermectins like doramectin is to affect chloride ion channel activity in the nervous system of nema-todes and arthropods. Doramectin binds to receptors that increase membrane permeability to chloride ions. This inhibits the electri-cal activity of nerve cells in nematodes and muscle cells in arthro-pods and causes paralysis and death of the parasites. Avermectins also enhance the release of gamma amino butyric acid (GABA) at presynaptic neurons. GABA acts as an inhibitory neurotransmitter and blocks the post-synaptic stimulation of the adjacent neuron in nematodes or the muscle ﬁber in arthropods. Avermectins are gen-erally not toxic to mammals as they do not have glutamate-gated chloride channels and these compounds do not readily cross the blood-brain barrier where mammalian GABA receptors occur. Pharmacokinetics After subcutaneous injection, the time to peak plasma concentra-tion in cattle is about 5 days. Bioavailability is, for practical pur-poses, equal with SC and IM injections in cattle. Contraindications/Precautions/Warnings The manufacturer warns to not use in other animal species as se-vere adverse reactions, including fatalities in dogs, may result. Consider using alternative treatments for demodicosis in dog breeds susceptible to MDR1-allele mutation (Collies, Australian Shepherds, Shelties, Long-haired Whippet) as they may be at higher risk for toxicity. Adverse Effects No listed adverse effects. Intramuscular injections may have a high-er incidence of injection site blemishes at slaughter than do subcu-taneous injections. When used for demodicosis in dogs, adverse effects are uncom-mon but may include pupil dilation, lethargy, blindness, or coma. Reproductive/Nursing Safety In studies performed in breeding animals (bulls and cows in early and late pregnancy), at a dose of 3X recommended had no effect on breeding performance. Overdosage/Acute Toxicity In ﬁeld trials, no toxic signs were seen in cattle given up to 25X the recommended dose. In breeding animals (bulls, and cows in early and late pregnancy), a dose 3 times the recommended dose had no effect on breeding performance. Drug Interactions None noted Doses !TDOGS: For treatment of generalized demodicosis: a) 600 mcg/kg SC once weekly. Continue treatment for 4 weeks past the time skin scrapings are negative. (Johnstone 2002) b) Get informed consent from owner for extra-label treatment. Give 600 mcg/kg (0. 6 mg/kg) SC once per week. (Hillier 2006g) !TCATS: For feline demodicosis (D. cati, D. gatoi): a) Get informed consent from owner for extra-label treatment. Give 600 mcg/kg (0. 6 mg/kg) SC once per week. Alterna-tive treatments include Lime sulfur dips or amitraz. (Hillier 2006g) !TCATTLE: a) For labeled indications (Injectable): 200 mcg/kg (1 m L per 110 lb. body weight) SC or IM. Injections should be made us-ing 16 to 18 gauge needles. Subcutaneous injections should be administered under the loose skin in front of or behind the shoulder. Intramuscular injections should be administered into the muscular region of the neck. Beef Quality Assurance guidelines recommend subcutaneous administration as the preferred route. (Label Directions; Dectomax®—Pﬁzer) b) For labeled indications (Pour-on): T opically at a dosage of 500 mcg/kg (1 m L per 22 lb. body weight). Administer topi-cally along the mid-line of the back in a narrow strip between the withers and tailhead. (Label Directions; Dectomax® Pour-On—Pﬁzer) !TSWINE: a) For labeled indications: 300 mcg/kg (1 m L per 75 lb. body weight) IM. Injections should be made using 16 g x 1. 5 inch needles for sows and boars and 18 g x 1 inch needle for young animals. Use a tuberculin syringe and a 20 g x 1 inch needle for piglets. Intramuscular injections should be administered into the muscular region of the neck. See the label for rec-ommended treatment program for sows, gilts, boars, feed-er pigs, weaners, growers and ﬁnishers. (Label Directions; Dectomax®—Pﬁzer) Monitoring !TEfﬁcacy Client Information !TRead and follow all labeled instructions carefully. !TCattle must not be slaughtered for human consumption within 35 days of treatment. !TNot for use in female dairy cattle 20 months of age or older. !TA withdrawal period has not been established for this product in pre-ruminating calves. !TShould not be used in calves to be processed for veal. !TSwine should not be slaughtered for human consumption within 24 days of treatment. Chemistry/Synonyms An avermectin antiparasitic compound, doramectin is isolated from fermentations from the soil organism Streptomyces avermitilis. Doramectin may also be known as UK-67994, or Dectomax®. Storage/Stability The commercially available injectable solution is a colorless to pale yellow, sterile solution. The injectable solution should be stored below 86°F (30°C). The topical pour on solution should be stored below 30°C (86°F) and protected from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Doramectin Injectable Solution: 10 mg/m L in 100 m L, 250 m L, and 500 m L multi-dose vials; Dectomax® (Pﬁzer); (OTC). Approved for use in cattle and swine When used at labeled doses: Slaughter With-drawal: cattle = 45 days, swine = 24 days. Do not use in female dairy cattle 20 months of age or older or in calves to be used for veal. A withdrawal period has not been established in preruminating calves. Doramectin Pour-On Solution: 5 mg/m L in 250 m L, 1 L, 2. 5 L and 5 L multi-dose containers; Dectomax® Pour-On (Pﬁzer); (OTC). Ap-proved for use in cattle. Slaughter withdrawal = 45 days. Not for use in female dairy cattle 20 months of age or older. A withdrawal period	pppbs.pdf
DOXAPRAM HCL 325 has not been established in preruminating calves. Do not use in calves to be used for veal. HUMAN-LABELED PRODUCTS: None DOXAPRAM HCL (docks-a-pram) Dopram-V® CNS/RESPIRATORY STIMULANT Prescriber Highlights TT CNS stimulant usually used to stimulate respirations in newborns or after anesthesia; also used for assessment of laryngeal function in small animals TT Not a substitute for aggressive artiﬁcial (mechanical) re-spiratory support when required TT Possible contraindications: Receiving mechanical venti-lation, hypersensitivity, seizure disorders, head trauma/ CVA, uncompensated heart failure, severe hypertension, respiratory failure secondary to neuromuscular disorders, airway obstruction, pulmonary embolism, pneumothorax, acute asthma, dyspnea, or whenever hypoxia is not asso-ciated with hypercapnia. TT Caution: History of asthma, arrhythmias, or tachycardias. Use extreme caution in patients with cerebral edema or increased CSF pressure, pheochromocytoma, or hyperthyroidism. TT Avoid IV extravasation or using a single injection site for a prolonged period TT Adverse Effects: Hypertension, arrhythmias, seizures, & hyperventilation leading to respiratory alkalosis Uses/Indications The manufacturer of Dopram®-V lists the following indications: For Dogs, Cats, and Horses: T o stimulate respiration during and after general anesthesia and/or to speed awakening and reﬂexes af-ter anesthesia. For Neonatal Dogs and Cats: stimulate respirations following dystocia or cesarean section. Doxapram has been used for treatment of CNS depression in food animals (not approved) and has been suggested as a treatment of respiratory depression in small animals caused by reactions to radiopaque contrast media or for barbiturate overdosage (see pre-cautions below). The use of doxapram to initiate and stimulate respirations in newborns is somewhat controversial as the drug has been shown in experimental animals to increase myocardial oxygen demand and reduce cerebral blood ﬂow. Doxapram has been shown to be useful to offset suppression of general anesthetic agents when laryngeal function is being assessed. Pharmacology/Actions Doxapram is a general CNS stimulant, with all levels of the CNS affected. The effects of respiratory stimulation are a result of di-rect stimulation of the medullary respiratory centers and, possibly, through the reﬂex activation of carotid and aortic chemoreceptors. Transient increases in respiratory rate and volume occur, but in-creases in arterial oxygenation usually do not ensue. This is because doxapram usually increases the work associated with respirations with resultant increased oxygen consumption and carbon dioxide production. Pharmacokinetics Little published pharmacokinetic data appears for domestic ani-mals. Onset of effect in humans and animals after IV injection usually occurs within 2 minutes. The drug is well distributed into tissues. In dogs, doxapram is rapidly metabolized and most is ex-creted as metabolites in the urine within 24-48 hours after admin-istration. Small quantities of metabolites may be excreted up to 120 hours after dosing. Contraindications/Precautions/Warnings Doxapram should not be used as a substitute for aggressive artiﬁcial (mechanical) respiratory support in instances of severe respiratory depression. Contraindications from the human literature include: seizure disorders, head trauma, uncompensated heart failure, severe hy-pertension, cardiovascular accidents, respiratory failure secondary to neuromuscular disorders, airway obstruction, pulmonary embo-lism, pneumothorax, acute asthma, dyspnea, or whenever hypoxia is not associated with hypercapnia. Doxapram should be used with caution in patients with a history of asthma, arrhythmias, or tachy-cardias. It should be used with extreme caution in patients with cerebral edema or increased CSF pressure, pheochromocytoma or hyperthyroidism. Patients with a history of hypersensitivity to the drug or are receiving mechanical ventilation should not receive doxapram. The above contraindications/precautions are not listed in the veterinary product literature provided by the manufacturer. Avoid the use of a single injection site for a prolonged pe-riod of time or extravasation when administering intravenously. Subcutaneous injection has been recommended however for use in neonatal feline and canine patients. Repeated IV doses in neonates should be done with caution as the product contains benzyl alcohol. Adverse Effects Hypertension, arrhythmias, seizures, and hyperventilation lead-ing to respiratory alkalosis has been reported. These effects appear most probable with repeated or high doses. The drug reportedly has a narrow margin of safety when used in humans. Doxapram has been shown in experimental animals to increase myocardial oxygen demand and reduce cerebral blood ﬂow. Reproductive/Nursing Safety Safety of doxapram has not been established in pregnant animals. The potential risks versus beneﬁts should be weighed before using. In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) It is not known whether this drug is excreted in milk. Overdosage/Acute Toxicity Reported LD50 for IV administration in neonatal dogs and cats is approximately 75 mg/kg. Clinical signs of overdosage include: respiratory alkalosis, hypertension, skeletal muscle hyperactivity, tachycardia, and generalized CNS excitation including seizures. Treatment is supportive. Drugs such as short acting IV barbiturates may be used to help decrease CNS hyperactivity. Oxygen therapy may be necessary.	pppbs.pdf
326 DOXAPRAM HCL TDrug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving doxapram and may be of signiﬁcance in veterinary patients: !TANESTHETICS, GENERAL : Doxapram may increase epinephrine re-lease; therefore, use should be delayed for approximately 10 min-utes after discontinuation of anesthetic agents (e. g., halothane, enﬂurane ) that have been demonstrated to sensitize the myocar-dium to catecholamines !TMUSCLE RELAXANTS : Doxapram may mask the effects of muscle relaxant drugs !TSYMPATHOMIMETIC AGENTS : Additive pressor effects may occur with sympathomimetic agents Doses !TDOGS: a) 1. 1 mg/kg (for gas anesthesia) or 5. 5-11 mg/kg (for barbitu-rate anesthesia) IV; adjust dosage for depth of anesthesia, re-spiratory volume and rate. Dosage may be repeated in 15-20 minutes if necessary. T o initiate or stimulate respirations in neonates after cae-sarian section or dystocia: May be administered either SC, sublingually, or via the umbilical vein in doses of 1-5 drops (1-5 mg) depending on size of neonate and degree of respi-ratory crisis. (Package Insert; Dopram®-V—Fort Dodge) b) T o assess laryngeal function: 2. 2 mg/kg IV to stimulate res-piration and increase intrinsic laryngeal motion. Onset of effect occurs within 15-30 seconds and persists for approxi-mately 2 minutes. Anesthetic depth may lighten substantially. Prepare for immediate intubation should airway obstruction or laryngeal paralysis occur. (Mc Kiernan 2007) !TCATS: a) 1. 1 mg/kg (for gas anesthesia) or 5. 5-11 mg/kg (for barbitu-rate anesthesia) IV; adjust dosage for depth of anesthesia, re-spiratory volume and rate. Dosage may be repeated in 15-20 minutes if necessary. T o initiate or stimulate respirations in neonates after caesar-ian section or dystocia: May be administered either SC, or sublingually in doses of 1-2 drops (1-2 mg) depending on severity of respiratory crisis. (Package Insert; Dopram®-V— Fort Dodge) b) Cats: 5-10 mg/kg IV (Boothe 1990) !TRABBITS/RODENTS/SMALL MAMMALS: For respiratory depression: a) Rabbits: 2-5 mg/kg SC or IV q15 minute b) Rodents: 2-5 mg/kg S C q15 minutes (Huerkamp 1995) c) Mice, Rats, Gerbils, Hamsters: 5-10 mg/kg IV; Guinea pigs: 5 mg/kg IV; Chinchillas: 2-5 mg/kg IV (Adamcak and Otten 2000) !TBIRDS: a) For respiratory depression: 5-10 mg/kg IM or IV (Harris 2003) !TREPTILES: a) T o stimulate respiration after general anesthesia: 5 mg/kg IV (Wilson 2002b) !TCATTLE & SWINE: a) For primary apnea in newborn calves: 2 mg/kg IV (Constable 2006) b) 5-10 mg/kg IV (Howard 1986) !THORSES: (Note : ARCI UCGFS Class 2 Drug) a) 0. 44 mg/kg (for halothane, methoxyﬂurane anesthesia) or 0. 55 mg/kg (for chloral hydrate ± magnesium sulfate anes-thesia) IV; adjust dosage for depth of anesthesia, respiratory volume and rate. Dosage may be repeated in 15-20 minutes if necessary. (Package Insert; Dopram®-V—Fort Dodge) b) 0. 5-1 mg/kg IV at 5 minute intervals (do not exceed 2 mg/ kg in foals); for foal resuscitation: 0. 02-0. 05 mg/kg/min IV (Robinson 1987). Note : Rarely recommended today. Monitoring !TRespiratory rate !TCardiac rate and rhythm !TBlood gases if available and indicated !TCNS level of excitation; reﬂexes !TBlood pressure if indicated Client Information !This agent should be used in an inpatient setting or with direct professional supervision. Chemistry/Synonyms Doxapram HCl is a white to off-white, odorless, crystalline powder that is stable in light and air. It is soluble in water, sparingly soluble in alcohol and practically insoluble in ether. Injectable products have a p H from 3. 5-5. Benzyl alcohol or chlorobutanol is added as a preservative agent in the commercially available injections. Doxapram HCl may also be known as: AHR-619, doxaprami hy-drochloridum, Docatone®, Dopram ®, Doxapril®, or Respiram®. Storage/Stability/Compatibility Store at room temperature and avoid freezing solution. Do not mix with alkaline solutions (e. g., thiopental, aminophylline, sodium bi-carbonate). Doxapram is physically compatible with D 5W or nor-mal saline. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Doxapram HCl for Injection: 20 mg/m L; 20 m L multi-dose vial; Do-pram-V® (Fort Dodge); Respiram® (MVT); (Rx). Approved for use in dogs, cats and horses. The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Doxapram HCl for Injection: 20 mg/m L in 20 m L multi-dose vials; Dopram® (Baxter Healthcare Corp); generic; (Bedford); (Rx)	pppbs.pdf
DOXEPIN HCL 327 T TDOXEPIN HCL (dox-e-pin) Sinequan® TRICYCLIC ANTIDEPRESSANT/ANTIHISTAMINE Prescriber Highlights TT Tricyclic antidepressant used primarily in small animals for adjunctive therapy of psychogenic dermatoses, par-ticularly those that have an anxiety component; also has antihistaminic (H-1) properties TT Contraindications: Prior sensitivity to tricyclics; concomi-tant use with MAOIs (selegiline?); probably contraindi-cated in dogs with urinary retention or glaucoma TT Most likely adverse effects: Hyperexcitability, GI distress, or lethargy; ventricular arrhythmias after overdoses possible Uses/Indications The primary use for doxepin in veterinary medicine is the adjunc-tive therapy of psychogenic dermatoses, particularly those that have an anxiety component. Its efﬁcacy as an antihistamine for atopic dermatoses is in question. Pharmacology/Actions Doxepin is a tricyclic agent that has antihistaminic, anticholinergic, and alpha 1-adrenergic blocking activity. In the CNS, doxepin in-hibits the reuptake of norepinephrine and serotonin (5-HT) by the presynaptic neuronal membrane, thereby increasing their synaptic concentrations. Doxepin is considered a moderate inhibitor of nor-epinephrine and weak inhibitor of serotonin. Pharmacokinetics Doxepin appears to be well absorbed after oral administration. The drug is extensively metabolized in the liver. Contraindications/Precautions/Warnings These agents are contraindicated if prior sensitivity has been noted with any other tricyclic. Concomitant use with monoamine oxidase inhibitors is generally contraindicated. Doxepin is probably con-traindicated in dogs with urinary retention or glaucoma. Adverse Effects While doxepin has less potential for cardiac adverse effects than many other tricyclics, it can cause ventricular arrhythmias, particu-larly after overdoses. In dogs, it may also cause hyperexcitability, GI distress, or lethargy. However, potential adverse effects can run the entire gamut of systems. Refer to other human drug references for additional information. Reproductive/Nursing Safety Rodent studies have demonstrated no teratogenic effects, but safety 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. ) Doxepin and its N-demethylated active metabolite are distrib-uted into milk. One case report of sedation and respiratory depres-sion in a human infant has been reported. Exercise caution when using in a nursing patient. Overdosage/Acute Toxicity Overdosage with tricyclics can be life-threatening (arrhythmias, cardiorespiratory collapse). Because the toxicities and therapies for treatment are complicated and controversial, it is recommended to contact an animal poison control center for further information in any potential overdose situation. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving doxepin and may be of signiﬁcance in veterinary patients: T ! ANTICHOLINERGIC AGENTS : Because of additive effects, use with doxepin cautiously T ! CIMETIDINE : May inhibit tricyclic antidepressant metabolism and increase the risk of toxicity T ! CNS DEPRESSANTS : Because of additive effects, use with doxepin cautiously T ! MEPERIDINE, PENTAZOCINE, DEXTROMETHORPHAN : Increased risk for serotonin syndrome T ! MONOAMINE OXIDASE INHIBITORS (including amitraz, and possibly selegiline ): Concomitant use (within 14 days) of tricyclics with monoamine oxidase inhibitors is generally contraindicated (se-rotonin syndrome) T ! SSRIs (e. g., ﬂuoxetine, paroxetine, sertraline, etc. ): Increased risk for serotonin syndrome T ! SYMPATHOMIMETIC AGENTS : Use in combination with tricyclic agents may increase the risk of cardiac effects (arrhythmias, hy-pertension, hyperpyrexia) Laboratory Considerations T ! ricyclics can widen QRS complexes, prolong PR intervals and invert or ﬂatten T-waves on ECG. T ! ricyclics may alter (increase or decrease) blood glucose levels. Doses T ! DOGS: For treatment of psychogenic dermatoses: a) 3-5 mg/kg PO q12h; maximum dose is 150 mg (per dog) q12h (Shanley and Overall 1992) b) 3-5 mg/kg, PO q8-12h. Begin at 3 mg/kg PO q12h for 2 weeks, then increase by 1 mg/kg PO q12h for 2 weeks up to the maximum dosage as needed; if no clinical response after at least 3-4 weeks of therapy, decrease dosage by 1 mg/kg PO q12h for 2 weeks until at the initial dosage (Virga 2003), (Virga 2005b) For antihistaminic effects in treatment of atopy: a) 2. 2 mg/kg PO three times daily (White 2007) b) 3-5 mg/kg twice daily; used especially if dog has anxiety or other behavioral condition (Peikes 2003) c) 0. 5-2 mg/kg PO q12h; may be best in nervous or highly strung dogs (Hillier 2006e) d) 1-2 mg/kg PO q12h (Thomas 2005a) T ! CATS: For treatment of psychogenic dermatoses: a) 0. 5-1 mg/kg PO q12-24h. Up to 25-50 mg (total dose) per cat. Allow 3-4 weeks for initial trial. (Virga 2003), (Virga 2005b) b) For excessive grooming: 0. 5-1 mg/kg PO q12h. (Siebert 2003a)	pppbs.pdf
328 DOXORUBICIN HCL T ! BIRDS: For treatment of anxiety, pruritus caused feather plucking in psittacines: a) 1-2 mg/kg PO q12h (Siebert 2003b) b) 0. 5-1 mg/kg PO twice daily (Rich 2005) Monitoring T ! Efﬁcacy T ! Adverse effects Client Information T ! Inform clients that several weeks may be required before efﬁcacy is noted and to continue dosing as prescribed. T ! All tricyclics should be dispensed in child-resistant packaging and kept well away from children or pets. Chemistry/Synonyms A dibenzoxazepine derivative tricyclic antidepressant, doxepin HCl occurs as a white powder that is freely soluble in alcohol. Doxepin may also be known as: doxepini hydrochloridum, NSC-108160, P-3693A, Adapin®, Anten®, Aponal®, Deptran®, Desidoxepin®, Doneurin®, Doxal®, Doxepia®, Gilex®, Mareen®, Quitaxon®, Sinequan®, Triadapin®, Xepin®, and Zonalon®. Storage/Stability/Compatibility Store hydroxyzine products protected from direct sunlight in tight, light-resistant containers at room temperature. 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. DOXORUBICIN HCL (dox-oh-roo-bi-sin) Adriamycin®, Doxil® ANTINEOPLASTIC Prescriber Highlights TT Injectable antibiotic antineoplastic widely used alone or in combination protocols for small animals TT Relatively contraindicated in patients with myelo-suppression, impaired cardiac function, or who have reached the total cumulative dose level of doxorubicin &/or daunorubicin TT Caution: Patients with hyperuricemia/hyperuricuria, or impaired hepatic function (dosage adjustments necessary) TT Breeds predisposed to developing cardiomyopathy (Doberman pinchers, Great Danes, Rottweilers, Boxers); monitor carefully TT Handle very carefully TT Teratogenic & embryotoxic TT Adverse Effects include bone marrow suppression, car-diac toxicity, nephrotoxicity (esp. cats), alopecia, gastro-enteritis (vomiting, diarrhea), & stomatitis TT Immediate-hypersensitivity reported (primarily in dogs); potentially brand speciﬁc TT Extravasation injuries can be serious HUMAN-LABELED PRODUCTS: Doxepin Capsules: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg & 150 mg; Sinequan® (Roerig); generic; (Rx) Doxepin Oral Concentrate: 10 mg/m L in 118 m L; Sinequan® (Ro-erig); generic; (Rx) Uses/Indications Doxorubicin is perhaps the most widely used antineoplastic agent at present in small animal medicine. It may be useful in the treat-ment of a variety of lymphomas, carcinomas, leukemias, and sarco-mas in both the dog and cat, either alone or in combination pro-tocols. Refer to the Dosage references or the Protocols found in the appendix for more information. Pharmacology/Actions Although possessing antimicrobial properties, doxorubicin's cyto-toxic effects precludes its use as an anti-infective agent. The drug causes inhibition of DNA synthesis, DNA-dependent RNA synthe-sis and protein synthesis, but the precise mechanisms for these ef-fects are not well understood. The drug acts throughout the cell cycle and also possesses some immunosuppressant activity. Doxorubicin is most cytotoxic to cardiac cells, followed by mela-noma, sarcoma cells, and normal muscle and skin ﬁbroblasts. Other rapidly proliferating “normal” cells, (such as bone marrow, hair fol-licles, GI mucosa), may also be affected by the drug. Pharmacokinetics Doxorubicin must be administered IV as it is not absorbed from the GI tract and is extremely irritating to tissues if administered SC or IM. After IV injection, the drug is rapidly and widely distributed, but does not appreciably enter the CSF. It is highly bound to tissue and plasma proteins, probably crosses the placenta and is distrib-uted into milk. Doxorubicin is metabolized extensively by the liver and other tissues via aldo-keto reductase primarily to doxorubicinol, which is active; other inactive metabolites are also formed. Doxorubicin and its metabolites are primarily excreted in the bile and feces. Only about 5% of the drug is excreted in the urine within 5 days of dos-	pppbs.pdf
DOXORUBICIN HCL 329 ing. Doxorubicin is eliminated in a triphasic manner. During the ﬁrst phase (t H ≈ 0. 6 hours) doxorubicin is rapidly metabolized, via the “ﬁrst pass” effect followed by a second phase (t H ≈ 3. 3 hours). The third phase has a much slower elimination half-life (17 hours for doxorubicin; 32 hours for metabolites), presumably due to the slow release of the drug from tissue proteins. Contraindications/Precautions/Warnings Doxorubicin is contraindicated or relatively contraindicated (mea-sure risk vs. beneﬁt) in patients with myelosuppression, impaired cardiac function, have reached the total cumulative dose level of doxorubicin and/or daunorubicin. It is also contraindicated in cats with preexisting renal insufﬁciency. It should be used with caution in patients with hyperuricemia/hyperuricuria, or impaired hepatic function. Dosage adjustments are necessary in patients with hepat-ic impairment. Breeds predisposed to developing cardiomyopathy (Doberman pinchers, Great Danes, Rottweilers, Boxers) should be monitored carefully while receiving doxorubicin therapy. Doxorubicin is actively transported by the p-glycoprotein pump and certain breeds susceptible to MDR1-allele mutation (Collies, Australian Shepherds, Shelties, Long-haired Whippet) are at higher risk for toxicity. Because doxorubicin can be very irritating to skin, gloves should be worn when administering or preparing the drug. Ideally, doxo-rubicin injection should be prepared in a biological safety cabinet. Should accidental skin or mucous membrane contact occur, wash the area immediately using soap and copious amounts of water. Adverse Effects Doxorubicin may cause several adverse effects including bone mar-row suppression, cardiac toxicity, alopecia, gastroenteritis (vomit-ing, diarrhea), and stomatitis. An immediate hypersensitivity reaction may be seen (particu-larly in dogs) characterized by urticaria, facial swelling, vomiting, arrhythmias (see below), and/or hypotension. The rate of infusion can have a direct impact on this effect. Pretreatment with a hista-mine 1 blocker such as diphenhydramine (IV prior to treatment at 10 mg for dogs up to 9 kg; 20 mg for dogs 9-27 kg; and 30 mg for dogs over 27 kg) or alternatively, dexamethasone (0. 55 mg/kg IV), is often recommended to reduce or eliminate these effects. There is some evidence to suggest that a given brand of doxorubicin may be more allergenic than another. Patients that have developed hy-persensitive reactions to one brand, may not react, if switched to another. Cardiac toxicity of doxorubicin falls into two categories, acute and cumulative. Acute cardiac toxicity may occur during IV admin-istration or several hours subsequent, and is manifested by cardiac arrest preceded by ECG changes (T-wave ﬂattening, S-T depression, voltage reduction, arrhythmias). Rarely, an acute hypertensive cri-sis has been noted after infusion. Acute cardiac toxicity does not preclude further use of the drug, but additional treatment should be delayed. The administration of diphenhydramine and/or glu-cocorticoids before doxorubicin administration may prevent these effects. Cumulative cardiac toxicity requires halting any further therapy and can be extremely serious. Diffuse cardiomyopathy with severe congestive heart failure refractory to traditional therapies is gener-ally noted. It is believed that the risk of cardiac toxicity is greatly increased in dogs when the cumulative dose exceeds 240 mg/m 2, but may be seen at doses as low as 90 mg/m2. Therefore, it is not recom mended to exceed 240 mg/m2, total dose, in dogs. It is un-known what the incidence of cardiotoxicity or the dosage ceiling for doxorubicin is in cats, but most clinicians believe that 240 mg/ m2 should also be used as the upper limit cumulative dose in cats. In cats, doxorubicin is a potential nephrotoxin and they should have renal function monitored both before and during therapy. Doxorubicin should be administered IV slowly, over at least 10 minutes, in a free ﬂowing line. Extravasation injuries secondary to perivascular administration of doxorubicin can be quite serious, with severe tissue ulceration and necrosis possible. Prevention of extravasation should be a pri-ority and animals should be frequently checked during the infusion. Should extravasation occur, one author (Coppoc 1988) makes the following recommendations for veterinary patients; immediately ﬂood the area with 5 m L of sodium bicarbonate injection 8. 4%, 15-30 m L of 0. 9% sodium chloride, and 4 mg dexamethasone. Then apply a steroid/DMSO (concentrations not noted) solution topically to the site and cover with an occlusive dressing (e. g., plastic wrap). Continue to treat using the occlusive dressing for 3-5 days. In humans with severe extravasation injuries due to doxorubicin, site excision and plastic surgery have been necessary. Reproductive/Nursing Safety Doxorubicin is teratogenic and embryotoxic in laboratory animals. It is unknown if it affects male fertility. In humans, the FDA cat-egorizes 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 out-weighs the risks. ) Doxorubicin is excreted in milk in concentrations that may ex-ceed those found in plasma. Because of risks to nursing offspring, consider using milk replacer if the dam is receiving doxorubicin. Overdosage/Acute Toxicity Inadvertent acute overdosage may be manifested by exacerbations of the adverse effects outlined above. A lethal dose for dogs has been reported as 72 mg/m2 (O'Keefe and Harris 1990). Supportive and symptomatic therapy is suggested should an overdose occur. Dexrazoxane may be useful to help prevent cardiac toxicity. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving doxorubicin and may be of signiﬁcance in veterinary patients: !TANTINEOPLASTIC AGENTS, OTHER : May potentiate the toxic effects of doxorubicin !TCALCIUM-CHANNEL BLOCKERS : Potentially could increase risk for cardiotoxicity associated with doxorubicin !TCYCLOPHOSPHAMIDE : May increase doxorubicin blood levels (AUC); doxorubicin may potentiate and prolong hematologic toxicity; coma and seizures have been reported in human pa-tients !TPHENOBARBITAL : May increase elimination and reduce blood lev-els of doxorubicin !TSTREPTOZOCIN : May inhibit doxorubicin metabolism Laboratory Considerations !TDoxorubicin may signiﬁcantly increase both blood and urine concentrations of uric acid	pppbs.pdf
330 DOXORUBICIN HCL TDoses For more information on using doxorubicin as part of chemo-therapy protocols, refer to the protocols 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: For susceptible neoplasms: a) 30 mg/m2 IV or intracavitary every 21 days or 10 mg/m2 IV every 7 days. Maximum cumulative dose: 240 mg/m2. Pre-treat with antihistamine. (Thompson 1989a) b) For investigational treatment of insulinomas: 30 mg/m2 IV every 2-3 weeks; use with streptozocin merits further inves-tigation (Meleo and Caplan 2000) c) For large dogs: 30 mg/m2 IV; small dogs: 25 mg/m2 or 1 mg/ kg IV every 2-3 weeks. (Moore 2005) d) Doxorubicin and Asparaginase protocol for canine lympho-ma in normocalcemic dogs and if CBC demonstrates >4,500 neutrophils/UL and platelets are adequate: If dog has large volumes of tumor, it must be hydrated and should be given ﬂuid therapy for 24-36 hours prior to treatment. Diphen-hydramine is given at 2. 2 mg/kg SC 30 minutes prior to che-motherapy. If dog weighs over 25 lb., doxorubicin is given at 30 mg/m2 into the injection port of free-ﬂowing IV drip over 20 minutes. For dogs less than 25 lb., doxorubicin is dosed at 1 mg/kg to avoid toxicity. L-asparaginase is given at 10,000 IU/m2 IM 30 minutes after completion of doxorubicin. Re-peat treatment every 21 days for a total of 5 treatments if adverse effects are not severe and blood counts are adequate. Anaphylaxis may occur immediately after asparaginase and if it occurs, asparaginase should not be given again. Anorexia, mild vomiting and diarrhea may occur in the ﬁrst 4 days af-ter chemotherapy. Neutrophil nadirs usually occur 7-9 days after treatment. If severe GI toxicity or sepsis occurs, reduce dose by 20-25%. A 3-month remission time is usual for this protocol, but some dogs remain in remission for long peri-ods of time. (Legendre 2003) !TCATS: For susceptible neoplasms: a) For lymphosarcoma, carcinomas, sarcomas, myeloma, and leukemias: 20-30 mg/m2 every 3-4 weeks (Couto 1989b) b) 25 mg/m2 or 1 mg/kg IV every 2-3 weeks. (Moore 2005) c) For investigational treatment of insulinomas: 30 mg/m2 IV every 3 weeks; use with streptozocin merits further investiga-tion (Meleo and Caplan 2000) !TFERRETS: For susceptible neoplasms: a) For investigational treatment of insulinomas: 30 mg/m2 IV every 3 weeks; use with streptozocin merits further investiga-tion (Meleo and Caplan 2000) Monitoring !TEfﬁcacy !Toxicity: a) CBC with platelets b) Dogs with pre-existing heart disease should be monitored with regular ECG's (insensitive to early toxic changes caused doxorubicin) and/or echocardiogram c) Evaluate hepatic function prior to therapy d) Urinalyses and serum creatinine/BUN in cats Client Information !TClients must be briefed on the possibilities of severe toxicity de-veloping from this drug, including drug-related mortality. Cli-ents should contact the veterinarian should the animal exhibit any clinical signs of profound depression, abnormal bleeding (including bloody diarrhea) and/or bruising. !TDoxorubicin may cause urine to be colored orange to red for 1-2 days after dosing; although uncommon in veterinary patients, it is not harmful should it occur. !TMild anorexia and occasional vomiting are commonly seen 2-5 days post-therapy. !TAvoid handling urine of treated dogs. Chemistry/Synonyms An anthracycline glycoside antibiotic antineoplastic, doxorubicin HCl occurs as a lyophilized, red-orange powder that is freely soluble in water, slightly soluble in normal saline, and very slightly soluble in alcohol. The commercially available powder for injection also contains lactose and methylparaben to aid dissolution. After recon-stituting, the solution has a p H from 3. 8-6. 5. The commercially available solution for injection has a p H of approximately 3. Doxorubicin HCl may also be known as: cloridrato de doxorru-bicina, doxorubicin hydrochloride liposome, doxorubicini hydro-chloridum, liposomal doxorubicin hydrochloride, NSC-123127, Adriamycin RDF®, Adriblastin®, Adriblastina®, Adriblastine®, Adrim®, Adrimedac®, Biorrub®, Caelyx®, DOXO-cell®, Doxolem ®, Doxorbin®, Doxorubin®, Doxotec ®, Doxtie ®, Farmiblastina®, Fauldoxo®, Flavicina®, Ifadox®, Myocet ®, Neoxan®, Ranxas®, Ribodoxo-L®, and Rubex®. Storage/Stability/Compatibility Lyophilized powder for injection should be stored away from direct sunlight in a dry place. After reconstituting with sodium chloride 0. 9%, the single-use lyophilized powder product is reportedly stable for 24 hours at room temperature and 48 hours when refrigerated. The manufacturer recom mends protecting from sunlight,not freezing the product and discarding any unused portion. However, one study found that powder reconstituted with sterile water to a concentra-tion of 2 mg/m L lost only about 1. 5% of its potency per month over 6 months when stored in the refrigerator. When frozen at-20°C, no potency loss after 30 days was detected and sterility was maintained by ﬁltering the drug through a 0. 22-micron ﬁlter before injection. The commercially available solution for injection is stable for 18 months when stored in the refrigerator (2-8°C) and protected from light. The manufacturer states that after reconstitution, the multi-dose vials may be stored for up to 7 days at room temperature in normal room light, and for up to 15 days in the refrigerator. Doxorubicin HCl is reportedly physically compatible with the following intravenous solutions and drugs: dextrose 3. 3% in so-dium chloride 3%, D 5W, Normosol R (p H 7. 4), lactated Ringer's injection, and sodium chloride 0. 9%. In syringes with: bleomycin sulfate, cisplatin, cyclophosphamide, droperidol, ﬂuorouracil, leu-covorin calcium, methotrexate sodium, metoclopramide HCl, mi-tomycin, and vincristine sulfate. The drug is physically compatible	pppbs.pdf
DOXYCYCLINE 331 during Y-site injection with bleomycin sulfate, cisplatin, cyclophos-phamide, droperidol, ﬂuorouracil, leucovorin calcium, methotrex-ate sodium, metoclopramide HCl, mitomycin, vinblastine sulfate and vincristine sulfate. Doxorubicin HCl compatibility information conﬂicts or is depen-dent on diluent or concentration factors with the following drugs or solutions: vinblastine sulfate (in syringes and as an IV additive). 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 Doxorubicin HCl is reportedly physically incompatible with the following solutions or drugs: aminophylline, cephalothin sodium, dexamethasone sodium phosphate, diazepam, ﬂuorouracil (as an IV additive only), furosemide, heparin sodium, and hydrocortisone sodium succinate. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Doxorubicin HCl (Conventional) Lyophilized Powder for Injection, (conventional): 10 mg, 20 mg, 50 mg, and 150 mg vials; Adriamycin RDF® (Pharmacia & Upjohn); generic (Bedford); (Rx). Reconstitute with appropriate amount of 0. 9% sodium chloride for ﬁnal concen-tration of 2 mg/m L. Doxorubicin HCl (Conventional) Injection (aqueous): 2 mg/m L in 5 m L, 10 m L, 25 m L, and 100 m L; Adriamycin PFS® (Pharmacia & Upjohn), generic (Bedford); (Rx) Doxorubicin, Liposomal Injection: 20 mg in 10 m L & 50 mg in 30 m L single-use vials; Doxil® (Ortho Biotech); (Rx) DOXYCYCLINE CALCIUM DOXYCYCLINE HYCLATE DOXYCYCLINE MONOHYDRATE (dox-i-sye-kleen) Vibramycin® TETRACYCLINE ANTIBIOTIC Prescriber Highlights TT Oral & parenteral tetracycline antibiotic TT Contraindications: Hypersensitivity TT Bone & teeth abnormalities are less likely to be caused then with other tetracyclines, but use with caution in pregnant & young animals TT May be used in patients with renal insufﬁciency TT Not for IV injection in horses; do not give IM or SC to any species TT Most common adverse effects are GI TT Drug Interactions Uses/Indications Although there are no veterinary-approved doxycycline products available, its favorable pharmacokinetic parameters (longer half-life, higher CNS penetration) when compared to either tetracycline HCl or oxytetracycline HCl make it a reasonable choice to use in small animals when a tetracycline is indicated, particularly when a tetracycline is indicated in an azotemic patient. In avian species, some clinicians feel that doxycycline is the drug of choice in the oral treatment of psittacosis, particularly when treating only a few birds. Pharmacology/Actions T etracyclines generally act as bacteriostatic antibiotics and inhibit protein synthesis by reversibly binding to 30S ribosomal subunits of susceptible organisms, thereby preventing binding to those ribo-somes of aminoacyl transfer-RNA. T etracyclines also are believed to reversibly bind to 50S ribosomes and, additionally, alter cyto-plasmic membrane permeability in susceptible organisms. In high concentrations, tetracyclines can also 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 Rickettsia. Against gram-positive bacteria, the tetracyclines have activity against some strains of staphylococcus and streptococci, but resistance by these organisms is increasing. Gram-positive bacteria that are usually covered by tetracyclines include: Actinomyces spp., Bacillus anthracis, Clostridium perfringens and tetani, Listeria mono-cytogenes and Nocardia. Among gram-negative bacteria that tetra-cyclines usually have in vitro and in vivo activity against, 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. Doxycycline generally has very similar activity as other tetracy-clines against susceptible organisms, but some strains of bacteria may be more susceptible to doxycycline or minocycline and addi-tional in vitro testing may be required. Pharmacokinetics Doxycycline is well absorbed after oral administration. Bio-availability is 90-100% in humans. No bioavailability data was lo-cated for veterinary species, but it is thought that the drug is also readily absorbed in monogastric animals. Unlike tetracycline HCl or oxytetracycline, doxycycline absorption may only be reduced by 20% by either food or dairy products in the gut. This is not consid-ered to be clinically important. T etracyclines, as a class, are widely distributed to the heart, kid-ney, lungs, muscle, pleural ﬂuid, bronchial secretions, sputum, bile, saliva, synovial ﬂuid, ascitic ﬂuid, and aqueous and vitreous humor. Doxycycline is more lipid-soluble and penetrates body tissues and ﬂuids better than tetracycline HCl or oxytetracycline, including to the CSF, prostate, and eye. While CSF levels are generally insufﬁcient to treat most bacterial infections, doxycycline has been shown to be efﬁcacious in the treatment of the CNS effects associated with Lyme disease in humans. The volume of distribution at steady-state in dogs is approximately 1. 5 L/kg. Doxycycline is bound to plasma proteins in varying amounts dependent upon species. The drug is approximately 25-93% bound to plasma proteins in humans, 75-86% in dogs, and about 93% in cattle and pigs. Cats have high-er binding to plasma proteins than dogs. Doxycycline's elimination from the body is relatively unique. The drug is primarily excreted into the feces via non-biliary routes in an inactive form. It is thought that the drug is partially inacti-vated in the intestine by chelate formation and then excreted into the intestinal lumen. In dogs, about 75% of a given dose is handled in this manner. Renal excretion of doxycycline can only account for about 25% of a dose in dogs, and biliary excretion less than 5%. The serum half-life of doxycycline in dogs is approximately 10-12 hours and a clearance of about 1. 7 m L/kg/min. In calves, the drug has similar pharmacokinetic values. Doxycycline does not accumu-late in patients with renal dysfunction.	pppbs.pdf
332 DOXYCYCLINE T TContraindications/Precautions/Warnings Doxycycline is contraindicated in patients hypersensitive to the drug. Because tetracyclines can retard fetal skeletal development and discolor deciduous teeth, they should only be used in the last half of pregnancy when the beneﬁts outweigh the fetal risks. Doxycycline is considered to be less likely to cause these abnormalities than other more water-soluble tetracyclines (e. g., tetracycline, oxytetra-cycline). Unlike either oxytetracycline or tetracycline, doxycycline can be used in patients with renal insufﬁciency. Until further studies documenting the safety of intravenous doxycycline in horses are done, the parenteral route of administer-ing this drug in horses should be considered contraindicated. Adverse Effects The most commonly reported side effects of oral doxycycline ther-apy in dogs and cats are nausea and vomiting. T o alleviate these ef-fects, the drug can be given with food without clinically signiﬁcant reductions in drug absorption. Oral doxycycline has been implicated in causing esophageal strictures in cats. If using oral tablets, be sure that “pilling” is fol-lowed by at least 6 m L of water. Do not dry pill. T etracycline therapy (especially long-term) may result in over-growth (superinfections) of non-susceptible bacteria or fungi. In humans, doxycycline (or other tetracyclines) has also been as-sociated with photosensitivity reactions and, rarely, hepatotoxicity or blood dyscrasias. Intravenous injection of even relatively low doses of doxycycline has been associated with cardiac arrhythmias, collapse, and death in horses. Reproductive/Nursing Safety 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 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: D (Contraindicated. These drugs have been shown to cause congenital malformations or embryotoxicity. ) T etracyclines are excreted in milk. Milk:plasma ratios vary be-tween 0. 25 and 1. 5. Avoid nursing if the dam requires doxycycline. Overdosage/Acute Toxicity With the exception of intravenous dosing in horses (see above), doxycycline is apparently quite safe in most mild overdose situ-ations. Oral overdoses would most likely be associated with GI disturbances (vomiting, anorexia, and/or diarrhea). Although doxycycline is less vulnerable to chelation with cations than other tetracyclines, oral administration of divalent or trivalent cation antacids may bind some of the drug and reduce GI distress. Should the patient develop severe emesis or diarrhea, ﬂuids and electrolytes should be monitored and replaced if necessary. Rapid intravenous injection of doxycycline has induced tran-sient collapse and cardiac arrhythmias in several species, presum-ably due to chelation with intravascular calcium ions. If overdose quantities are inadvertently administered, these effects may be more pronounced. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving doxycycline and may be of signiﬁcance in veterinary patients: !TANTACIDS, ORAL : When orally administered, tetracyclines can che-late divalent or trivalent cations that can decrease the absorption of the tetracycline or the other drug if it contains these cations. Oral antacids, saline cathartics, or other GI products containing aluminum, calcium, magnesium, zinc, or bismuth cations are most commonly associated with this interaction. Doxycycline has a relatively low afﬁnity for calcium ions, but it is recommended that all oral tetracyclines be given at least 1-2 hours before or after the cation-containing product. !TBISMUTH SUBSALICYLATE, KAOLIN, PECTIN : May reduce absorption !TIRON, ORAL : Oral iron products are associated with decreased tetracycline absorption, and administration of iron salts should preferably be given 3 hours before or 2 hours after the tetracy-cline dose. !TPENICILLINS : Bacteriostatic drugs, like the tetracyclines, may inter-fere with bactericidal activity of the penicillins, cephalosporins, and aminoglycosides. There is a fair amount of controversy re-garding the actual clinical signiﬁcance of this interaction, how-ever. !TPHENOBARBITAL : May decrease doxycycline half-life and reduce levels !TWARFARIN : T etracyclines may depress plasma prothrombin activ-ity and patients on anticoagulant (e. g., warfarin) therapy may need dosage adjustment. Laboratory Considerations !Tetracyclines (not minocycline) may cause falsely elevated values of urine catecholamines when using ﬂuorometric methods of de-termination. !Tetracyclines 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®, Test-Tape®). Doses !TDOGS: For susceptible infections: a) General use for infection: 3-5 mg/kg PO q12h for 7-14 days; For soft tissue, urinary tract: 4. 4-11 mg/kg PO or IV q12h for 7-14 days; For acute E. canis infection: 5 mg/kg PO q12h or 10 mg/kg PO q24h for 14-16 days; For chronic E. canis infection: 10 mg/kg PO q24h for 30-42 days. (Greene, Hartmannn et al. 2006) b) For canine ehrlichiosis (anaplasmosis): 5-10 mg/kg PO q12h for 7-10 days (Greig 2000) c) For Lyme disease: 10 mg/kg PO q24h for 21-28 days (Appel and Jacobson 1995) d) For salmon poisoning disease: 10 mg/kg IV twice a day for at least 7 days (Rikihisa and Zimmerman 1995) e) For the renal carrier state of leptospirosis: 5-10 mg/kg PO twice daily for an additional 14 days after penicillin G ther-apy (25,000-40,000 U/kg IV or IM q12-24h for 14 days) (Ross and Rentko 2000) f) For Toxoplasma gondii: 5-10 mg/kg PO q12h for 4 weeks (Lappin 2000) g) For Rocky Mountain Spotted-Fever (Rickettsia rickettsii): 5 mg/kg PO q12h (Breitschwerdt 2000) For its antiarthritic effect: a) 3-4 mg/kg PO once daily for 7-10 days. (Greene, Hart-mannn et al. 2006)	pppbs.pdf
DOXYCYCLINE 333 !TCATS: Do not dry pill cats with oral doxycycline; follow with at least 6 m L of water or use a compounded slurry (“triple ﬁsh” or simi-lar) to administer. For susceptible infections: a) 5 mg/kg PO or IV q12h; administer with food if GI upset oc-curs; avoid in young animals; avoid or reduce dose in animals with severe liver disease (Vaden and Papich 1995) b) For clinical hemoplasmosis or bartonellosis: 10 mg/kg PO q12-24h (Lappin 2006a) c) For feline ehrlichiosis: 5 mg/kg twice daily (Kordick, Lappin et al. 1995) d) For Toxoplasma gondii: 5-10 mg/kg PO q12h for 4 weeks (Lappin 2000) e) For Hemotropic mycoplasmosis: 5-10 mg/kg PO once daily for 14 days; round dose to nearest whole tablet or capsule; For Bartonellosis: 50 mg (total dose) PO q12h for 14-28 days; For systemic infections, bacteremia: 5-11 mg/kg PO or IV q12h as long as necessary; For Ehrlichiosis or Anaplasmosis: 5-10 mg/kg PO q12h for 21 days. (Greene, Hartmannn et al. 2006) !THORSES: WARNING: Doxycycline intravenously in horses has been associ-ated with fatalities. Until further work is done demonstrating the safety of this drug, it cannot be recommended for parenteral use in this species. a) For Lyme disease: 10 mg/kg PO once to twice daily for up to 30 days (Divers 1999) !TRABBITS/RODENTS/SMALL MAMMALS: a) Mice, Rats: For mycoplasmal pneumonia: 5 mg/kg PO twice daily with enroﬂoxacin (10 mg/kg PO twice daily) (Burke 1999) b) Chinchillas, Gerbils, Guinea Pigs, Hamsters, Mice, Rats: 2. 5-5 mg/kg PO q12h. Do not use in young or pregnant ani-mals. (Adamcak and Otten 2000) !TBIRDS: For Psittacosis (Chlamydiosis): a) Routes of treatment include intramuscular injections, oral dosage with a suspension, medicated mash (approximately 1000 mg per kg of feed), and water-soluble approaches. IM: 75-100 mg/kg IM every 5-7 days for the ﬁrst 4 weeks and subsequently every 5 days for the duration of a 45 day treatment. PO: 40-50 mg/kg PO once daily for cockatiels, Senegal par-rots, Blue fronted and Orange winged amazons, 25 mg/kg PO once daily for African Grey parrots, Gofﬁn's cockatoos, Blue and gold macaws and Green winged macaws. Empiri-cally: 25-50 mg/kg PO once a day is the recommended start-ing dosage for unstudied avian species. (Speer 1999) b) In psittacines: 17. 6-26. 4 mg/kg PO twice daily using the oral syrup or suspension. For initial therapy in severe cases: 22-44 mg/kg IV once or twice; do not give IM. Long-term therapy (45 days) can be given as 200 mg (from capsules) per pound of food. (Clubb 1986) c) Using the oral liquid/suspension: 50 mg/kg PO every 24 hours, or divided every 12 hours (use less for macaws). Using the hyclate salt on corn, beans, rice and oatmeal: 1 gram per kg of feed. Using the injectable product (Vibaravenos®—may not be available commercially in the USA): 100 mg/kg IM once weekly (75 mg/kg IM once weekly in macaws and love-birds) (Bauck and Hoefer 1993) d) Ratites: 2-3. 5 mg/kg PO twice daily (Jenson 1998) !TREPTILES: For susceptible infections: a) For chelonians: 10 mg/kg PO once daily for 4 weeks. Useful for bacterial respiratory infections in tortoises having sus-pected Mycoplasma infections. b) In most species: 10 mg/kg PO once daily for 10-45 days (Gauvin 1993) Monitoring !TClinical efﬁcacy !TAdverse effects Client Information !TDo not “dry pill” as esophageal damage can occur; if using oral tablets or capsules, especially in cats, give medication followed by at least one 6 m L (a little more than a teaspoonful) of liquid. In cats, buttering the lips after administration to induce salivation and reduce esophageal transit time has been suggested. !TOral doxycycline products may be administered without regard to feeding, but giving with some food may reduce gastrointesti-nal effects. Milk or other dairy products do not signiﬁcantly alter the amount of doxycycline absorbed. Chemistry/Synonyms A semi-synthetic tetracycline that is derived from oxytetracycline, doxycycline is avail able as hyclate, calcium and monohydrate salts. The hyclate salt is used in the injectable dosage form and in oral tab-lets and capsules. It occurs as a yellow, crystalline powder that is solu-ble in water and slightly soluble in alcohol. After reconstitution with sterile water, the hyclate injection has a p H of 1. 8-3. 3. Doxycycline hyclate may also be known as doxycycline hydrochloride. The monohydrate salt is found in the oral powder for reconsti-tution. It occurs as a yellow, crystalline powder that is very slightly soluble in water and sparingly soluble in alcohol. The calcium salt is formed in situ during manufacturing. It is found in the commer-cially available oral syrup. Doxycycline may also be known as: doxycycline monohydrate, doxycyclinum, and GS-3065; many trade names are available. Storage/Stability/Compatibility Doxycycline hyclate tablets and capsules should be stored in tight, light resistant containers at temperatures less than 30°C, and pref-erably at room temperature (15-30°C). After reconstituting with water, the monohydrate oral suspension is stable for 14 days when stored at room temperature. The hyclate injection when reconstituted with a suitable diluent (e. g., D 5W, Ringer's injection, Sodium Chloride 0. 9%, or Plasma-Lyte 56 in D 5W) to a concentration of 0. 1 to 1 mg/m L may be stored for 72 hours if refrigerated. Frozen reconstituted solutions (10 mg/m L in sterile water) are stable for at least 8 weeks if kept at-20°C, but should not be refrozen once thawed. If solutions are stored at room temperature, different manufacturers give different recommendations regarding stability, ranging from 12-48 hours. Infusions should generally be completed within 12 hours of admin-istration. Doxycycline hyclate for injection is reportedly physically com-patible with the following IV infusion solutions and drugs: D 5W, Ringer's injection, sodium chloride 0. 9%, or Plasma-Lyte 56 in D5W, Plasma-Lyte 148 in D 5W, Normosol M in D 5W, Normosol R in D 5W, invert sugar 10%, acyclovir sodium, hydromorphone HCl, magnesium sulfate, meperidine HCl, morphine sulfate, per-phenazine and ranitidine HCl. Compatibility is dependent upon factors such as p H, concentration, temperature, and diluent used;	pppbs.pdf
334 EDETATE CALCIUM DISODIUM consult specialized references or a hospital pharmacist for more speciﬁc information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None for systemic use. Doxycycline gel: 8. 5% activity once mixed. (2 syringe system); Doxi-robe® (Pﬁzer); (Rx). Approved for dogs; oral application for the pre-vention and treatment of periodontal disease. HUMAN-LABELED PRODUCTS: Doxycycline (as the hyclate) Tablets & Capsules: 20 mg, 50 mg, & 100 mg; Periostat® (Colla Genex), Vibramycin® & Vibra-Tabs® (Pﬁzer); generic; (Rx) Doxycycline (as the hyclate) Delayed-Release Tablets & Capsules: 75 mg & 100 mg and 40 mg (30 mg immediate release & 10 mg delayed release); Doryx® (Warner Chilcott); Oracea® (Colla Genex); (Rx) Doxycycline (as monohydrate) Tablets and Capsules: 50 mg, 75 mg & 100 mg; Monodox® (Oclassen); Adoxa ® (Bioglan); generic; (Rx) Doxycycline Capsules (coated-pellets) (as hyclate): 75 mg and 100 mg; Doryx® (Warner Chilcott); Doxycycline (Eon); (Rx) Doxycycline (as the monohydrate) Powder for Oral Suspension: 5 mg/m L after reconstitution in 60 m L; Vibramycin® (Pﬁzer); (Rx) Doxycycline (as the calcium salt) Oral Syrup: 10 mg/m L in 473 m L; Vibramycin® (Pﬁzer); (Rx) Doxycycline Injection: 42. 5 mg (as hyclate, 10%) in 2 syringe mixing system and blunt cannula; Atridox® (Colla Genex); (Rx) Doxycycline (as the hyclate) Lyophilized Powder for Injection: 100 mg and 200 mg in vials; Doxy®-100 and-200 (AAP); generic; (Rx) EDETATE CALCIUM DISODIUM CALCIUM EDTA (ed-a-tayt) Calcium Disodium Versenate® ANTIDOTE Prescriber Highlights TT Heavy metal chelator used primarily for lead or zinc toxicity TT Contraindications: Patients with anuria TT Extreme caution: Decreased renal function TT Recommend using SC route when treating small ani-mals; do not give PO TT Adverse Effects: Renal toxicity (renal tubular necrosis); may cause depression & GI clinical signs in dogs Uses/Indications Ca EDTA is used as a chelating agent in the treatment of lead poi-soning. Succimer is more commonly recommended today for treat-ing lead poisoning in dogs and cats. Ca EDTA may used in combination with dimercaprol treatment. Pharmacology/Actions The calcium in Ca EDTA can be displaced by divalent or trivalent metals to form a stable water soluble complex that can be excreted in the urine. One gram of Ca EDTA can theoretically bind 620 mg of lead, but in reality only about 5 mg per gram is actually excreted into the urine in lead poisoned patients. In addition to chelating lead, Ca EDTA chelates and eliminates zinc from the body. Ca EDTA also binds cadmium, copper, iron, and manganese, but to a much lesser extent than either lead or zinc. Ca EDTA is relatively ineffec-tive for use in treating mercury, gold, or arsenic poisoning. There is some evidence that thiamine supplementation may in-crease the clinical efﬁcacy of Ca EDTA in treating acute lead poison-ing in cattle. Pharmacokinetics Ca EDTA is well absorbed after either IM or SC administration. It is distributed primarily in the extracellular ﬂuid. Unlike dimercaprol, Ca EDTA does not penetrate erythrocytes or enter the CNS in ap-preciable amounts. The drug is rapidly excreted renally, either as unchanged drug or chelated with metals. Changes in urine p H or urine ﬂow do not signiﬁcantly alter the rate of excretion. Decreased renal function can cause accumulation of the drug and can increase its nephrotoxic potential. In humans with normal renal function, the average elimination half-life of Ca EDTA is 20-60 minutes after IV administration, and 1. 5 hours after IM administration. Contraindications/Precautions/Warnings Ca EDTA is contraindicated in patients with anuria. It should be used with extreme caution and with dosage adjustment in patients with diminished renal function. Most small animal clinicians recommend using the SC route when treating small animals, as IV administration of Ca EDTA has been associated with abrupt increases in CSF pressure and death in children with lead-induced cerebral edema. Lead should be removed from the GI tract before using Ca EDTA. Do not administer Ca EDTA orally as it may increase the amount of lead absorbed from the GI tract. Animals with clinical signs of cerebral edema should not be over hydrated. Adverse Effects The most serious adverse effect associated with this compound is renal toxicity (renal tubular necrosis), but in dogs, Ca EDTA can cause depression, vomiting, and diarrhea. GI clinical signs may be alleviated by zinc supplementation. Chronic therapy may lead to zinc deﬁciency; zinc supplementa-tion should be considered in these animals. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters). It is not known whether this drug is excreted in milk. Overdosage/Acute Toxicity Doses greater than 12 g/kg are lethal in dogs; refer to Adverse Effects for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving Ca EDTA and may be of signiﬁcance in veterinary patients: T ! GLUCOCORTICOIDS : The renal toxicity of Ca EDTA may be enhanced by the concomitant administration of glucocorticoids T ! INSULIN (NPH, PZI ): Concurrent administration of Ca EDTA with zinc insulin preparations (NPH, PZI) will decrease the sustained action of the insulin preparation	pppbs.pdf
EDETATE CALCIUM DISODIUM 335 !TNEPHROTOXIC DRUGS, OTHER : Use with caution with other nephro-toxic compounds (e. g., aminoglycosides, amphotericin B ) Laboratory Considerations !TCa EDTA may cause increased urine glucose values and/or cause inverted T-waves on ECG Doses The manufacturer of the injectable (human) product recommends diluting the injection to a concentration of 2-4 mg/m L with ei-ther normal saline or 5% dextrose when used for intravenous use. Because the injection is painful when given IM, it is recommended to add 1 m L of procaine HCl 1% to each m L of injection before administering IM. !TDOGS & CAT S: For lead poisoning: a) Be sure there is no lead in GI tract before using. Give 100 mg/kg SC divided into 4 daily doses in 5% dextrose for 5 days. May require second course of treatment, particularly if blood lead levels >0. 10 ppm. Do not exceed 2 g/day and do not treat for more than 5 consecutive days. (Grauer and Hjelle 1988b) b) 25 mg/kg SC four times daily for 5 days. Give as 1% solution in D 5W. Provide a 5-7 day rest period between courses of treatment to minimize potential for nephrotoxicity. Succi-mer is now the treatment of choice for lead in small animals. (Poppenga 2002) c) Cats: 27. 5 mg/kg in 15 m L D 5W SC four times daily for 5 days. Recheck blood lead 2-3 weeks later and repeat therapy (with either Ca EDTA or penicillamine) if greater than 0. 2 ppm. (Reid and Oehme 1989) For zinc toxicity: a) 100 mg/kg divided into four SC doses per day. Dilute in D5W to reduce local irritation at site of injection. Exact dosage is not known nor how long therapy should continue. If pos-sible, monitor serum zinc concentrations and maintain ani-mal's hydration status. (Meurs and Breitschwerdt 1995) !TRABBITS/RODENTS/SMALL MAMMALS: a) Chinchillas: 30 mg/kg SC q12h (Adamcak and Otten 2000) !THORSES: For lead poisoning: a) Remove animal from source of lead. If severely affected give Ca EDTA at 75 mg/kg IV slowly in D 5W or saline daily for 4-5 days (may divide daily dose into 2-3 administrations per day). Stop therapy for 2 days and repeat for another 4-5 days. Give adequate supportive and nutritional therapy. (Oe-hme 1987d) !TFOOD ANIMALS: Note : FARAD recommends a 2 day meat and milk withdrawal time after use in food animals. (Haskell, Payne et al. 2005) For lead poisoning: a) 110 mg/kg per day in 3-4 divided doses; dilute to 1 gram/m L in D5W; ﬁrst dose IV, then subcutaneously (Post and Keller 2000) b) Cattle: 67 mg/kg slow IV twice daily for 2 days; withhold dose for 2 days and then give again for 2 days. Cattle may require 10-14 days to recover and may require several series of treat-ments. (Bailey 1986b) c) Cattle: 73. 3 mg/kg/day slow IV divided 2-3 times a day for 3-5 days. If additional therapy is required, a 2-day rest pe-riod followed by another 5-day treatment regimen is recom-mended. (Sexton and Buck 1986) !TBIRDS: For lead poisoning: a) In psittacines: 35 mg/kg IM twice daily for 5-7 days. After initial therapy, may give orally until all lead fragments are dissolved and/or passed from GI tract. (Mc Donald 1989) b) In raptors (falcons): In this study, 25% Ca EDTA was given undiluted IM at a dose of 100 mg/kg q12h for 5-25 consecu-tive days. Falcons were treated if blood lead was >65 mcg/ d L for 5 day courses, until blood lead was <20 mcg/d L. No evidence of muscle damage, nephrotoxicity or hepatotoxicity seen. (Samour and Naldo 2004) Monitoring !TBlood lead or zinc (serial), and/or urine d-ALA !TRenal function tests, urinalyses, hydration status !TSerum phosphorus and calcium values !TPeriodic cardiac rate/rhythm monitoring may be warranted dur-ing administration Client Information !TBecause of the potential toxicity of this agent and the seriousness of most heavy metal intoxications, this drug should be used with close professional supervision only. Chemistry/Synonyms A heavy metal chelating agent, edetate calcium disodium (Ca EDTA) occurs as an odorless, white, crystalline powder or granules and is a mixture of dihydrate and trihydrate forms. It has a slight saline taste and is slightly hygroscopic. Ca EDTA is freely soluble in water and very slightly soluble in alcohol. The commercially available injec-tion (human) has a p H of 6. 5-8 and has approximately 5. 3 m Eq of sodium per gram of Ca EDTA. Edetate calcium disodium may also be known as: sodium cal-cium edetate, calcium disodium edathamil, calcium disodium edetate, calcium disodium ethylenediaminetetra-acetate, calcium disodium versenate, calcium EDTA, disodium calcium tetracemate, E385, natrii calcii edetas, sodium calciumedetate, Calcium Disodium Versenate®, Calcium Vitis®, Calciumedetat-Heyl®, Chelante®, Chelintox®, or Ledclair®. Storage/Stability/Compatibility Ca EDTA should be stored at temperatures less than 40°, and prefer-ably at room temperature (15-30°C). The injection can be diluted with either normal saline or 5% dextrose. Dosage Forms/Regulatory Status Note : Do not confuse with Edetate Disodium which should not be used for lead poisoning as it may cause severe hypocalcemia. VETERINARY-LABELED PRODUCTS: None in the USA; may be available from compounding pharmacies. HUMAN-LABELED PRODUCTS: Edetate Calcium Disodium Injection: 200 mg/m L in 5 m L amps (1 gram/amp); Calcium Disodium Versenate® (3M Pharm. ); (Rx)	pppbs.pdf
336 EDROPHONIUM CHLORIDE EDROPHONIUM CHLORIDE (ed-roe-foe-nee-um) Tensilon®, Enlon® CHOLINERGIC (ANTICHOLINESTERASE) AGENT Prescriber Highlights TT Short-acting parenteral quanternary ammonium cholin-ergic used primarily to test for myasthenia gravis TT Secondary indications are to reverse nondepolarizing agents or to treat some SVT's TT Relatively contraindicated: Asthma or mechanical urinary or intestinal tract obstruction TT Caution: Bradycardias or atrioventricular block TT Overdoses can cause cholinergic crisis Uses/Indications The primary use for edrophonium is in the diagnosis of myasthe-nia gravis. It can also be used for the reversal of nondepolarizing agents (e. g., vecuronium, pancuronium, metocurine, atracurium, gallamine or tubocurarine). Because of its short duration of ac-tion, its clinical usefulness for this indication is questionable as longer acting drugs such as neostigmine or pyridostigmine may be more useful. Edrophonium, in a controlled intensive care-type set-ting, may also be useful in the diagnosis and treatment of some supraventricular arrhythmias, particularly when other more tradi-tional treatments are ineffective. Pharmacology/Actions Edrophonium is an anticholinesterase agent that is very short act-ing. It brieﬂy attaches to acetylcholinesterase thereby inhibiting its hydrolytic activity on acetylcholine. As acetylcholine accumulates, the following clinical signs may be noted: miosis, increased skel-etal and intestinal muscle tone, bronchoconstriction, ureter con-striction, salivation, sweating (in animals with sweat glands), and bradycardia. Pharmacokinetics Edrophonium is only effective when given parenterally. After IV administration, it begins to have effects on skeletal muscle within one minute and effects may persist for up to 10 minutes. Myasthenic patients may have effects persisting longer after the ﬁrst dose. Edrophonium's exact metabolic fate and excretion characteristics have not been well described. Contraindications/Precautions/Warnings Edrophonium is considered relatively contraindicated in patients with bronchial asthma, or mechanical urinary or intestinal tract obstruction. It should be used with caution (with adequate moni-toring and treatment available) in patients with bradycardias or atrioventricular block. Some human patients are documented to be hypersensitive to the drug and exhibit severe cholinergic reactions. It is recommended to have IV atropine and an endotracheal tube readily available before using edrophonium. Adverse Effects Adverse effects associated with edrophonium are generally dose re-lated and cholinergic in nature. Although usually mild and easily treated with a “tincture of time”, severe adverse effects are possible with large overdoses (see below). Reproductive/Nursing Safety Edrophonium's safety proﬁle during pregnancy is not established; use only when necessary. While no problems have been documented in nursing humans or animals, its safety 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 reproduction studies and no adequate studies in humans. ) It is unknown whether edrophonium enters maternal milk. Overdosage/Acute Toxicity Overdosage of edrophonium may induce a cholinergic crisis. Clinical signs of cholinergic toxicity can include: GI effects (nausea, vomiting, diarrhea), salivation, sweating (in animals able to do so), respiratory effects (increased bronchial secretions, bronchospasm, pulmonary edema, respiratory paralysis), ophthalmic effects (mio-sis, blurred vision, lacrimation), cardiovascular effects (bradycardia or tachycardia, cardiospasm, hypotension, cardiac arrest), muscle cramps and weakness. Treatment of edrophonium overdose consists of both respira-tory and cardiac supportive therapy and, atropine, if necessary. Refer to the atropine monograph for more information on its use for cholinergic toxicity. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving edrophonium and may be of signiﬁcance in veterinary patients: T ! ATROPINE : Atropine will antagonize the muscarinic effects of edro-phonium and some clinicians routinely use the two together, but concurrent use should be used cautiously as atropine can mask the early clinical signs of cholinergic crisis T ! DEXPANTHENOL : Theoretically, dexpanthenol may have additive ef-fects when used with edrophonium T ! DIGOXIN : Edrophonium's cardiac effects may be increased in patients receiving digoxin; excessive slowing of heart rate may occur T ! MUSCLE RELAXANTS : Edrophonium may prolong the Phase I block of depolarizing muscle relaxants (e. g., succinylcholine, decametho-nium ) and edrophonium antagonizes the actions of non-depolar-izing neuromuscular blocking agents (e. g., pancuronium, tubocura-rine, gallamine, vecuronium, atracurium, etc. ) Doses T ! DOGS: For presumptive diagnosis of myasthenia gravis (MG): a) Exercise animal to the point of collapse, then give edropho-nium at 0. 1 mg/kg IV. In animals whose exercise intolerance is minimal, it may be hard to evaluate. (Shelton 2002) b) 1-5 mg (total dose) IV (Kline 2001) c) 1-10 mg (total dose) IV; presumptive positive test results in transient improvement in clinical weakness; sometimes ob-jective criteria for this test are difﬁcult to establish. (Le Cou-teur 2005) d) 0. 1-0. 2 mg/kg IV; have atropine and endotracheal tube read-ily available in case of overdose. (Abramson 2005) e) Pre-treat with atropine (0. 02-0. 04 mg/kg IM or SC); then give edrophonium at 0. 1 mg/kg IV. In affected animals, pare-sis should resolve within one minute and effects should last for up to 15 minutes. (Korenegay 2006)	pppbs.pdf
EMODEPSIDE + PRAZIQUANTEL 337 T ! CATS: For presumptive diagnosis of myasthenia gravis (MG): a) 0. 1 mg/kg IV, preceded by atropine to block muscarinic ef-fects. Improvement should occur within one minute and persist for up to 15 minutes. (Kornegay 2003b) b) 0. 25-0. 5 mg per cat IV (Joseph, Carrillo et al. 1988), (Kline 2001) c) 0. 25-0. 5 mg (total dose) per cat IV; have atropine and endo-tracheal tube readily available in case of overdose. (Abram-son 2005) d) Pre-treat with atropine (0. 02-0. 04 mg/kg IM or SC); then give edrophonium at 0. 1 mg/kg IV. In affected animals, pare-sis should resolve within one minute and effects should last for up to 15 minutes. (Korenegay 2006) Monitoring T ! Cholinergic adverse effects T ! Improvement (for 1-15 minutes) of paresis for presumptive di-agnosis of MG Client Information T ! Edrophonium is a drug that should be used in a controlled clini-cal setting T ! Clients should be briefed on the side effects that can occur with its use Chemistry/Synonyms A synthetic quanternary ammonium cholinergic (parasympath-omimetic) agent, edrophonium chloride occurs as a white crystal-line powder having a bitter taste. Approximately 2 grams are soluble in 1 m L of water. The injection has a p H of approximately 5. 4. Edrophonium chloride may also be known as: edrophonii chlo-ridum, Anticude®, Camsilon®, Enlon®, Reversol®, or Tensilon®. Storage/Stability/Compatibility Edrophonium chloride injection should be stored at room temperature. It is reportedly physically compatible at Y-site injections with hep-arin sodium, hydrocortisone sodium succinate, potassium chloride and vitamin B complex with C. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more speciﬁc information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Edrophonium Chloride for Injection: 10 mg/m L in 1 m L amps & 10 m L & 15 m L vials; Enlon® (Ohmeda); R eversol ® (Organon); Tensi-lon® (ICN); (Rx) Edrophonium Chloride/Atropine Sulfate for Injection: 10 mg/m L with 0. 14 mg/m L atropine sulfate in 5 m L amps and 15 m L multi-dose vials; Enlon-Plus® (Ohmeda); (Rx) EFA-Caps® — see Fatty Acids EMODEPSIDE + PRAZIQUANTEL (ee-moe-dep-side + pra-zi-kwon-tel) Profender TOPICAL ANTIPARASITIC (NEMATO CIDE; CESTOCIDE Prescriber Highlights TT Topical cestocide & nematocide labeled for cats TT Appears safe in cats >1 kg & at least 8 weeks old TT Applied to back of cat's neck; do not allow patient or other cats to lick area of application for at least one hour Uses/Indications Emodepside/Praziquantel topical solution (Profender ®) is indicated for the treatment and control of hookworm infections caused by Ancylostoma tubaeforme (adults, immature adults, and fourth stage larvae), roundworm infections caused by Toxocara cati (adults and fourth stage larvae), and tapeworm infections caused by Dipylidium caninum (adults) and Taenia taeniaeformis (adults) in cats. Pharmacology/Actions Emodepside has a unique mode of action in comparison to other antiparasitic compounds. The drug attaches pre-synaptically at the neuromuscular junction to a latrophilin-like receptor, resulting in an increase in intracellular calcium and diacylglycerol levels. At the end of the signal transduction cascade, vesicles containing inhibi-tory neuropeptide fuse with pre-synaptic membranes. Inhibitory neuropeptides such as PF1-and/or PF2-like receptor are then re-leased into the synaptic cleft, stimulating postsynaptic receptors and resulting in an inhibition of pharyngeal pumping and locomo-tion of the nematode. The end result is ﬂaccid paralysis and death of the parasite. Praziquantel's exact mechanism of action against cestodes has not been determined, but it may be the result of interacting with phospholipids in the integument causing ion ﬂuxes of sodium, potassium and calcium. At low concentrations in vitro, the drug appears to impair the function of their suckers and stimulates the worm's motility. At higher concentrations in vitro, praziquantel in-creases the contraction (irreversibly at very high concentrations) of the worm's strobilla (chain of proglottids). In addition, praziquan-tel causes irreversible focal vacuolization with subsequent cestodal disintegration at speciﬁc sites of the cestodal integument. Pharmacokinetics Following dermal application of the product (Profender ®) to cats, emodepside and praziquantel are absorbed through the skin and into the systemic circulation. Absorption of both active ingredi-ents through the skin is relatively rapid, with serum concentrations detectable within 2 hours for emodepside and within 1 hour for praziquantel. Peak concentrations occur within 6 hours for prazi-quantel and 2 days for emodepside. After a single application, both emodepside and praziquantel were detectable for up to 28 days fol-lowing treatment were noted. Contraindications/Precautions/Warnings There are no absolute contraindications for use of this product on cats noted on the label. However, safe use has not been evaluated in cats: less than 8 weeks of age or weighing less than 2. 2 lb (1 kg), used for breeding, during pregnancy, or in lactating queens. Use with caution in sick or debilitated, or heartworm positive cats.	pppbs.pdf
338 ENALAPRIL MALEATE Adverse Effects In pre-approval efﬁcacy studies, the most common side effects ob-served were dermal-and gastrointestinal-related. In a ﬁeld study, adverse reactions reported by cat owners included licking/exces-sive grooming (3%), scratching treatment site (2. 5%), salivation (1. 7%), lethargy (1. 7%), alopecia (1. 3%), agitation/nervousness (1. 2%), vomiting (1%), diarrhea (0. 5%), eye irritation in 3 cats (0. 5%), respiratory irritation (0. 2%) and shaking/tremors (0. 2%). All adverse reactions were self-limiting. The following adverse events were reported voluntarily during post-approval use of the product in foreign markets: application site reaction (hair loss, dermatitis, pyoderma, edema, and erythema), salivation, pruritus, lethargy, vomiting, diarrhea, dehydration, ataxia, loss of appetite, facial swelling, rear leg paralysis, seizures, hyperesthesia, twitching, and death. Reproductive/Nursing Safety Safe use has not been evaluated in cats used for breeding, during pregnancy, or in lactating queens. Studies performed in laboratory animals (rats, rabbits suggest that emodepside may interfere with fetal development in those species. Overdosage/Acute Toxicity Oral doses of emodepside of 200 mg/kg were tolerated by rats without mortalities. The oral LD50 in rats is >500 mg/kg; in mice >2,500 mg/kg. The acute dermal toxicity dose of emodepside in rats is high; a dose of 2,000 mg/kg was tolerated without mortality. Praziquantel has a wide margin of safety. In rats and mice, the oral LD 50 i s a t l e a s t 2 g / k g. A n o r a l L D 50 c o u l d n o t b e d e t e r-mined in dogs, as at doses greater than 200 mg/kg, the drug in-duced vomiting. Parenteral doses of 50-100 mg/kg in cats caused transient ataxia and depression. Injected doses at 200 mg/kg were lethal in cats. Kittens approximately 8 weeks of age were treated topically with the combination product up to 5X at 2 week intervals for treatments. Clinical signs of transient salivation and/or tremors were seen in a few animals in the 5X group, all of which were self-limiting. Seven-to eight-month-old cats treated topically with the topi-cal solution at 10X developed transient salivation, tremor, and lethargy. Studies where the product was administered orally in cats have caused salivation, vomiting, anorexia, tremors, abnormal respira-tions, and ataxia. Adverse effects in all animals treated in these stud-ies resolved without treatment. Drug Interactions No drug interactions have been documented for this product, but emodepside is reportedly a substrate for P-glycoprotein. Use with other drugs that are P-glycoprotein substrates or inhibitors (e. g., ivermectin, erythromycin, prednisolone, cyclosporine ) could cause pharmacokinetic drug interactions. Doses T ! CATS: For labeled indications: a) Minimum dose is 3 mg/kg emodepside & 12 mg/kg praziqu-antel applied to the skin on the back of the neck as a single topical dose. A second treatment should not be necessary. If re-infection occurs, the product can be re-applied after 30 days. (Label information; Profender®—Bayer) Monitoring ! ! Clinical efﬁcacy Client Information T ! Do not apply to broken skin or if hair coat is wet. T ! Do not get in the cat's mouth or eyes or allow the cat to lick the application site for one hour. Oral exposure can cause salivation and vomiting; treatment at the base of the head will minimize the opportunity for ingestion while grooming. T ! In households with multiple pets, keep animals separated to pre-vent licking of the application site. T ! Not for human use. Keep out of reach of children. T o prevent accidental ingestion of the product, children should not come in contact with the application site for 24 hours while the product is being absorbed. Pregnant women, or women who may become pregnant, should avoid direct contact with, or wear disposable gloves when applying, this product. Chemistry/Synonyms Emodepside is an N-methylated 24-membered cyclooctadepsipep-tide, consisting of four alternating residues of N-methyl-L-leucine, two residues of D-lactate, and two residues of D-phenylacetate. Praziquantel occurs as a white to practically white, hygroscop-ic, bitter tasting, crystalline powder, either odorless or having a faint odor. It is very slightly soluble in water and freely soluble in alcohol. Praziquantel may also be known as: EMBAY-8440, or praziqu-antelum. Storage/Stability Store product at or below 25°C (77°F); do not allow to freeze. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Emodepside (1. 98% w/w; 21. 4 mg/m L) and Praziquantel (7. 94% w/w; 85. 8 mg/m L) T opical Solution in 0. 35 m L (cats 2. 2-5. 5 lb. ), 0. 7 m L (cats >5. 5-11 lb. ) & 1. 12 m L (cats >11-17. 6 lb. ) tubes: Pro-fender® (Bayer); (Rx) Approved for use on cats. HUMAN-LABELED PRODUCTS: None ENALAPRIL MALEATE ENALAPRILAT (e-nal-a-pril) Enacard®, Vasotec® ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITOR Prescriber Highlights TT Veterinary & human ACE inhibitor used primarily as a vasodilator in the treatment of heart failure or hyperten-sion; may also be of beneﬁt in the treatment of chronic renal failure or protein losing nephropathies TT Contraindications: hypersensitivity to ACE inhibitors TT Caution: pregnancy, renal insufﬁciency (doses may need to be reduced), patients with hyponatremia, coronary or cerebrovascular insufﬁciency, preexisting hematologic abnormalities or a collagen vascular disease (e. g., SLE) TT Adverse Effects: GI distress (anorexia, vomiting, diar-rhea); Potentially: weakness, hypotension, renal dysfunc-tion & hyperkalemia	pppbs.pdf
ENALAPRIL MALEATE 339 Uses/Indications The principle use of enalapril/enalaprilat in veterinary medicine at present is as a vasodilator in the treatment of heart failure. Recent studies have demonstrated that enalapril, particularly when used in conjunction with furosemide, does improve the quality of life in dogs with heart failure. It is not clear, however, whether it has any signiﬁcant effect on survival times. It may also be of beneﬁt in treating the effects associated with valvular heart disease (mi-tral regurgitation) and left to right shunts. It is being explored as adjunctive treatment in chronic renal failure and protein losing nephropathies. While ACE inhibitors are a mainstay for treating hypertension in humans, they have not been particularly useful in treating hyper-tension in dogs or cats. Pharmacology/Actions Enalapril is converted in the liver to the active compound enalapri-lat. Enalaprilat prevents the formation of angiotensin-II (a potent vasoconstrictor) by competing with angiotensin-I for the enzyme angiotensin-converting enzyme (ACE). ACE has a much higher af-ﬁnity for enalaprilat than for angiotensin-I. Because angiotensin-II concentrations are decreased, aldosterone secretion is reduced and plasma renin activity is increased. The cardiovascular effects of enalaprilat 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. In animals with glomerular disease, ACE in-hibitors probably decrease proteinuria and help to preserve renal function. Pharmacokinetics Enalapril/enalaprilat has different pharmacokinetic properties than captopril in dogs. It has a slower onset of action (4-6 hours) but a longer duration of action (12-14 hours). In humans, enalapril is well absorbed after oral administration, but enalaprilat is not. Approximately 60% of an oral dose is bioavailable. Both enalapril and enalaprilat are distributed poorly into the CNS and are distrib-uted into milk in trace amounts. Enalaprilat crosses the placenta. In humans, the half-life of enalapril is about 2 hours; enalaprilat about 11 hours. Half-lives are increased in patients with renal failure or severe CHF. Contraindications/Precautions/Warnings Enalaprilat is contraindicated in patients who have demonstrated hypersensitivity to the ACE inhibitors. It should be used with cau-tion and close supervision in patients with renal insufﬁciency and doses may need to be reduced. Enalaprilat should also be used with caution in patients with hyponatremia or sodium depletion, coronary or cerebrovascular insufﬁciency, preexisting hematologic abnormalities, or a collagen vascular disease (e. g., SLE). Patients with severe CHF should be monitored very closely upon initiation of therapy. Adverse Effects Enalapril/enalaprilat's adverse effect proﬁle in dogs is principally GI distress (anorexia, vomiting, diarrhea). Potentially, weakness, hypotension, renal dysfunction and hyperkalemia could occur. Because it lacks a sulfhydryl group (unlike captopril), there is less likelihood that immune-mediated reactions will occur, but rashes, neutropenia, and agranulocytosis have been reported in humans. In humans, ACE inhibitors commonly cause coughs, but this occurs rarely in dogs or cats. Reproductive/Nursing Safety Enalapril crosses the placenta. High doses in rodents have caused decreased fetal weights and increases in fetal and maternal death rates; teratogenic effects have not been reported. In humans, the FDA categorizes this drug as category C for use during pregnancy in the ﬁrst trimester (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In humans, the FDA categorizes this drug as category D for use during pregnancy in second and third trimesters (There is evidence of human fetal risk, but the potential beneﬁts from the use of the drug in preg-nant women may be acceptable despite its potential risks. ) Enalapril/enalaprilat is excreted into milk. Safe use during nurs-ing cannot be assumed. Overdosage/Acute Toxicity In dogs, a dose of 200 mg/kg was lethal, but 100 mg/kg was not. In overdose situations, the primary concern is hypotension; sup-portive treatment with volume expansion with normal saline is rec-ommended to correct blood pressure. Because of the drug's long duration of action, prolonged monitoring and treatment may be required. Recent overdoses should be managed by using gut empty-ing protocols when warranted. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving enalaprilat and may be of signiﬁcance in veterinary patients: !TANTIDIABETIC AGENTS (insulin, oral agents ): Possible increased risk for hypoglycemia; enhanced monitoring recommended !TDIURETICS (e. g., furosemide, hydrochlorothiazide ): Potential for in-creased hypotensive effects; some veterinary clinicians recom-mend reducing furosemide doses (by 25-50%) when adding enalapril or benazepril to therapy in CHF. !TDIURETICS, POTASSIUM-SPA RING (e. g., spironolactone, triamterene ): Increased hyperkalemic effects, enhanced monitoring of serum potassium recommended !THYPOTENSIVE AGENTS, OTHER : Potential for increased hypotensive effect !TLITHIUM : Increased serum lithium levels possible; increased moni-toring required !TNSAIDS : May reduce the anti-hypertensive or positive hemody-namic effects of enalapril; may increase risk for reduced renal function !TPOTASSIUM SUPPLEMENTS : Increased risk for hyperkalemia Laboratory Considerations 123/I134!TWhen using iodohippurate sodium I or T echnetium Tc99 pententate renal imaging in patients with renal artery stenosis, ACE inhibitors may cause a reversible decrease in localization and excretion of these agents in the affected kidney which may lead to confusion in test interpretation. Doses !TDOGS: a) As a vasodilator in heart failure: 0. 5 mg/kg PO twice daily (Kittleson 2000) b) For adjunctive treatment of heart failure: 0. 5 mg/kg once daily initially with or without food. If response is inadequate increase to 0. 5 mg/kg twice daily (Package Insert; Enacard®— Merial) For adjunctive treatment of glomerular disease: a) For adjunctive treatment of glomerular disease: 0. 5 mg/kg PO q12-24h (Grauer and Di Bartola 2000)	pppbs.pdf
340 ENOXAPARIN SODIUM b) For adjunctive treatment of glomerular disease/proteinuria: 0. 5 mg/kg PO once daily. If no reduction in proteinuria after 2-4 weeks, increase to twice daily. (Vaden 2003) As an adjunctive treatment for ureteroliths: a) 0. 25-0. 5 mg/kg PO q12-24h; may potentially reduce inter-stitial expansion and ﬁbrosis. (Lulich 2006) T ! CATS: As a vasodilator in heart failure: a) Initially, 0. 25 mg/kg q12-24h (De Lellis and Kittleson 1992) b) 0. 25-0. 5 mg/kg (roughly 1. 25-2. 5 mg per cat) PO once a day (q24h) (Meurs 2006d) c) 0. 5 mg/kg PO once daily, twice daily if necessary (Ware and Keene 2000) For proteinuria, hypertension in chronic kidney disease: a) 0. 25 mg/kg PO once daily to 0. 5 mg/kg PO twice daily; rarely higher (Polzin 2006) T ! FERRETS: For adjunctive therapy for heart failure: a) 0. 5 mg/kg PO once every other day (q48h) initially and may be increased to once a day if tolerated. Dissolve tablet(s) in distilled water and add a methylcellulose suspending agent (e. g., Ora-Plus®) and cherry syrup for ﬂavor. (Hoeffer 2000) b) For dilative cardiomyopathy: 0. 25-0. 5 mg/kg PO once a day to every other day (Williams 2000) T ! BIRDS: For adjunctive therapy for heart failure: a) 1. 25 mg/kg PO two to three times daily (Pees, Kuhring et al. 2006) 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 clinical signs associ-ated with hypotension arise) Client Information T ! May be given with or without food T ! Do not abruptly stop or reduce therapy without veterinarian's approval T ! Contact veterinarian if vomiting or diarrhea persist or are severe or if animal's condition deteriorates Chemistry/Synonyms Angiotensin-converting enzyme (ACE) inhibitors, enalapril maleate and enalaprilat are structurally related to captopril. Enalapril is a prodrug and is converted in vivo by the liver to enalaprilat. Enalapril maleate occurs as a white to off white crystalline powder. 25 mg are soluble in one m L of water. Enalaprilat occurs as a white to off white crystalline powder and is slightly soluble in water. Enalapril maleate may also be known as: enalaprili maleas, and MK-421; many trade names are available. Enalaprilat may also be known as: enalaprilic acid, MK-422, Enacard®, Glioten®, Lotrial®, Pres®, Renitec®, Reniten®, Vasotec®, and Xanef®. Storage/Stability/Compatibility The commercially available tablets should be stored at temperatures less than 30°C in tight containers. When stored properly, the tablets have an expiration date of 30 months after manufacture. Enalaprilat injection should be stored at temperatures less than 30°C. After dilution with D 5W, normal saline, or D 5 in lac-tated Ringer's it is stable for up to 24 hours at room temperature. Enalaprilat has been documented to be physically incompatible with amphotericin B or phenytoin sodium. Many other medications have been noted to be compatible with enalaprilat at various con-centrations. 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: Enalapril Maleate Tablets: 1 mg, 2. 5 mg, 5 mg, 10 mg, & 20 mg; Enacard® (Merial); (Rx). Approved for use in dogs. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Enalapril Maleate Tablets: 2. 5 mg, 5 mg, 10 mg & 20 mg; Vasotec® (Biovail); generic (Rx). Enalaprilat Injection: (for IV use) equivalent to 1. 25 mg/m L in 1 m L and 2 m L vials; generic; (Rx) ENOXAPARIN SODIUM (en-ocks-a-par-in) Lovenox® ANTIC OAG ULANT Prescriber Highlights TT Low molecular weight (fractionated) heparin that may be useful for treatment or prophylaxis of thromboembolic disease TT Preferentially inhibits factor Xa & only minimally impacts thrombin & clotting time (TT or a PTT) TT Hemorrhage unlikely, but possible TT Must be given subcutaneously, potentially every 6 hours TT Expense may be an issue, particularly in large dogs or horses Uses/Indications Enoxaparin may be useful for prophylaxis or treatment of deep vein thrombosis or pulmonary embolus. Recent pharmacokinetic work in dogs and cats, raises questions whether the drug can be effec-tively and practically administered long-term. In humans, it is also indicated for prevention of ischemic complications associated with unstable angina/non Q-wave MI. Pharmacology/Actions By binding to and accelerating antithrombin III, low molecular weight heparins (LMWHs) enhance the inhibition of factor Xa and thrombin. The potential advantage to using these products over standard (unfractionated) heparin is that they preferentially inhibit factor Xa; only minimally impacting thrombin and clotting times (TT or a PTT). Pharmacokinetics In dogs after SC administration, enoxaparin has a shorter duration of anti-Xa activity than in humans and probably must be dosed more frequently. Cats appear to have a much shorter duration of activity (anti-Xa) associated with LMWHs than do humans and to maintain a thera-peutic target of anti-XA activity of 0. 5-1 IU/m L requires 1. 5 mg/kg SC q6h dosing of enoxaparin. (Alwood, Downend et al. 2007)	pppbs.pdf
ENOXAPARIN SODIUM 341 After subcutaneous injection in humans, enoxaparin is absorbed rapidly, with a bioavailability of about 92%; peak plasma levels (ac-tivity) occur in 3-5 hours. Anti-factor Xa activity persists for up to 24 hours; doses are usually given once to twice a day. Enoxaparin is metabolized in the liver and excreted in the urine as both un-changed drug and metabolites; elimination half-life is about 4-5 hours. Contraindications/Precautions/Warnings Enoxaparin is contraindicated in patients who are hypersensitive to it, other LMWHs, heparin, or porcine products. Use enoxaparin cautiously in patients with signiﬁcant renal dysfunction as drug ac-cumulation could result. Do not administer via IM or IV routes; enoxaparin must be given via deep subcutaneous injection only. Enoxaparin cannot be used interchangeably with other LMWHs or heparin sodium be-cause the dosages differ for each. Adverse Effects In humans, adverse effects do not routinely occur; hemorrhage is a possibility and has been reported in up to 13% of patients in one study. Injection site hematoma, anemia, thrombocytopenia, nau-sea, and fever have also been reported. Reproductive/Nursing Safety In humans, enoxaparin is designated by the FDA as a category B drug (Animal studies have not 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 during the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Overdosage/Acute Toxicity Overdosage may lead to hemorrhagic complications. If treatment is necessary, protamine sulfate may be administered via slow IV. One mg of protamine sulfate can inhibit the effects of one mg of enoxaparin. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving enoxaparin and may be of signiﬁcance in veterinary patients: !TANTICOAGULANTS, ORAL (warfarin ): Increased risk for hemorrhage !TPLATELET-AGGREGATION INHIBITORS (aspirin, clopidogrel ): Increased risk for hemorrhage !TTHROMBOLYTIC AGENTS : Increased risk for hemorrhage Laboratory Considerations !TLow molecular weight heparins may cause asymptomatic, fully reversible increases in AST or ALT; bilirubin is only rarely in-creased in these patients. Therefore, interpret these tests with caution; increases do not necessarily indicate hepatic damage or dysfunction. Doses !TDOGS: a) 0. 8 mg/kg SC q6h appears to effectively and consistently maintain therapeutic levels of anti-Xa in normal dogs. (Lunsford, Mackin et al. 2005) !TCATS: a) Cats appear to have a much shorter duration of activity (an-ti-Xa) associated with LMWHs than do humans; to main-tain a therapeutic target of anti-XA activity of 0. 5-1 IU/m L requires 1. 5 mg/kg SC q6h dosing of enoxaparin. (Alwood, Downend et al. 2007) b) For cardiogenic embolism: Current recommended protocols are 1-1. 5 mg/kg SC q12-24h. (Hogan 2006) !THORSES: a) No published dosage recommendation at the time of writ-ing. A study (Schwarzwald, Feige et al. 2002) investigating the pharmacokinetic variables of enoxaparin in horses demon-strated that the drug has similar activity (effect, duration) as in humans and the once daily SC injections may be useful for anticoagulant therapy. Monitoring !TCBC (with platelet count); baseline and ongoing during therapy !TUrinalysis !TStool occult blood test !TRoutine coagulation tests (a PTT, PT) are usually insensitive mea-sures of activity and usually not warranted !TFactor Xa activity (available at Cornell Coagulation Laboratory) may be useful, particularly if bleeding occurs or patient has renal dysfunction Client Information !TIf this drug is to be used on an outpatient basis, clients must be instructed in proper injection technique for subcutaneous injec-tion. If not using the pre-ﬁlled syringes, use a very small gauge insulin or tuberculin syringe and needle (e. g., 27 g). !TClients should immediately report any signs associated with bleeding or pulmonary thrombosis. !TClients should understand that if they do not use the drug regu-larly (as prescribed), clots may form. Chemistry/Synonyms A low molecular weight heparin (LMWH), enoxaparin sodium is obtained by alkaline depolymerization of heparin derived from pork intestinal mucosa. The average molecular weight is about 4500 and ranges from 3500-5500 (heparin sodium has a molecu-lar weight around 12000). 1 mg of enoxaparin is equivalent to 100 units of anti-factor Xa. Enoxaparin sodium may also be known as: Enoxaparinum natricum, PK-10169, RP-54563, Clexane®, Decipar®, Klexane®, Lovenox®, Plaucina®, and Trombenox®. Storage/Stability/Compatibility The commercially available injection should be stored at room temperature (25°C, 77°F); excursions permitted to 15-30°C (59-86°F). One study showed that diluting 100 mg/m L commercially avail-able solution with sterile water to 20 mg/m L was stable for 4 weeks when stored in a glass vial or in plastic syringes at room tempera-ture or refrigerated. (Dager, Gosselin et al. 2004) Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Enoxaparin Sodium for Injection: 30 mg/0. 3 m L, 40 mg/0. 4 m L, 60 mg/0. 6 m L, 80 mg/0. 8 m L, 100 mg/1 m L, 120 mg/0. 8 m L, & 150 mg/1 m L preservative free in amps, single-dose preﬁlled syringes; 300 mg/3 m L containing 15 mg/m L benzyl alcohol in 3 m L multidose vials; Lovenox® (Aventis); (Rx)	pppbs.pdf
342 ENROFLOXACIN ENROFLOXACIN (en-roe-ﬂox-a-sin) Baytril® FLUORO QUINOLONE ANTIBIOTIC Prescriber Highlights TT Veterinary oral & injectable ﬂuoroquinolone antibiotic effective against a variety of pathogens; not effective against anaerobes TT In dogs, oral bioavailability is better than ciproﬂoxacin TT Contraindications: Hypersensitivity; relatively contra-indicated for young, growing animals due to cartilage abnormalities TT FDA prohibits extra-label use in food animals TT Caution: Hepatic or renal insufﬁciency, dehydration TT Higher doses (>5 mg/kg/day) not recommended in cats; may cause blindness TT Adverse Effects: GI distress, CNS stimulation, crystalluria, or hypersensitivity; IV administration can potentially be very risky in small animals TT Administer PO (to dogs/cats) preferably on an empty stomach (unless vomiting occurs) TT Drug interactions TT Should not be used in humans (CNS effects) Uses/Indications Enroﬂoxacin is approved for use in dogs and cats (oral only) for the management of diseases associated with bacteria susceptible to enroﬂoxacin. Because of the dosage restriction (5 mg/kg) for cats, enroﬂoxacin is generally used in this species only for the most sus-ceptible bacterial infections. It is also been approved for use in cattle (not dairy cattle or veal calves). Pharmacology/Actions Enroﬂoxacin is a bactericidal agent. The bactericidal activity of en-roﬂoxacin is concentration dependent, with susceptible bacteria cell death occurring within 20-30 minutes of exposure. Enroﬂoxacin has demonstrated a signiﬁcant post-antibiotic effect for both gram-negative and-positive bacteria and is active in both stationary and growth phases of bacterial replication. Its mechanism of action 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 activity. These agents have good activity against many gram-negative bacilli and cocci, including most species and strains of Pseudomonas 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 Brucella 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 these infec-tions. These drugs have weak activity against most anaerobes and are ineffective in treating anaerobic infections. Bacterial resistance development is an ongoing concern, as many isolates of Pseudomonas aeruginosa are now resistant to enroﬂoxa-cin. Resistance occurs by mutation, particularly with Pseudomonas aeruginosa, Klebsiella pneumonia, Acinetobacter and enterococci, but plasmid-mediated resistance is not thought to occur. Pharmacokinetics Enroﬂoxacin is well absorbed after oral administration in most spe-cies. In dogs, enroﬂoxacin's bioavailability (approximately 80%) is about twice that of ciproﬂoxacin after oral dosing. 50% of Cmax is reportedly attained within 15 minutes of dosing and peak levels (Cmax) occur within one hour of dosing. The presence of food in the stomach may delay the rate, but not the extent of absorption. In sheep, enroﬂoxacin administered orally is about 65-75% bioavail-able. Enroﬂoxacin is distributed throughout the body. Volume of dis-tribution in dogs is approximately 3-4 L/kg. Only about 27% is bound to canine plasma proteins. Highest concentrations are found in the bile, kidney, liver, lungs, and reproductive system (including prostatic ﬂuid and tissue). Enroﬂoxacin reportedly concentrates in macrophages. Therapeutic levels are also attained in bone, synovial ﬂuid, skin, muscle, aqueous humor and pleural ﬂuid. Low con-centrations are found in the CSF; levels may only reach 6-10% of those found in the serum. In cattle, the volume of distribution is about 1. 5 L/kg and in sheep, 0. 4 L/kg. Enroﬂoxacin is eliminated via both renal and non-renal mecha-nisms. Approximately 15-50% of the drug is eliminated unchanged into the urine, by both tubular secretion and glomerular ﬁltration. Enroﬂoxacin is metabolized to various metabolites, most of which are less active than the parent compounds. Approximately 10-40% of circulating enroﬂoxacin is metabolized to ciproﬂoxacin in most species including humans, dogs, cats, adult horses, cattle, turtles, and snakes. Foals, pigs, and some lizards apparently do not convert much enroﬂoxacin, if any, to ciproﬂoxacin. These metabolites are eliminated both in the urine and feces. Because of the dual (renal and hepatic) means of elimination, patients with severely impaired renal function may have slightly prolonged half-lives and higher serum levels that may not require dosage adjustment. The approxi-mate elimination half-lives in various species are: dogs 4-5 hours; cats 6 hours; sheep 1. 5-4. 5 hours; horses 5-6 hours, turtles 18 hours; and alligators 55 hours. Contraindications/Precautions/Warnings Enroﬂoxacin is labeled as contraindicated in small and medium breed dogs from 2 to 8 months of age. Bubble-like changes in ar-ticular 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 before treatment since they may be in the rapid-growth phase past 8 months of age. Quinolones are contraindicated in pa-tients hypersensitive to them. Because ciproﬂoxacin has occasionally been reported to cause crystalluria in humans, animals should not be allowed to become dehydrated during therapy with either ciproﬂoxacin or enroﬂoxa-cin. Enroﬂoxacin may cause CNS stimulation and should be used with caution in patients with seizure disorders. Patients with severe renal or hepatic impairment may require dosage adjustments to prevent drug accumulation. Use of the canine or bovine injectable products in cats or ad-ministered to dogs via other non-approved parenteral routes (IV, SC) is controversial and may result in signiﬁcant adverse effects. Parenteral administration in cats at doses less than 5 mg/kg have reportedly caused ophthalmic toxicity (blindness). Because of the	pppbs.pdf
ENROFLOXACIN 343 high p H (approx. 11) of the solution, subcutaneous administration in any species may cause pain and tissue damage. If administered rapidly or undiluted IV to dogs, there is an increased risk for car-diac arrhythmias, hypotension, vomiting, and mast cell degranula-tion (histamine and other mediator release). The extra-label use in dogs of the IM 22. 7 mg/m L (2. 27%) product diluted 1:1 to 1:10 with sodium chloride 0. 9% for slow IV administration (over at least 10 minutes; some give over 30-45 minutes) has anecdotally been described. However, the rapid ab-sorption of enroﬂoxacin after IM administration in dogs (peak levels in about 30 minutes) questions the necessity of using this non-approved route (IV) of administration. Injectable enroﬂoxa-cin must not be mixed with, or come into contact with any IV so-lution containing magnesium (e. g., Normosol-R, Plasmalyte-R,-A, or-56); morbidity and mortality secondary to micro-precipitants lodging in patient lungs have been reported. Dilution and extra-label use in small animals of the large animal product (100 mg/m L; 10%) via any route is discouraged. Enroﬂoxacin should not be used by humans; it may cause hal-lucinations, vivid dreams, and headache. Adverse Effects With the exception of potential cartilage abnormalities in young animals (see Contraindications above), the adverse effect proﬁle of enroﬂoxacin is usually limited to GI distress (vomiting, anorexia). In dogs, rare incidences of elevated hepatic enzymes, ataxia, seizures, depression, lethargy, and nervousness have also been reported. Hypersensitivity reactions or crystalluria could potentially occur. In cats, rare incidences of ocular toxicity have been reported characterized by mydriasis, retinal degeneration, and blindness. These effects were generally seen at higher dosage ranges (>15 mg/ kg) and have necessitated a reduction in dosage recommendations in cats to a maximum of 5 mg/kg/day. Other rare adverse effects seen in cats may include: vomiting, anorexia, elevated hepatic en-zymes, diarrhea, ataxia, seizures, depression/lethargy, vocalization, and aggression. Reproductive/Nursing Safety The safety of enroﬂoxacin in pregnant dogs has been investigated. Breeding, pregnant, and lactating dogs receiving up to 15 mg/kg day demonstrated no treatment related effects. However, because of the risks of cartilage abnormalities in young animals, the ﬂuoroqui-nolones are not generally recommended for use during pregnancy unless the beneﬁts of therapy clearly outweigh the risks. Limited studies in male dogs at various dosages have indicated no effects on male breeding performance. Safety in breeding, pregnant, or lactating cats has not been established. Overdosage/Acute Toxicity It is unlikely an acute overdose in dogs with enroﬂoxacin would result in clinical signs more serious than either anorexia or vomit-ing, but the adverse effects noted above could occur. Dogs receiving 10X the labeled dosage rate of enroﬂoxacin for at least 14 days de-veloped only vomiting and anorexia. Death occurred in some dogs when fed 25 times the labeled rate for 11 days, however. In cats overdoses can be serious (blindness, seizures). There were 306 exposures to enroﬂoxacin reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) during 2005-2006. In these cases 277 were dogs with 31 show-ing clinical signs and the remaining 43 cases were cats with 4 show-ing clinical signs. Common ﬁndings in dogs recorded in decreasing frequency included vomiting, diarrhea, seizures, ataxia and fascicu-lation. Findings in cats recorded in decreasing frequency included seizures, vomiting and blindness. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ciproﬂoxacin or enro-ﬂoxacin and may be of signiﬁcance in veterinary patients: Al+++!TANTACIDS/DAIRY PRODUCTS : Containing cations (Mg++,, Ca++) may bind to enroﬂoxacin and prevent its absorption; sepa-rate doses of these products by at least 2 hours !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/cip-roﬂoxacin has minimal activity against anaerobes, in vitro syn-ergy has been reported when used with clindamycin against strains of Peptostreptococcus, Lactobacillus and Bacteroides fragilis. !TCYCLOSPORINE : Fluoroquinolones may exacerbate the nephro-toxicity and reduce the metabolism of cyclosporine (used systemically) !TFLUNIXIN : Has been shown in dogs to increase the AUC and elimi-nation half-life of enroﬂoxacin and enroﬂoxacin increases the AUC and elimination half-life of ﬂunixin; it is unknown if other NSAIDs interact with enroﬂoxacin in dogs !TGLYBURIDE : Severe hypoglycemia possible !TIRON, ZINC (oral): Decreased enroﬂoxacin/ciproﬂoxacin absorp-tion; separate doses by at least two hours !TMETHOTREXATE : Increased MTX levels possible with resultant toxicity !TNITROFUR ANTOIN : May antagonize the antimicrobial activity of the ﬂuoroquinolones and their concomitant use is not recommended !TPHENYTOIN : Enroﬂoxacin/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 enroﬂoxacin; separate doses of these drugs by at least 2 hours !TTHEOPHYLLINE : Enroﬂoxacin/ciproﬂoxacin may increase theophyl-line blood levels !TWARFARIN : Potential for increased warfarin effects Laboratory Considerations !TEnroﬂoxacin 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 enroﬂoxacin !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) 5-20 mg/kg per day PO, may be given once daily or divided and given twice daily (q12h). Treatment should continue for at least 2-3 days beyond cessation of clinical signs, to a maximum duration of therapy is 30 days. (Package insert; Baytril®—Bayer) b) For sepsis: 5-20 mg/kg IV q12h (Hardie 2000) c) For skin, urinary infections: 2. 5-5 mg/kg PO q12h for 7-14 days;	pppbs.pdf
344 ENROFLOXACIN For deep pyodermas, complicated urinary infections: 5 mg/ kg PO once daily (q24h) for 7-14 days (treatment may be required for 10-12 weeks for deep pyoderma, especially in German shepherds); For lower respiratory tract infections: 5-10 mg/kg PO once daily (q24h) for 7-84 days; For prostate infections: 5 mg/kg PO twice daily (q12h) for 7-14 days; For histiocytic ulcerative colitis: 5 mg/kg PO twice daily (q12h) for 21-90 days; For hemotropic mycoplasmosis: 5 mg/kg PO, IM q12h for 7-14 days; For systemic orthopedic infections: 5-11 mg/kg PO, IV, IM, SC q12h for 10 days; For Pseudomonas infections in soft tissues: 11-20 mg/kg PO, IM, SC q12h for 7 days minimum, treat as long as necessary; For bacteremia, sepsis: 11 mg/kg PO, IV, IM, SC q12h for as long as necessary. (Greene, Hartmannn et al. 2006) !TCATS: For susceptible infections: a) 5 mg/kg per day PO, may be given once daily or divided and given twice daily (q12h). Treatment should continue for at least 2-3 days beyond cessation of clinical signs, to a maximum duration of therapy is 30 days. (Package insert; Baytril®—Bayer) !THORSES: Note : Usage of enroﬂoxacin in horses remains somewhat con-troversial. While there has been much discussion regarding the potential for cartilage abnormalities or other arthropathies in horses, objective data are lacking. At present, however, enroﬂox-acin probably should only be used in adult horses when other antibiotics are inappropriate. If using Baytril® injection orally in horses, it can be very irritating to the mouth. This may be alleviated by coating the liquid with molasses or preparing a gel (below) and rinsing the horse's mouth with water after admin-istration. An oral gel formulated from the bovine injectable product has been described (Epstein, Cohen et al. 2004). 100 m L of the 100 mg/m L bovine injection (Baytril ®100) is used. Stevia (0. 35 g) is mixed with approximately 15 m L of liquid enroﬂoxacin until dis-solved. Apple ﬂavoring 0. 6 m L is added until dissolved. Sodium carboxymethylcellulose (2 g) is sprinkled over the mixture and stirred until incorporated. Immediately begin gradually adding the remaining enroﬂoxacin (85 m L) before the mixture solidi-ﬁes. Approximate concentration is 100 mg/m L. Stable for up to 84 days if kept in the refrigerator and protected from light. a) 7. 5 mg/kg PO or IV once daily for susceptible respiratory in-fections (Ainsworth and Hackett 2004) b) Using the compounded gel as described above. 7. 5 mg/kg PO once daily. Horses should be fasted for 11-14 hours prior to dosing and for 1-2 hours after dosing, but should have ac-cess to water. Rinse horse's mouth with water after dosing to reduce risks for oral ulceration. (Epstein, Cohen et al. 2004) !TCATTLE: a) Enroﬂoxacin (Baytril® 100) is approved for the treatment of bovine respiratory disease associated with Pasteurella hae-molytica, Pasteurella multocida, and Haemophilus sommus. It is administered by injection and is intended for the treat-ment of individual animals. The labeled dosage is: 2. 5-5 mg/ kg SC once daily for 3-5 days or 7. 5-12. 5 mg/kg SC once. The product is prescription only and is not for use in cattle intended for dairy production or in veal calves. Animals in-tended for human consumption must not be slaughtered within 28 days from the last treatment. Extralabel use of ﬂuo-roquinolones in food animals is prohibited by the FDA. !TFERRETS: For susceptible infections: a) 10-20 mg/kg PO, IM, SC twice daily (Williams 2000) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: 5 mg/kg PO, SC, IM or IV q12h for 14 days. Drug of choice for Pasteurella. If giving SC, dilute or skin may slough. Do not give injectable product PO because it is very unpalatable (Ivey and Morrisey 2000) b) Hedgehogs: 5-10 mg/kg PO or SC q12h (Smith 2000) c) Chinchillas: 5-10 mg/kg PO, IM q12h (Hayes 2000) d) For mycoplasmal pneumonia in mice and rats: 10 mg/kg PO twice daily with doxycycline (5 mg/kg PO twice daily) (Burke 1999) e) Chinchillas, Gerbils, Guinea Pigs, Hamsters, Mice, Rats: 5-10 mg/kg PO or IM q12h or 5-20 mg/kg PO or SC q24h. In drinking water: 50-200 mg/liter for 14 days. Do not use in young animals. (Adamcak and Otten 2000) !TCAMELIDS: For susceptible infections in alpacas: a) 5 mg/kg SC or 10 mg/kg PO once daily (Gandolf, Papich et al. 2005) !TBIRDS: For susceptible gram-negative infections: a) Ratites: 1. 5-2. 5 mg/kg PO or SC twice daily. Drinking wa-ter: 10% solution, 10 mg/kg for 3 days; 5 mg/kg IM (IM in-jections cause severe muscle necrosis) twice daily for 2 days (Jenson 1998) b) 15 mg/kg PO, or IM or 250 mg/L of drinking water (Bauck and Hoefer 1993) A method to make a 10. 2 mg/m L oral suspension of enroﬂoxacin has been described: Make a stock solution of “HMC 0. 15%” by mixing 7. 5 m L of Lubrivet® with 92. 5 m L of water. Crush three (3) whole 68 mg tablets with a “pinch” of citric acid. Add crushed mixture to a dispensing vial and 15 m L of “HMC 0. 15%. ” Shake well to dissolve tablet coating; add a sufﬁcient quantity of “HMC 0. 15%” to a total of 20 m L and allow to stand at room tempera-ture for 30 minutes to allow tablet coating to completely dissolve. Shake well before use and keep refrigerated. A 14-day expiration date has been assigned. By crushing six (6) tablets, a 20. 4 mg/m L suspension may be compounded using the same technique. !TREPTILES: For susceptible respiratory infections for most species: a) 5 mg/kg IM every 5 days for 25 days; For chronic respiratory infections in tortoises: 15 mg/kg IM every 72 hours for 5-7 treatments (Gauvin 1993) Monitoring !TClinical efﬁcacy !TAdverse effects !TIn cats, monitor for mydriasis and/or retinal changes. Client Information !TDo not crush ﬁlm-coated tablets, as drug is very bitter tasting !TAnimals should have access to water at all times !TDo not exceed dosage recommendations in cats; blindness can occur	pppbs.pdf
EPHEDRINE SULFATE 345 Chemistry/Synonyms A ﬂuoroquinolone antibiotic, enroﬂoxacin occurs as a pale yellow, crystalline powder. It is slightly soluble in water. Enroﬂoxacin is re-lated structurally to the human-approved drug ciproﬂoxacin (enro-ﬂoxacin has an additional ethyl group on the piperazinyl ring) Enroﬂoxacin may also be known as: Bay-Vp-2674 or Baytril®. Storage/Stability/Compatibility Unless otherwise directed by the manufacturer, enroﬂoxacin tablets should be stored in tight containers at temperatures less than 30°C. Protect from strong UV light. Enroﬂoxacin has been reported to be soluble and stable in water, but solubility is p H dependent and altering the p H of the commercially available injections can cause precipitation. The canine-approved product (2. 27%) for IM injection should be stored protected from light; do not freeze. The cattle-approved product (10%) injectable solution should be stored protected from sunlight. It should not be refrigerated, frozen or stored above 40°C (104°F). If exposed to cold tempera-tures, precipitation may occur; to redissolve, warm and then shake the vial. Injectable enroﬂoxacin must not be mixed with, or come into contact with any IV solution containing magnesium (e. g., Normosol-R, Plasmalyte-R,-A, or-56); morbidity and mortality secondary to micro-precipitants lodging in patient lungs have been reported. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Enroﬂoxacin Tablets (Film-Coated) & Oral Taste Tablets: 22. 7 mg, 68 mg, 136 mg; Baytril® (Bayer Corp); (Rx). Approved for use in dogs and cats. Enroﬂoxacin Injection: 22. 7 mg/m L (2. 27%) in 20 m L vials; Baytril® (Bayer Corp); (Rx). Approved for use in dogs. Enroﬂoxacin Injection: 100 mg/m L in 100 m L and 250 m L bottles. Approved for use in cattle only. Not for use in cattle intended for dairy production or in calves to be processed for veal. Any extra-label use in food animals is banned by the FDA. Slaughter Withdrawal = 28 days when used as labeled. A withdrawal period has not been estab-lished in pre-ruminating calves. Baytril 100® (Bayer); (Rx) HUMAN-LABELED PRODUCTS: None. Note : Use of enroﬂoxacin by humans cannot be recommended due to a high degree of CNS effects. EPHEDRINE SULFATE (e-fed-rin) SYMPAT HOMIMETIC BRONCHODILATOR/ V ASOPRESSOR Prescriber Highlights TT Sympathomimetic used primarily for oral treatment of urinary incontinence & topically for nasal uses TT Contraindications: Severe CV disease, especially with ar-rhythmias TT Caution: Patients with glaucoma, prostatic hypertrophy, hyperthyroidism, diabetes mellitus, cardiovascular disor-ders or hypertension TT Adverse Effects: CNS stimulation, tachycardia, hyperten-sion, or anorexia TT Excreted into milk, may affect neonates Uses/Indications Ephedrine is used chieﬂy for the treatment of urethral sphincter hypotonus and resulting incontinence in dogs and cats. It has also been used in an attempt to treat nasal congestion and/or broncho-constriction in small animals. It can also be used parenterally as a pressor agent in the treatment of shock or anesthesia-associated hypotension. Pharmacology/Actions While the exact mechanism of ephedrine's actions are undeter-mined, it is believed that it indirectly stimulates both alpha-, beta 1-, beta2-adrenergic receptors by causing the release of norepineph-rine. Prolonged use or excessive dosing frequency can deplete nor-epinephrine from its storage sites and tachyphylaxis (decreased re-sponse) may ensue. Tachyphylaxis has not been docu mented in dogs or cats, however, when used for urethral sphincter hypotonus. Pharmacologic effects of ephedrine include: increased vasocon-striction, heart rate, coronary blood ﬂow, blood pressure, mild CNS stimulation, and decreased bronchoconstriction, nasal congestion and appetite. Ephedrine can also increase urethral sphincter tone and produce closure of the bladder neck; its principle veterinary indications are as a result of these effects. Pharmacokinetics Ephedrine is rapidly absorbed after oral or parenteral administra-tion. Although not conﬁrmed, ephedrine is thought to cross both the blood-brain barrier and the placenta. Ephedrine is metabolized in the liver and excreted unchanged in the urine. Urine p H may signiﬁcantly alter excretion characteristics. In humans: at urine p H of 5, half-life is about 3 hours; at urine p H of 6. 3, half-life is about 6 hours. Contraindications/Precautions/Warnings Ephedrine is contraindicated in patients with severe cardiovascular disease, particularly with arrhythmias. Ephedrine should be used with caution in patients with glaucoma, prostatic hypertrophy, hy-perthyroidism, diabetes mellitus, cardiovascular disorders or hy-pertension. When administered IV, administration rate should not exceed 10 mg/minute (in humans); it is suggested to scale the rate for vet-erinary patients. Adverse Effects	pppbs.pdf
346 EPHEDRINE SULFATE Most likely side effects include restlessness, irritability, tachycardia, or hypertension. Anorexia may be a problem in some animals. Reproductive/Nursing Safety Ephedrine's effects on fertility, pregnancy or fetal safety are not known. Use with caution during pregnancy. The drug is excreted in milk and may have deleterious effects on nursing 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. ) Ephedrine is excreted in milk. If ephedrine is absolutely neces-sary for the dam, consider using milk replacer. Overdosage/Acute Toxicity Clinical signs of overdosage may consist of an exacerbation of the adverse effects listed above or, if a very large overdose, severe car-diovascular (hypertension to rebound hypotension, bradycardias to tachycardias, and cardiovascular collapse) or CNS effects (stimula-tion to coma) can be seen. If the overdose was recent, empty the stomach using the usual precautions and administer charcoal and a cathartic. Treat clinical signs supportively as they occur. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ephedrine and may be of signiﬁcance in veterinary patients: !TALPHA-BLOCKERS (e. g., phentolamine, prazosin ): May negate the therapeutic effects of ephedrine !TANESTHETICS, GENERAL : An increased risk of arrhythmias develop-ing can occur if ephedrine is administered to patients who have received cyclopropane or a halogenated hydrocarbon anesthetic agent. Propranolol may be administered should these occur. !TBETA-BLOCKERS : Concomitant use of ephedrine with beta-block-ers may diminish the effects of both drugs !TDIGOXIN : An increased risk of arrhythmias may occur if ephedrine is used concurrently with digitalis glycosides. !TMONAMINE OXIDASE INHIBITORS (including amitraz ): Ephedrine should not be given within two weeks of a patient receiving monoamine oxidase inhibitors; severe hypertension, hyperpy-rexia possible !TSYMPATHOMIMETIC AGENTS, OTHER : Ephedrine should not be ad-ministered with other sympathomimetic agents (e. g., phenylpropa-nolamine ) as increased toxicity may result !TRESERPINE : May reverse the pressor effects of ephedrine !TTHEOPHYLLINE : Ephedrine may increase the risk for theophylline toxicity !TTRICYCLIC ANTIDEPRESSANTS : May decrease the pressor effects of ephedrine !TURINARY ALKALINIZERS (e. g., sodium bicarbonate, citrates, carbonic anhydrase inhibitors ): May reduce the urinary excretion of ephed-rine and prolong its duration of activity. Dosage adjustments may be required to avoid toxic clinical signs. Laboratory Considerations !TBeta-adrenergic agonists may decrease serum potassium concen-trations. Clinical relevance is unknown. Doses !TDOGS: For treatment of bronchospasm: a) For maintenance therapy: 1-2 mg/kg PO q8-12h (Mc Kier-nan 1992) b) 2 mg/kg PO q8-12h (Bonagura 1994) For treatment of urinary incontinence responsive to adrenergic drugs: a) 5-15 mg (total dose) PO q8h (Labato 1994) b) 1. 2 mg/kg PO q8h or 5-15 mg (total dose) PO q8h (Bartges 2003a) For treatment of hypotension associated with anesthesia: a) 0. 03-0. 1 mg/kg IV bolus. Dilute 5 mg in 10 m L of saline and give the lower dosage ﬁrst as sinus tachycardia may accom-pany the higher dose. May repeat in 5 minutes after ﬁrst dose if hypotension does not improve. (Pablo 2003a) b) 0. 1-0. 25 mg/kg IV bolus (Mazzaferro 2005) c) 0. 1 mg/kg IV; short (5-15 min) duration of action (Dodam 2005) !TCATS: For treatment of bronchospasm: a) For emergency treatment 2-5 mg PO (Mc Kiernan 1992) For treatment of urinary incontinence responsive to adrenergic drugs: a) 2-4 mg (total dose) PO q8h (Labato 1994) b) 2-4 mg/kg PO q6-12h or 2-4 mg (total dose) PO q8h (Bar-tges 2003a) c) 2-4 mg per cat PO q8-12h (Polzin 2005c) Monitoring !TClinical effectiveness !TAdverse effects (see above) Client Information !TIn order for this drug to be effective, it must be administered as directed by the veterinarian; missed doses will negate its effect. It may take several days for the full beneﬁt of the drug to take place. !TContact veterinarian if the animal demonstrates ongoing changes in behavior (restlessness, irritability) or if incontinence persists or increases. Chemistry/Synonyms A sympathomimetic alkaloid, ephedrine sulfate occurs as ﬁne, odorless, white crystals or powder. Approximately 770 mg are sol-uble in one m L of water. The commercially available injection has a p H of 4. 5-7. Ephedrine sulfate may also be known as ephedrine sulphate. Storage/Stability/Compatibility Store ephedrine sulfate products in tight, light resistant containers at room temperature unless otherwise directed. When used parenterally, ephedrine sulfate is usually adminis-tered directly and not diluted. 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.	pppbs.pdf
EPINEPHRINE 347 HUMAN-LABELED PRODUCTS: Ephedrine Sulfate Capsules: 25 mg; generic (West-Ward); (OTC) Ephedrine Sulfate Injection: 50 mg/m L in 1 m L vials & preservative free in 1 m L amps; generic; (Rx) In the USA, ephedrine sulfate is classiﬁed as a list 1 chemical (drugs that can be used as precursors to manufacture methamphetamine) and in some states it may be a controlled substance or have other restrictions placed upon its sale. Be alert to persons desiring to pur-chase this medication. EPINEPHRINE (ep-i-nef-rin) Adrenalin® ALPHA-& BETA-ADRENERGIC AGONIST Prescriber Highlights TT Alpha-& beta-adrenergic agonist agent used systemically for treating anaphylaxis & cardiac resuscitation TT Contraindications: Narrow-angle glaucoma, hypersen-sitivity to epinephrine, shock due to non-anaphylactoid causes, during general anesthesia with halogenated hydrocarbons, during labor (may delay the second stage), cardiac dilatation or coronary insufﬁciency; cases where vasopressor drugs are contraindicated (e. g., thyrotoxi-cosis, diabetes, hypertension, toxemia of pregnancy) TT Use extreme caution patients with a preﬁbrillatory car-diac rhythm TT Caution: Hypovolemia (not a substitute for adequate vol-ume replacement) TT Do not inject with local anesthetics into small append-ages of the body (e. g., toes, ears, etc. ); may cause necro-sis/sloughing TT Adverse Effects: Anxiety, tremor, excitability, vomiting, hypertension (overdosage), arrhythmias, hyperuricemia, & lactic acidosis (prolonged use or overdosage) TT Concentrations must not be confused TT Drug interactions Uses/Indications Epinephrine is employed primarily in veterinary medicine as a treatment for anaphylaxis or cardiac resuscitation. Because of its vasoconstrictive properties, epinephrine is added to local anesthet-ics to retard systemic absorption and prolong effect. Pharmacology/Actions Epinephrine is an endogenous adrenergic agent that has both alpha and beta activity. It relaxes smooth muscle in the bronchi and the iris, antagonizes the effects of histamine, increases glycogenolysis, and raises blood sugar. If given by rapid IV injection it causes direct stimulation of the heart (increased heart rate and contractility), and increases systolic blood pressure. If given slowly IV, it usually pro-duces a modest rise in systolic pressure and a decrease in diastolic blood pressure. T otal peripheral resistance is decreased because of beta effects. Pharmacokinetics Epinephrine is well-absorbed following IM or SC administration. IM injections are slightly faster absorbed than SC administra-tion; absorption can be expedited by massaging the injection site. Epinephrine is rapidly metabolized in the GI tract and liver after oral administration and is not effective via this route. Following SC injection, the onset of action is generally within 5-10 minutes. The onset of action following IV administration is immediate and intensiﬁed. Epinephrine does not cross the blood-brain barrier, but does cross the placenta and is distributed into milk. Epinephrine's actions are ended primarily by the uptake and me-tabolism of the drug into sympathetic nerve endings. Metabolism takes place in both the liver and other tissues by monoamine oxi-dase (MAO) and catechol-O-methyltransferase (COMT) to inac-tive metabolites. Contraindications/Precautions/Warnings Epinephrine is contraindicated in patients with narrow-angle glaucoma, hypersensitivity to epinephrine, shock due to non-ana-phylactoid causes, during general anesthesia with halogenated hy-drocarbons or cyclopropane, during labor (may delay the second stage), and cardiac dilatation or coronary insufﬁciency. Epinephrine should also not be used in cases where vasopressor drugs are con-traindicated (e. g., thyrotoxicosis, diabetes, hypertension, toxemia of preg nancy). It should not be injected with local anesthetics into small appendages of the body (e. g., toes, ears, etc. ) because of the chance of necrosis and sloughing. Use epinephrine with caution in cases of hypovolemia; it is not a substitute for adequate ﬂuid replacement therapy. It should be used with extreme caution in patients with a preﬁbrillatory car-diac rhythm, because of its excitatory effects on the heart. While epinephrine's usefulness in asystole is well documented, it can cause ventricular ﬁbrillation; use cautiously in cases of ventricular ﬁbrillation. Adverse Effects Epinephrine can induce feelings of fear or anxiety, tremor, excitabil-ity, vomiting, hypertension (overdosage), arrhythmias (especially if patient has organic heart disease or has received another drug that sensitizes the heart to arrhythmias), hyperuricemia, and lactic aci-dosis (prolonged use or overdosage). Repeated injections can cause necrosis at the injection site. 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. ) It is not known if this drug is excreted in milk. Overdosage/Acute Toxicity Clinical signs seen with overdosage or inadvertent IV administra-tion of SC or IM dosages can include: sharp rises in systolic, dia-stolic, and venous blood pressures, cardiac arrhythmias, pulmonary edema and dyspnea, vomiting, headache, and chest pain. Cerebral hemorrhages may result because of the increased blood pressures. Renal failure, metabolic acidosis and cold skin may also result. Because epinephrine has a relatively short duration of effect, treatment is mainly supportive. If necessary, the use an alpha-adrenergic blocker (e. g., phentolamine) or a beta-adrenergic block-er (e. g., pro pranolol) can be considered to treat severe hypertension and cardiac arrhythmias. Prolonged periods of hypotension may follow, which may require treatment with norepinephrine.	pppbs.pdf
348 EPINEPHRINE Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving epinephrine and may be of signiﬁcance in veterinary patients: !TALPHA-BLOCKERS (e. g., phentolamine, phenoxybenzamine, prazosin ): May negate the therapeutic effects of epinephrine !TANESTHETICS, GENERAL : An increased risk of arrhythmias develop-ing can occur if epinephrine is administered to patients who have received cyclopropane or a halogenated hydrocarbon anesthetic agent. Propranolol may be administered should these occur. !TANTIHISTAMINES : Certain antihistamines ( diphenhydramine, chlo-rpheniramine, etc. ) may potentiate the effects of epinephrine !TBETA-BLOCKERS : Propranolol (or other beta-blockers) may potentiate hypertension, and antagonize epinephrine's car-diac and bronchodilating effects by blocking the beta effects of epinephrine !TDIGOXIN : An increased risk of arrhythmias may occur if epineph-rine is used concurrently with digitalis glycosides !TNITRATES : May reverse the pressor effects of epinephrine !TLEVOTHYROXINE : May potentiate the effects of epinephrine !TOXYTOCIC AGENTS : Hypertension may result if epinephrine is used with oxytocic agents !TSYMPATHOMIMETIC AGENTS, OTHER : Epinephrine should not be ad-ministered with other sympathomimetic agents (e. g., isoprotere-nol) as increased toxicity may result !TPHENOTHIAZINES : May reverse the pressor effects of epinephrine !TRESERPINE : May potentiate the pressor effects of epinephrine !TTRICYCLIC ANTIDEPRESSANTS : May potentiate the effects of epinephrine Doses Note : Be certain when preparing injection that you do not confuse 1:1000 (1 mg/m L) with 1:10,000 (0. 1 mg/m L) concentrations. T o convert a 1:1000 solution to a 1:10,000 solution for IV or intratra-cheal use, dilute each m L with 9 m L of normal saline for injection. Epinephrine is only one aspect of treating cardiac arrest; refer to specialized references or protocols for more information. !TDOGS: Cardiac resuscitation (asystole): a) Both high dose (0. 1-0. 2 mg/kg) and low dose (0. 01-0. 02 mg/kg) IV or IO epinephrine have been advocated. In hu-man medicine, generally the low dose is attempted ﬁrst and if no response go to the high dose. In veterinary medicine (at present), either dose seems acceptable. Doses may be repeat-ed at 3-5 minute intervals if there is no response. (Drobatz 2004) b) Although controversial, high dose epinephrine (0. 2 mg/kg) is probably more effective than low dose (0. 02 mg/kg for car-diopulmonary cerebral resuscitation. It can be given every 3-5 minutes IV, preferably in a central vein. If venous access is not obtained, multiply the dose by 2-10 times and admin-ister into the distal trachea with a syringe and a red rubber tube. (Proulx 2002) c) 0. 01-0. 1 mg/kg IV or IT q2-5 minutes (Rozanski 2002) For anaphylaxis: a) 0. 01-0. 02 mg/kg IV; or the dosage may be doubled and giv-en via the endotracheal tube if IV line is not yet established. In less severe cases, may be given IM or SC (Cohen 1995) b) 0. 2-0. 5 mg (total dose) SC or IM (Wohl 2005) c) For bronchoconstriction: 20 mcg/kg (0. 02 mg/kg) IV, IM, SC, or IT (Johnson 2000) For treatment of hypotension associated with anesthesia: a) 0. 05-0. 4 mcg/kg/min IV (Dodam 2005), (Mazzaferro 2005) !TCATS: For cardiac resuscitation: 0. 05-0. 5 mg (0. 5-5 m L) of 1:10,000 solution intratracheally or intravenously. May need to repeat ev-ery 5 minutes. If intratracheal or IV sites are inaccessible, the intracardiac (IC) route may be used. IC dose is 0. 5 to 5 micro-grams/kg (0. 0005 to 0. 005 mg/kg). (Wingﬁeld 1985) For bronchoconstriction/anaphylaxis: a) 0. 01-0. 02 mg/kg IV; or the dosage may be doubled and giv-en via the endotracheal tube if IV line is not yet established. In less severe cases, may be given IM or SC. (Cohen 1995) b) 20 mcg/kg (0. 02 mg/kg) IV, IM, SC, or IT (Johnson 2000) For feline asthma/anaphylaxis: a) 0. 1 m L of a 1:1,000 dilution SC or IV (Noone 1986) b) Dilute 1 m L of 1:1,000 in 10 m L of saline and give 1 m L/10 kg body weight IV or IM. May repeat q5-15 minutes. (Kittleson 1985a) !TBIRDS: a) 0. 1 mg/kg IV or intracardiac (Harris 2003) !THORSES: (Note : ARCI UCGFS Class 2 Drug) For anaphylaxis: a) 3-5 m L of 1:1,000 per 450 kg of body weight either IM or SC; For foal resuscitation: 0. 1 m L/kg of 1:1,000 IV (prefer-ably diluted with saline) (Robinson 1987) For cardiopulmonary resuscitation of newborn foals: a) 0. 01-0. 02 mg/kg (0. 5-1 m L of a 1:1000 solution for a 50 kg foal) IV every 3 minutes until return of spontaneous circu-lation. If given intratracheally (IT), dose is 0. 1-0. 2 m L/kg. (Corley 2003) !TRUMINANTS, SWINE: For treatment of anaphylaxis: a) 0. 5-1 m L/100 lbs. body weight of 1:1,000 SC or IM; dilute to 1:10,000 if using IV; may be repeated at 15 minute intervals Often used in conjunction with corticosteroids and diphen-hydramine (Clark 1986) Monitoring !TCardiac rate/rhythm !TRespiratory rate/auscultation during anaphylaxis !TUrine ﬂow, if possible !TBlood pressure and blood gases, if indicated and possible Client Information !TPre-loaded syringes containing an appropriate amount of epi-nephrine may be dispensed to clients for treatment of anaphy-laxis in animals with known hypersensitivity. !TAnaphylactic clinical signs (depending on species) should be dis-cussed. !TClients should be instructed in proper injection technique (IM or SC) and storage conditions for epinephrine. !TDo not use epinephrine if it is outdated, discolored, or contains a precipitate.	pppbs.pdf
EPOETIN ALFA/ERYTHROPOIETIN 349 Chemistry/Synonyms An endogenous catecholamine, epinephrine occurs as white to nearly white, microcrystalline powder or granules. It is only very slightly soluble in water, but it readily forms water-soluble salts (e. g., HCl) when combined with acids. Both the commercial prod-ucts and endogenous epinephrine are in the Levo form, which is about 15 times more active than the dextro-isomer. The p H's of commercial injections are from 2. 5-5. Epinephrine is commonly called adrenalin. Storage/Stability/Compatibility Epinephrine HCl for injection should be stored in tight containers protected from light. Epinephrine will darken (oxidation) upon ex-posure to light and air. Do not use the injection if it is pink, brown, or contains a precipitate. The stability of the injection is dependent on the form and the preservatives present and may vary from one manufacturer to another. Epinephrine is rapidly destroyed by alka-lies, or oxidizing agents. Epinephrine HCl is reported to be physically compatible with the following intravenous solutions and drugs: Dextran 6% in dextrose 5%, Dextran 6% in normal saline, dextrose-Ringer's combinations, dextrose-lactated Ringer's combinations, dextrose-saline combina-tions, dextrose 2. 5%, dextrose 5% (becomes unstable at a p H >5. 5), dextrose 10%, Ringer's injection, lactated Ringer's injection, normal saline, and sodium lactate 1/6 M, amikacin sulfate, cimetidine HCl, dobutamine HCl, metaraminol bitartrate, and verapamil HCl. Epinephrine HCl is reported to be physically incompatible with the following intravenous solutions and drugs: Ionosol-D-CM, Ionosol-PSL (Darrow's), Ionosol-T with dextrose 5% ( Note: other Ionosol product are compatible), sodium chloride 5%, and sodium bicarbonate 5%, aminophylline, cephapirin sodium, hyaluronidase, mephentermine sulfate, sodium bicarbonate, and warfarin sodium. 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. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Epinephrine HCl for Injection 1 mg/m L (1:1,000) in 1 m L amps and syringes and 10 m L, 30 m L and 100 m L vials; Amtech® Epinephrine Injection USP (Phoenix Scientiﬁc); Am-Vet® Epinephrine 1:000 (Neo-gen); Epinephrine (Vedco, Vet T ek); Epinject® (Vetus); Epinephrine 1:000 (Agri Pharm, Durvet, Bimeda, Butler, Phoenix Pharmaceutical); Epinephrine Injection (Agri Labs); (Rx). Labeled for dogs, cats, cattle, horses, sheep and swine. The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Epinephrine HCl for Injection: 1 mg/m L (1:1000) in 1 m L amps, 5 m L vials, 0. 3 m L single dose auto-injectors; Adrenalin Chloride® (Monarch); Epi Pen® (Dey); generic; (Abbott); (Rx) Epinephrine HCl for Injection: 0. 5 mg/m L (1:2000) in 0. 3 m L single dose auto-injectors; Epi Pen Jr® (Dey); (Rx) Epinephrine HCl for Injection: 0. 1 mg/m L (1:10,000) in 10 m L sy-ringes & vials; generic, (Abbott); (Rx) Epinephrine bitartrate is available as a powder form (aerosol) for in-halation, topical solution and a solution for nebulization; ophthalmic preparations are available. EPOETIN ALFA ERYTHROPOIETIN (eh-poe-ee-tin al-fah) EPO, r Hu EPO, Epogen®, Procrit® ERYTHROPOETIC AGENT Prescriber Highlights TT Hormone that regulates erythropoiesis; used for anemia associated with chronic renal failure TT Contraindications: Patients with uncontrolled hyperten-sion or in those who are hypersensitive to it TT Adverse Effects: Autoantibodies with resultant resistance to treatment, hypertension, seizures, iron depletion, local reactions at injection sites, fever, arthralgia, & mucocuta-neous ulcers TT Adequate monitoring vital Uses/Indications EPO has been used to treat dogs and cats for anemia associated with chronic renal failure. Some clinicians state that because of the ex-pense and potential risks associated with its use, PCV's should be in the “teens”before considering beginning EPO therapy. Development of antibodies to EPO has severely limited its clinical usefulness in veterinary medicine for chronic use. EPO may be demonstrated in the future to have signiﬁcant beneﬁts in reducing the number or volume of transfusions, or as a neuroprotective agent. Pharmacology/Actions Erythropoietin is a naturally occurring substance produced in the kidney and considered a hormone as it regulates erythropoiesis. It stimulates erythrocyte production by stimulating the differentia-tion and proliferation of committed red cell precursors. EPO also stimulates the release of reticulocytes. Recombinant Human EPO alfa (r-Hu EPO-alpha) serves as a substitute for endogenous EPO, primarily in patients with renal disease. Various uremic toxins may be responsible for the decreased production of EPO by the kidney. Pharmacokinetics EPO is only absorbed after parenteral administration. It is unclear whether the drug crosses the placenta or enters milk. The drug's metabolic fate is unknown. In patients with chronic renal failure, half-lives are prolonged approximately 20% over those with normal renal function. Depending on initial hematocrit and dose, correc-tion of hematocrit may require 2-8 weeks. Contraindications/Precautions/Warnings EPO is contraindicated in patients with uncontrolled hypertension or in those who are hypersensitive to it (see Adverse Effects below). EPO cannot be recommended for use in equines. In animals with moderate to severe hypertension or iron deﬁciency, therapy should be started with caution or withheld until corrected. Patients receiving EPO, generally require exogenous administra-tion of iron supplements. Adverse Effects In dogs and cats, the most troublesome aspect of EPO therapy is the development of autoantibodies (20-70% incidence) with resultant resistance to further treatment. Perhaps up to 30% of all patients will develop antibodies signiﬁcant enough to cause profound anemia,	pppbs.pdf
350 EPOETIN ALFA/ERYTHROPOIETIN arrestment of erythropoiesis, and transfusion dependency. Should a patient develop refractory anemia while receiving adequate EPO doses and have normal iron metabolism, a bone marrow aspirate should be considered. A myeloid:erythroid ratio of greater than 6 predicts signiﬁcant autoantibody formation and contraindicates further EPO therapy. Some clinicians believe that the drug (EPO) should be withdrawn if PCV starts to drop while on therapy. Other effects reported include: systemic hypertension, high blood viscosity, seizures, and iron depletion. Local reactions at in-jection sites (which may be a predictor of antibody formation), fe-ver, arthralgia, and mucocutaneous ulcers are also possible. Other effects that have been noted that may be a result of the animal's disease (or compounded by such), include cardiac disease (may be related to hypertension associated with chronic renal failure). In humans, hyperkalemia, seizures, and iron deﬁciency have been reported. Therapy should be discontinued if any of the following are rec-ognized: polycythemia, fever, anorexia, joint pain, cellulitis, cutane-ous or mucosal ulceration (Cowgill 2002). Reproductive/Nursing Safety Some teratogenic effects (decrease in body weight gain, delayed os-siﬁcation, etc. ) have been noted in pregnant rats given high dosages. Rabbits receiving 500 mg/kg during days 6-18 of gestation showed no untoward effects on offspring; however, use during pregnancy only when beneﬁts outweigh the potential risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduc-tion studies and no adequate studies in humans. ) It is not known whether epoetin alfa is excreted in milk, but it is unlikely to pose much risk to nursing offspring. Overdosage/Acute Toxicity Acute overdoses appear to be relatively free of adverse effects. Single doses of up to 1600 Units/kg in humans demonstrated no signs of toxicity. Chronic overdoses may lead to polycythemia or other ad-verse effects. Cautious phlebotomy may be employed should poly-cythemia occur. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving EPO and may be of sig-niﬁcance in veterinary patients: !TANDROGENS : May increase the sensitivity of erythroid progenitors; this interaction has been used for therapeutic effect; ( Note : This effect has not been conﬁrmed in well-controlled studies nor has the safety of this combination been determined. ) !TDESMOPRESSIN : With EPO can decrease bleeding times !TPROBENECID : Probenecid has been demonstrated to reduce the renal tubular excretion of EPO; clinical signiﬁcance remains un-clear at this time Laboratory Considerations No laboratory interactions of major clinical importance have been described. Doses !TDOGS : As adjunctive therapy for the treatment of anemia associated with end-stage renal disease: a) Initially, 100 Units/kg SC 3 times weekly, until the bottom of the target hematocrit range of 37-45% is attained. Once the lower range of the target hematocrit is attained, the dos-ing interval is changed to twice weekly. As the hematocrit ap-proaches the upper target value, reduce to once weekly. The dosage schedule is then further modiﬁed as required and EPO administered between one and three times weekly to maintain hematocrit within the target range. A lower initial dosage of 50-100 Units/kg 3 times weekly may be used if slower response is acceptable and appropriate for the patient. If adequate control is not achieved within 8-12 weeks, then dose can be increased by an additional 25-50 Units/kg every 3-4 weeks while maintaining dosing interval at 3 times a week. Withhold treatment temporarily if hema-tocrit exceeds target range. Once hematocrit is reestablished at the upper limit of the target range, re-institute treatment at a lower dosing schedule. Do not adjust dosage or dosing interval more often than once every three weeks (due to the long lag time for a response). Generally, a maintenance dose of 75-100 U/kg SC 1-2 times weekly is sufﬁcient (not less than once per week, and not more than 3 times a week). Iron supplementation required. (Cowgill 2002) b) Initially, 48. 4-145 units/kg SC three times a week. Most dogs and cats should be started at 97 units/kg SC 3 times a week. Use high end dose initially when anemia is severe (HCT less than 14%) and low end dose if hypertension is present or when anemia is not severe. Monitor hematocrit weekly until a target hematocrit of 37-45% is reached. When hematocrit reaches low end of target decrease dosing to two times week-ly. Continue monitoring and adjusting dose and frequency as necessary, but take lag phase into account and do not adjust too rapidly. If animal requires >145 units/kg three times a week, evaluate for epoetin resistance. Oral iron supplements recommended for all patients on epoetin. (Polzin, Osborne et al. 2000) !TCATS: As adjunctive therapy for the treatment of anemia associated with end-stage renal disease: a) As above (for each speciﬁc author), but the target hematocrit is: 30-40%. (Cowgill 2002), (Polzin, Osborne et al. 2000) b) Consider using epoetin when PCV is <20%; dose at 75-100 U/kg SC three times a week until PCV is in the low normal range (35%), then reduce dose and frequency to 50-75 U/ kg two times per week. Monitor PCV and blood pressure. It is important to administer iron at start of regime and until appetite is good. (Scherk 2003d) !TFERRETS: a) 50-150 IU/kg IM 3 times weekly; may decrease to once weekly if RBC indices are signiﬁ cantly improved (Williams 2000) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: 50-150 IU/kg SC every 2-3 days until PVC is nor-mal; then once weekly (q7 days) for at least 4 weeks (Ivey and Morrisey 2000) Monitoring !THematocrit; PCV; (Initially weekly to every other week for 2-4 months, then when dose and Hct are stable, at 1-2 month intervals) !TBlood Pressure (initially, at least monthly then every 1-2 months thereafter) !TRenal Function Status !TIron status (serum iron, TIBC), RBC indices (initially and regu-larly during therapy to insure adequate iron availability)	pppbs.pdf
EPRINOMECTIN 351 Client Information T ! For outpatient administration, training in proper injection tech-niques, drug handling and storage should be performed Chemistry/Synonyms A biosynthetic form of the glycoprotein human hormone eryth-ropoietin, epoetin alfa (EPO) has a molecular weight of approxi-mately 30,000. It is commercially available as a sterile, preservative-free, colorless solution. Sodium chloride solution is added to adjust tonicity and is buffered with sodium citrate or citric acid. Human albumin (2. 5 mg per vial) is also added to the solution. Epoetins may also be known by the following synonyms and internationally registered trade names: erythropoietin, r-Hu EPO, BI-71. 052 (epoetin gamma), BM-06. 019 (epoetin beta), EPO (epoetin alfa), EPOCH (epoetin beta), Bioyetin®, Culat®, Epogin®, Epomax®, Epopen ®, Epotin®, Epoxitin®, Eprex ®, Erantin®, Eritina®, Eritrogen®, Eritromax®, Erypo ®, Espo®, Exetin-A®, Globuren®, Hemax®, Hemax-Eritron®, Hypercri ®, Mepotin®, Neo Recormon®, Neorecormon®, Procrit ®, Pronivel®, Recormon®, Repotin®, Tinax®, and Wepox ®. Storage/Stability/Compatibility The injectable solution should be stored in the refrigerator (2-8°C); do not freeze. Do not shake the solution as denaturation of the protein with resultant loss of activity may occur. If light exposure is limited to 24 hours or less, no effects on potency should occur. When stored as directed, the solution has an expiration date of 2 years after manufacture. Do not mix with other drugs or use the same IV tubing with other drugs running. Because the solution contains no preservatives, the manufacturer recommends using each vial only as a single use. A method of diluting the Amgen product to facilitate giving very small dosages has been described (Grodsky 1994). Using a 1:20 di-lution (1 part Epogen® to 19 parts bacteriostatic normal saline does not require any additional albumin to prevent binding of the drug to container). No data is available commenting on this dilution's stability. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. It is also prohibited on the premises of a racing facility. HUMAN-LABELED PRODUCTS: Epoetin Alfa, Recombinant for Injection: 2000 units/m L, 3000 units/ m L, 4000 units/m L, 10,000 units/m L, 20,000 units/m L and 40,000 units/m L in 1 m L and 2 m L (10,000U only) both single-dose and multidose vials; Epogen® (Amgen), Procrit® (Ortho Biotech); (Rx) EPRINOMECTIN (e-pri-no-mek-tin) Ivomec® Eprinex® TOPICAL A VERMECTIN A NTIPARASITIC AGENT Prescriber Highlights TT Topically applied avermectin antiparasiticide for cattle TT Used as labeled; there are no milk or meat withdrawal times required Uses/Indications In cattle, eprinomectin is indicated for a variety gastrointestinal roundworms including adult and L4 stages of Haemonchus pla-cei, Ostertagia ostertagi, Trichostrongylus axei and colubriformis, Cooperia oncophora/punctata/surnabada, Nematodirus helvetianus, Oesophagostomum radiatum, Bunostomum phlebotomum, and Trichuris spp. (adults only); cattle grubs; lice; mange mites; horn ﬂies (for 7 days after treatment), and lungworms (Dictyocaulus vivaparus—for 21 days after treatment). T opical eprinomectin may be useful for the topical treatment of ear mites (Psoroptes cuniculi) in rabbits. One small study (6 sub-jects) showed partial response when rabbits were dosed at 5 mg/kg topically, twice at 14 day intervals. (Ulutas, Voyvoda et al. 2005) Pharmacology/Actions Eprinomectin binds selectively to glutamate-gated chloride ion channels that occur in invertebrate nerve and muscle cells. This leads to an increase in cell membrane permeability to chloride ions, leading to paralysis and death of the parasite. Like ivermectin, eprinomectin enhances the release of gamma amino butyric acid (GABA) at presynaptic neurons. GABA acts as an inhibitory neu-rotransmitter and blocks the post-synaptic stimulation of the adja-cent neuron in nematodes or the muscle ﬁber in arthropods. These compounds are generally not toxic to mammals as they do not have glutamate-gated chloride channels and do not readily cross the blood-brain barrier. Pharmacokinetics No information noted. Contraindications/Precautions/Warnings Do not give orally or intravenously. Adverse Effects At the time of review, no adverse reactions have been reported. Overdosage/Acute Toxicity Calves given up to 5X dosage showed no signs of adverse effects. One subject (of 6) showed signs of mydriasis when given a 10X dose. Drug Interactions No interactions noted Doses T ! CATTLE: For labeled indications: a) 1 m L per 10 kg (22 lb) body weight applied topically along backline in a narrow strip from the withers to the tailhead (Package Insert; Ivomec® Eprinex®—Merial) Client Information T ! When used as labeled, there are no milk or meat withdrawal times required. T ! Weather conditions (including rainfall) during administration do not affect efﬁcacy. T ! Do not apply to backline if covered with mud or manure. T ! Dispose of containers in an approved landﬁll or by incineration; do not contaminate water as eprinomectin may adversely affect ﬁsh and aquatic organisms. Chemistry/Synonyms A member of the avermectin-class of antiparasitic agents, epri-nomectin is also known as MK-397 or 4-epi-acetylamino-4-deoxy-avermectin B1.	pppbs.pdf
352 EPSIPRANTEL; ERGOCALCIFEROL Storage/Stability The commercially available product should be stored protected from light and kept at 86°F (30°C) or less. Storage up to 104°F (40°C) is permitted for a short period. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Eprinomectin T opical (Pour-On) Solution: 5 mg/m L in 250 m L/8. 5 ﬂ oz and 1 L/33. 8 ﬂ oz bottle with a squeeze-measure-pour-system, or a 2. 5 L/84. 5 ﬂ oz and 5 L/169 ﬂ oz collapsible pack for use with ap-propriate automatic dosing equipment; Ivomec® Eprinex® (Merial); (OTC). Approved for use in beef or dairy cattle. HUMAN-LABELED PRODUCTS: None Epsom Salts — see Magnesium Sulfate EPSIPRANTEL (ep-si-pran-tel) Cestex® CESTOCIDAL A NTIPARASITIC AGENT Prescriber Highlights TT Oral cestocide for dogs & cats TT Not appreciably absorbed when given orally TT Not approved in puppies or kittens less than 7 weeks old TT Adverse Effects: GI (vomiting, diarrhea) possible Uses/Indications Epsiprantel is indicated for the treatment (removal) of Dipylidium caninum and Taenia pisiformis in dogs, and Dipylidium caninum and Taenia taeniaeformis in cats. Pharmacology/Actions Epsiprantel's exact mechanism of action against cestodes has not been determined. The tapeworm's ability to regulate calcium is ap-parently affected, causing tetany and disruption of attachment to the host. Alteration to the integument makes the worm vulnerable to digestion by the host animal. Pharmacokinetics Unlike praziquantel, epsiprantel is absorbed very poorly after oral administration and the bulk of the drug is eliminated in the feces. Less than 0. 1% of the drug is recovered in the urine after dosing. No metabolites have thus far been detected. Contraindications/Precautions/Warnings There are no labeled contraindications to this drug, but the manu-facturer states not to use it in puppies or kittens less than 7 weeks of age. Adverse Effects Adverse effects would be unexpected with this agent, although vomiting and/or diarrhea could potentially occur. Reproductive/Nursing Safety Safety for use in pregnant or breeding animals has not been deter-mined, but teratogenic effects would be highly unlikely since the drug is so poorly absorbed. Overdosage/Acute Toxicity Acute toxicity resulting from an inadvertent overdose is highly unlikely. Doses as high as 36X the recommended dose resulted in vomiting in some of the kittens tested. Single doses of 36X those recommended in dogs caused no adverse effects. Drug Interactions/Laboratory Considerations None reported; theoretically, prokinetic agents or fast acting laxa-tives may reduce the drug's efﬁcacy Doses T ! DOGS: a) 5. 5 mg/kg (2. 5 mg/lb) PO once; round up to the next larger tablet size (Package insert; Cestex®—Pﬁzer) T ! CATS: a) 2. 75 mg/kg PO once. Cats up to 10 lb. should receive one 12. 5 mg tablet; cats 11-20 lb. should receive one 25 mg tablet (Package insert; Cestex®—Pﬁzer) Monitoring T ! Clinical efﬁcacy Client Information T ! Fasting is not required nor is it recommended before dosing T ! Because the worm may be partially or completely digested, worm fragments may not be seen in the feces after treatment. T ! A single dose is usually effective, but measures should be taken to prevent reinfection, particularly against D. caninum. Chemistry/Synonyms A pyrazino-benzazepine oral cesticide, epsiprantel occurs as a white powder that is sparingly soluble in water. Epsiprantel may also be known as BRL-38705 or Cestex®. Storage/Stability Tablets should be stored at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Epsiprantel Oral Tablets (Film-coated): 12. 5, 25, 50 & 100 mg; Cestex® (Pﬁzer); (Rx). Approved for use in dogs and cats. HUMAN-APPROVED PRODUCTS: None ERGOCALCIFEROL (er-goh-kal-sif-er-ole) Vitamin D2, Calciferol, Drisdol® VITAMIN D ANALOG Prescriber Highlights TT May be used to treat hypocalcemia associated with hypoparathyroidism, but DHT or calcitriol usually recom-mended ﬁrst TT Less expensive than DHT or calcitriol, but takes large initial doses for effect, effects take longer to be seen, & if hypercalcemia develops, takes longer (up to 18 weeks) for toxicity relief	pppbs.pdf
ERGOCALCIFEROL 353 Uses/Indications Ergocalciferol is sometimes used in dogs or cats to treat hypocalce-mia secondary to parathyroid gland failure, particularly when dihy-drotachysterol or calcitriol are too expensive for the owner. When compared to those agents, ergocalciferol takes longer to have a max-imal effect on serum calcium. Additionally, if hypercalcemia should develop, ergocalciferol's effects persist longer than either calcitriol or dihydrotachysterol. Pharmacology/Actions Ergocalciferol is ﬁrst hydroxylated in the liver to 25-hydroxyvita-min D (has some activity) and then activated in the kidneys to 1,25-dihydroxyvitamin D, the primary active form of the drug. Vitamin D is considered a hormone and, in conjunction with parathormone (PTH) and calcitonin, regulates calcium homeostasis in the body. Active analogues (or metabolites) of vitamin D enhance calcium and phosphate absorption from the GI tract, promote reabsorption of calcium by the renal tubules, and increase the rate of accretion and resorption of minerals in bone. Pharmacokinetics Speciﬁc pharmacokinetic values for dogs and cats were not located. But the following information (human-based) generally applies: In the presence of bile salts, ergocalciferol is absorbed from the small intestine; after conversion to its 25-hydroxylated form in the liver and kidneys, it is stored in the liver and fat. Cats do not appear to convert ergocalciferol to its 25-hydroxylate form as well as cholecal-ciferol. Several days of therapy may be required until distribution steady state is achieved. In dogs and cats, maximal effect on calcium homeostasis is usually noted from 5-21 days after treatment was begun; effects may persist for up to 18 weeks once treatment is dis-continued (Feldman 2005a). Contraindications/Precautions/Warnings Ergocalciferol, at therapeutic dosages, is contraindicated in patients with hypercalcemia, vitamin D toxicity, malabsorption syndrome, or abnormal sensitivity to the effects of vitamin D. It should be used with extreme caution in patients with hyperphosphatemia. As pa-tients with kidney dysfunction may not convert ergocalciferol into the primary active metabolite, calcitriol or DHT would be preferred since they do not require activation by the kidney. Chronic therapy should not be initiated unless owners are willing to commit to on-going patient monitoring. Adverse Effects The primary concern with using ergocalciferol is “overshooting” the dosage with resultant hypercalcemia and, potentially, hyper-phosphatemia or nephrocalcinosis. Hypercalcemia can persist for weeks to months. Reproductive/Nursing Safety Hypervitaminosis D in pregnant females has been implicated in causing teratogenic effects in animals and infants. Potential beneﬁts of therapy must be weighed against the risks if considering use in pregnant dogs or cats. As large doses of vitamin D can be excreted into milk, consider using milk replacer in offspring of dams receiving therapeutic dos-ages of ergocalciferol. Overdosage/Acute Toxicity Because of the potential serious ramiﬁcations of overdoses, con-tacting an animal poison control center is strongly recommended. The toxic acute oral dose of ergocalciferol in dogs is reported as 4 mg/kg (160,000 units/kg). Acute ingestions should be managed using established proto-cols 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 it and exogenous cal-cium therapy. If the hypercalcemia is severe, furosemide, calcium-free IV ﬂuids (e. g., normal saline), urine acidiﬁcation, and corticos-teroids may be employed. Because of the long duration of action of ergocalciferol (potentially up to 18 weeks), hypercalcemia may persist. Restart therapy (if desired) at a reduced dosage only when calcium serum levels return to the normal range. Diligent monitor-ing is required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ergocalciferol and may be of signiﬁcance in veterinary patients: !TCORTICOSTEROIDS : Can reduce the effects of vitamin D analogs !TDIGOXIN or VERAPAMIL : Patients on these drugs are sensitive to the effects of hypercalcemia; intensiﬁed monitoring is required !TMINERAL OIL : May reduce the amount of ergocalciferol absorbed !TTHIAZIDE DIURETICS : May cause hypercalcemia when given in con-junction with Vitamin D analogs Laboratory Considerations !TSerum cholesterol levels may be falsely elevated by vitamin D ana-logs when using the Zlatkis-Zak reaction for determination. Doses !TDOGS /CATS: For maintenance therapy of parathyroid failure after using par-enteral calcium to control hypocalcemic tetany: a) Dihydrotachysterol or calcitriol are preferred, but ergocalcif-erol is less expensive. If using ergocalciferol, patient should be hospitalized. Initially give ergocalciferol at 4000-6000 units/kg PO once daily. After 1-5 days, parenteral calcium can usually be discontinued. Patient should remain hospi-talized until serum calcium concentration remains between 8-10 mg/d L without parenteral calcium support, then pa-tient can be discharged. Continue ergocalciferol, but admin-ister every other day. Weekly serum calcium concentrations should be performed and ergocalciferol dosage adjusted to maintain serum calcium concentrations between 8-9. 5 mg/ d L. Maintenance doses usually range from 1000-2000 units/ kg PO once daily to once weekly. Goal is to prevent hypocal-cemic tetany, but not induce hypercalcemia. Once animal is stable, monthly rechecks for 6 months are strongly advised; then every 2-3 months thereafter. (Feldman 2005a) Monitoring !TSee dosage information above Client Information !TWhile ergocalciferol is less expensive than DHT or calcitriol, it is usually not recommended as it takes longer to have an effect and can persist in the body longer than DHT or calcitriol !TUsing vitamin D products may require lifelong treatment and regular laboratory monitoring !TWhile this agent can treat low calcium, it can cause calcium levels in the blood to become too high; this effect can last for many weeks, even after the medication is discontinued	pppbs.pdf
354 ERTAPENEM SODIUM Chemistry/Synonyms Ergocalciferol is obtained by irradiating (with ultraviolet light) er-gosterol, a sterol present in fungi and yeasts. It occurs as white or almost white crystals or yellowish crystalline powder and is practi-cally insoluble in water, but is soluble in fatty oils. One mg of ergo-calciferol provides 40,000 units of vitamin D activity. Ergocalciferol may be known as calciferol, vitamin D2, viosterol, activated ergosterol, or irradiated ergosterol; there are many inter-national trade names. Storage/Stability Ergosterol is sensitive to light, heat and air. Store capsules or liquid at room temperature (15-30°C) and protect from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Ergocalciferol Oral Liquid (Drops): 8,000 units/m L (200 mcg/m L) in 60 m L btls; Drisdol® Drops (Sanoﬁ), Calciferol® Drops (Schwarz); (OTC) Ergocalciferol Capsules: 50,000 units (1. 25 mg); Drisdol® (Sanoﬁ), Vitamin D (Pliva); (Rx) ERTAPENEM SODIUM (er-ta-pen-um) Invanz® CARBAPENEM ANTIBIOTIC Prescriber Highlights TT Carbapenem antibiotic similar to imipenem & meropen-em, but has narrower spectrum of activity TT Not effective against Pseudomonas or Acinetobacter TT May only need to be dosed once daily TT Very limited information available for use in dogs or cats; must be considered investigational Uses/Indications Ertapenem may be useful in treating resistant gram-negative bac-terial infections, particularly when aminoglycoside use would be risky (i. e., renal failure) or not effective (i. e., resistance or CNS in-fections), and when meropenem is not available. While ertapenem has a broad spectrum, it is not active against Pseudomonas aerugi-nosa. It potentially could be useful against mixed anaerobic/gram-negative aerobic infections when Pseudomonas is not considered a likely pathogen. Pharmacology/Actions Ertapenem is a carbapenem antibiotic similar to imipenem and meropenem. Like other beta-lactams, it inhibits bacterial cell wall synthesis and is usually bactericidal. Ertapenem has a broad antibacterial spectrum similar to that of imipenem, but it is more active against Enterobacteriaceae and an-aerobes, has equivalent activity against gram-positive bacteria, and minimal activity against Pseudomonas aeruginosa and Acinetobacter. Methicillin-resistant Staphylococci and Enterococcus are usually re-sistant to ertapenem. Because ertapenem, like meropenem, is more stable than imipenem to renal dehydropeptidase I, it does not re-quire the addition of cilastatin to inhibit that enzyme. Pharmacokinetics At the time of writing, no pharmacokinetic data was available for dogs or cats. In humans, the drug must be administered parenterally as it is not appreciably absorbed after oral administration. Intramuscular bioavailability is about 90% and peak plasma levels occur in ap-proximately 2. 3 hours. Ertapenem exhibits concentration-depen-dent binding to human plasma proteins. At plasma concentrations of <100 mcg/m L it is 95% bound; at 300 mcg/m L, 85% bound. Ertapenem biotransformation is not dependent on hepatic mecha-nisms as the major metabolite (inactive) is formed by hydrolysis of the beta-lactam ring. Approximately 80% of an IV dose is ex-creted in the urine, evenly split between inactive metabolites and unchanged drug. Approximately 10% is excreted in the feces. In young, healthy adults, elimination half-life is about 4 hours; about 2. 5 hours in pediatric patients. Contraindications/Precautions/Warnings Ertapenem is contraindicated in patients hypersensitive to it or oth-er carbapenems and those that have developed anaphylaxis after re-ceiving any beta-lactam antibiotic. It is contraindicated in patients hypersensitive to lidocaine or other amide-type local anesthetics (if used IM with 1% lidocaine as the diluent). As ertapenem has not been widely used clinically in veterinary medicine and little information for use in dogs or cats is published, consider its use investigational. Adverse Effects The adverse effect proﬁle for ertapenem in dogs or cats is unknown. In humans, intravenous injection site reactions are the most com-mon adverse reaction. Gastrointestinal effects (nausea, vomiting, diarrhea), headache, or tachycardia have occasionally been report-ed. Rarely, hypersensitivity or CNS effects (hallucinations, agita-tion, seizures, etc. ) have been seen. Reproductive/Nursing Safety Ertapenem has been shown to cross the placenta in rats, but no teratogenic effects have been reported. In humans, ertapenem is designated by the FDA as a category B drug (Animal studies have not 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 during the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Although risk cannot be ruled out, it is likely that ertapenem is safe to use while nursing. Overdosage/Acute Toxicity Inadvertent overdoses are unlikely. Humans receiving 3 grams intravenously had an increased incidence of nausea and diar-rhea. Should an overdose occur and adverse effects noted, treat supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ertapenem and may be of signiﬁcance in veterinary patients: T ! PROBENECID : In humans, coadministration of ertapenem with probenecid can increase ertapenem AUC by 25% and elimina-tion half-life by about 20%. Because of these relatively small ef-fects, the manufacturer does not recommend using probenecid to extend the half-life of ertapenem.	pppbs.pdf
ERYTHROMYCIN 355 Laboratory Considerations No speciﬁc laboratory interactions or concerns were noted. Doses T ! DOGS /CATS: Note : There is very little information available regarding ertap-enem use in dogs or cats and, therefore use must be considered investigational. If the drug is to be administered, it is suggested to use the human pediatric dose of 15 mg/kg IV or IM every 12 hours (not to exceed a daily dosage of 1 gram). Monitor the lit-erature for additional data and recommendations. Monitoring T ! Clinical efﬁcacy (WBC, fever, etc. ) T ! Adverse effects (potentially: GI, neurotoxicity, hypersensitivity); in humans receiving ertapenem for a prolonged period, hepatic, hematopoietic, and renal function are suggested for periodic assessment Client Information T ! Clients should understand the investigational nature of using this drug in animals and that it should be administered only by veterinary professionals Chemistry/Synonyms Ertapenem sodium is a synthetic 1-(beta) methyl carbapenem an-tibiotic that occurs as a white to off-white, hygroscopic, crystalline powder. It is soluble in water and normal saline. Ertapenem may also be known as L-749345, ML-0826, ZD-4433, ertapenemum or Invanz®. Storage/Stability/Compatibility The 1 gram injectable product contains approximately 6 m Eq of sodium and 175 mg of sodium bicarbonate (as an excipient). It should be stored at temperatures at, or below, 25°C. For intravenous use, vial contents can be reconstituted with 10 m L of water for injection, bacteriostatic water for injection, or 0. 9% sodium chloride injection. After shaking to dissolve the powder, im-mediately transfer to a 50 m L bag of 0. 9% sodium chloride. Do not use diluents containing dextrose. Once reconstituted and diluted in normal saline for IV use, ertapenem is stable at room temperature for 6 hours. If refrigerated, it can be stored for 24 hours and used within 4 hours after removal from the refrigerator. Do not freeze reconstituted solutions. If ertapenem is to be given IM, dilute the vial with 3. 2 m L of 1% lidocaine HCl injection (without epinephrine). Use within one hour. Do not give IV. Do not mix ertapenem with other medications or use IV solu-tions containing dextrose. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Ertapenem Sodium Powder for Injection: 1 g (as ertapenem) vials; Invanz® (Merck); (Rx) ERYTHROMYCIN ERYTHROMYCIN ESTOLATE ERYTHROMYCIN ETHYLSUCCINATE ERYTHROMYCIN LACTOBIONATE (er-ith-roe-mye-sin) Gallimycin® MACROLIDE ANTIBIOTIC Prescriber Highlights TT Macrolide antibiotic; also used as a prokinetic agent TT Contraindicated in rabbits, gerbils, guinea pigs, & hamsters; oral use in ruminants, adult horses(?), hypersensitivity TT Adverse Effects: GI distress (oral), pain on IM injection; thrombophlebitis (IV), hyperthermia (foals) TT Many drug interactions possible Uses/Indications Erythromycin is approved for use to treat infections caused by sus-ceptible organisms in swine, sheep, and cattle. It is often employed when an animal is hypersensitive to penicillins or if other antibiot-ics are ineffective against a certain organism. Erythromycin,at present,is considered to be one of the treatments of choice (with rifampin) for the treatment of C. (Rhodococcus) equi infections in foals. Erythromycin estolate and microencapsulated base appear to be the most efﬁcacious forms of the drug in foals due to better absorption and less frequent adverse effects. Erythromycin may be used as a prokinetic agent to increase gas-tric emptying in dogs and cats. It may also be beneﬁcial in treating reﬂux esophagitis. Pharmacology/Actions Erythromycin is usually a bacteriostatic agent, but in high concen-trations or against highly susceptible organisms it may be bacteri-cidal. The macrolides (erythromycin and tylosin) are believed to act by binding to the 50S ribosomal subunit of susceptible bacteria, thereby inhibiting peptide bond formation. Erythromycin has in vitro activity against gram-positive cocci (staphylococci, streptococci), gram-positive bacilli, (Bacillus an-thracis, Corynebacterium, Clostridium spp., (not C. difﬁcile), Listeria, Erysipelothrix), and some strains of gram-negative bacilli, including Haemophilus, Pasturella, and Brucella. Some strains of Actinomyces, Mycoplasma, Chlamydia, Ureaplasma, and Rickettsia are also inhibited by erythromycin. Most strains of the family Enterobacteriaceae (Pseudomonas, E. coli, Klebsiella, etc. ) are resis-tant to erythromycin. Erythromycin is less active at low p Hs and many clinicians sug-gest alkalinizing the urine if using the drug to treat UTI's. At sub-antimicrobial doses, erythromycin mimics the effects of motilin (cats, humans, rabbits) or 5-hydroxytryptophan 3 (5-HT 3) and stimulates migrating motility complexes and antegrade peri-stalsis. By inducing antral contractions, gastric emptying is en-hanced. Erythromycin also increases lower esophageal pressure. Erythromycin's prokinetic mechanism of action in dogs is not completely understood, but probably is via activation of 5-HT 3 receptors.	pppbs.pdf
356 ERYTHROMYCIN Pharmacokinetics Erythromycin is absorbed after oral administration in the upper small intestine. Several factors can inﬂuence the bioavailability of erythromycin, including salt form, dosage form, GI acidity, food in the stomach, and stomach emptying time. Both erythromycin base and stearate are susceptible to acid degradation; enteric coatings are often used to alleviate this. Both the ethylsuccinate and esto-late forms are dissociated in the upper small intestine and then ab-sorbed. After IM or SC injection of the polyethylene-based veteri-nary product (Erythro®-200; Gallimycin®-200) in cattle, absorption is very slow. Bioavailabilities are only about 40% after SC injection and 65% after IM injection. Erythromycin is distributed throughout the body into most ﬂu-ids and tissues including the prostate, macrophages, and leukocytes. CSF levels are poor. In foals, erythromycin levels in bronchiolar la-vage cells are equivalent to those found in the serum, but concentra-tions in pulmonary epithelial lining ﬂuid are lower. Erythromycin may be 73-81% bound to serum proteins and the estolate salt, 96% bound. Erythromycin will cross the placenta; fetal serum levels are 5-20% of maternal levels. Erythromycin levels of about 50% of those found in the serum can be detected in milk. The volume of distribution for erythromycin in dogs is reportedly 2 L/kg; 3. 7-7. 2 L/kg in foals; 2. 3 L/kg in mares; and 0. 8-1. 6 L/kg in cattle. In lactat-ing dairy cattle, the milk to plasma ratio about 6-7. Erythromycin is primarily excreted unchanged in the bile, but is also partly metabolized by the liver via N-demethylation to inactive metabolites. Some of the drug is reabsorbed after biliary excretion. Only about 2-5% of a dose is excreted unchanged in the urine. The reported elimination half-life of erythromycin in various species is: 60-90 minutes in dogs and cats, 60-70 minutes in foals and mares, and 190 minutes in cattle. Contraindications/Precautions/Warnings Erythromycin is contraindicated in patients hypersensitive to it. In humans, the estolate form has been associated rarely with the development of cholestatic hepatitis. This effect has not apparently been reported in veterinary species, but the estolate should prob-ably be avoided in patients with preexisting liver dysfunction. As it may induce a toxic enterocolitis, erythromycin (and other macrolides) is contraindicated in rabbits, gerbils, guinea pigs, and hamsters. Many clinicians believe that erythromycin is contraindicated in adult horses (see Adverse Effects below), and oral erythromycin should not be used in ruminants as severe diarrhea may result. Adverse Effects Adverse effects are relatively infrequent with erythromycin when used in small animals, swine, sheep, or cattle. When injected IM, lo-cal reactions and pain at the injection site may occur. Oral erythro-mycin may occasionally cause GI disturbances such as diarrhea, an-orexia, and vomiting. Rectal edema and partial anal prolapse have been associated with erythromycin in swine. Intravenous injections must be given very slowly, as they can readily cause thrombophlebi-tis. Allergic reactions can occur but are thought to be rare. Oral erythromycin should not be used in ruminants as severe diarrheas may result. In foals treated with erythromycin, a mild, self-limiting diarrhea can occur; however, severe enterocolitis is possible. Erythromycin may alter temperature homeostasis in foals. Foals between the ages of 2-4 months old have been reported to develop hyperthermia with associated respiratory distress and tachypnea. Physically cool-ing off these animals has been successful in controlling this effect. Adult horses may develop severe, sometimes fatal, diarrhe-as from erythromycin making the use of the drug in adults very controversial. When used as prokinetic agent, erythromycin may actually in-crease clinical signs of intestinal distress as it can stimulate empty-ing of larger food particles into the intestine than is normal. Reproductive/Nursing Safety While erythromycin has not demonstrated teratogenic effects in rats, and the drug is not thought to possess serious teratogenic po-tential, it should only be used during pregnancy when the beneﬁts outweigh the risks. In humans, the FDA categorizes erythromycin and its salts, except ethylsuccinate, as category B for 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. ) In a separate system evaluating the safety of drugs in canine and fe-line pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although speciﬁc studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse ef-fects in laboratory animals or women. ) In humans, the FDA categorizes erythromycin ethylsuccinate 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. ) Erythromycin is excreted in milk and may concentrate (observed milk:plasma ratio of 0. 5). Erythromycin is considered compatible with breastfeeding by the American Academy of Pediatrics. Overdosage/Acute Toxicity With the exception of the adverse effects outlined above, ery-thromycin is relatively non-toxic; however, shock reactions have been reported in baby pigs receiving erythromycin overdosages. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving erythromycin and may be of signiﬁcance in veterinary patients: !TAZOLE ANTIFUNGALS (ketoconazole, ﬂuconazole, itraconazole ): Pos-sible increased erythromycin levels !TCISAPRIDE : Erythromycin can inhibit the metabolism of cisapride and the manufacturer states that use of these drugs together (in humans) is contraindicated !TCHLORAMPHENICOL : in vitro evidence of antagonism !TCLINDAMYCIN, LINCOMYCIN : in vitro evidence of antagonism !TDIGOXIN : Erythromycin may increase the serum level of digoxin !TDILTIAZEM, VERAPAMIL : May increase erythromycin levels !TERGOT ALKALOIDS : Acute ergot toxicity possible !TOMEPRAZOLE : Erythromycin and omeprazole can increase the plasma levels of one another !TWARFARIN : Erythromycin may potentiate the effects of oral anti-coagulant drugs Erythromycin can inhibit the metabolism of other drugs that use the CYP3A subfamily of the cytochrome P450 enzyme system. Depending on the therapeutic index of the drug(s) involved, thera-peutic drug monitoring and/or dosage reduction may be required if the drugs must be used together. These drugs include: !! ALFENTANIL !! BROMOCRIPTINE !! BUSPIRONE	pppbs.pdf
ERYTHROMYCIN 357 T!! CARBAMAZEPINE !! CYCLOSPORINE !! DISOPYRAMIDE (also risk of increased QT interval) !! METHYLPREDNISOLONE !! MIDAZOLAM, ALPRAZOLAM, TRIAZOLAM !! QUINIDINE (also risk of increased QT interval) !! SILDENAFIL !! TACROLIMUS (systemic ) !! THEOPHYLLINE Laboratory Considerations !TErythromycin may cause falsely elevated values of AST (SGOT), and ALT (SGPT) when using colorimetric assays. !TFluorometric determinations of urinary catecholamines can be al-tered by concomitant erythromycin administration. Doses !TDOGS: For susceptible infections: a) 10-20 mg/kg PO three times daily (Aucoin 2000) b) For localized, soft tissue infections: 10-15 mg/kg PO q8h or 15-25 mg/kg PO q12h for 7-10 days; For systemic, bacteremia infections: 22 mg/kg PO or IV q8h for as long as necessary (Greene and Watson 1998) As a prokinetic agent: a) 0. 5-1 mg/kg PO q8h (Hall and Washabau 2000) !TCATS: For susceptible infections: a) 10-20 mg/kg PO three times daily (Aucoin 2000) b) For localized, soft tissue infections: 10-15 mg/kg PO q8h or 15-25 mg/kg PO q12h for 7-10 days; For systemic, bacteremia infections: 22 mg/kg PO or IV q8h for as long as necessary (Greene and Watson 1998) As a prokinetic agent: a) 0. 5-1 mg/kg PO q8h (Hall and Washabau 2000) !TFERRETS: For susceptible infections: a) 10 mg/kg PO 4 times daily (Williams 2000) !TBIRDS: For susceptible infections: a) Oral suspension: 60 mg/kg PO q12h (Hoeffer 1995) b) Ratites: 5-10 mg/kg PO 3 times daily (Jenson 1998) !TCATTLE: For susceptible infections: a) 4-8 mg/kg IM q12-24h (Jenkins 1987b) b) For bronchopneumonia and ﬁbrinous pneumonia in cattle associated with bacteria sensitive to erythromycin and resis-tant to sulfas, penicillin G and tetracyclines: Using Erythro-200®: 44 mg/kg IM q24h usually for a maximum of 4 days. Inject no more than 10 m L at any one site. Do not inject at any site previously used. Severe local tissue reactions may oc-cur. Recommend a 30-day slaughter withdrawal at this dos-age. (Hjerpe 1986) For mastitis: a) Dry cow (using dry cow formula): Milk out affected quarter, clean and disinfect. Infuse contents of one syringe into each affected quarter at time of drying off. Close teat oriﬁce with gentle pressure and massage udder. b) Lactating cow (using lactating cow formula): As above, but repeat after each milking for 3 milkings (Label directions; Erythro®-Dry and Erythro®-36—Ceva) !THORSES: For treatment of C. (Rhodococcus) equi infections in foals: a) Erythromycin: 15-25 mg/kg PO q12-24h daily, with Ri-fampin (5 mg/kg, PO q12h). Treatment may be necessary for 1-3 months. (Chafﬁn 2006b) b) Erythromycin: 25 mg/kg PO q12h with rifampin: 3-5 mg/ kg PO q12h. If rifampin use becomes cost prohibitive, use erythromycin alone. Treat for 4-6 weeks or until lungs are clear of abscesses on radiographs. (Foreman 1999) For treatment of proliferative enteropathy caused by L. intracel-lularis infections in foals: a) Erythromycin estolate: 25 mg/kg PO q6-8h, with rifampin: 10 mg/kg PO q12h for a minimum of 21 days (Lavoie and Drolet 2003) For susceptible infections: a) Foals: Erythromycin estolate: 25 mg/kg PO q6h; Erythromy-cin gluceptate: 5 mg/kg IV q4-6h (Caprile and Short 1987); (Brumbaugh 1999) As a prokinetic agent: a) 0. 1-1 mg/kg, IV or erythromycin lactobionate 2. 2 mg/kg IV over a 30-60 minute period every 6 hours. Dose in a 450 kg horse is 1 gram. (Moore 1999) !TSWINE: For susceptible infections: a) For respiratory infections: 2. 2-6. 6 mg/kg IM once daily b) For scours in young pigs: 22 mg/kg IM in one or more daily doses (Label directions; Erythro®-100 and Erythro®-200— Ceva) !TSHEEP: For susceptible infections: a) For respiratory infections in older animals: 2. 2 mg/kg IM once daily as indicated. b) For prevention of “dysentery” in newborn lambs when the likely causative agent is susceptible to erythromycin: 123 mg/ kg IM once soon after birth (Label directions; Erythro®-100 and Erythro®-200—Ceva) Monitoring !TClinical efﬁcacy !TAdverse effects (periodic liver function tests if patient receiving erythromycin estolate long-term; may not be necessary for foals receiving erythromycin and rifampin for Rhodococcus infections) Client Information !The intramuscular 100 mg/m L ( Erythro-100®) product (Erythro-200®) has quite speciﬁc instructions on where and how to inject the drug. Refer to the label directions or package insert for more information before using. !TWhen administering orally to small animals, give on an empty stomach unless gastrointestinal signs (vomiting, lack of appetite, diarrhea) occur, then give with food. The estolate, ethylsuccinate or enteric-coated forms of erythromycin may be given with or without food. !TIf gastrointestinal adverse effects are severe or persist, contact veterinarian. Chemistry/Synonyms A macrolide antibiotic, produced from Streptomyces erythreus, erythromycin is a weak base that is available commercially in sev-eral salts and esters. It has a p K a of 8. 9. Erythromycin base occurs as a bitter tasting,odorless or practical-ly odorless, white to slight yellow, crystalline powder. Approximately 1 mg is soluble in 1 m L of water; it is soluble in alcohol.	pppbs.pdf
358 ESMOLOL HCL Erythromycin estolate occurs as a practically tasteless and odor-less, white, crystalline powder. It is practically insoluble in water and approximately 50 mg are soluble in 1 m L of alcohol. Erythromycin es-tolate may also be known as erythromycin propionate lauryl sulfate. Erythromycin ethylsuccinate occurs as a practically tasteless and odorless, white to slight yellow, crystalline powder. It is very slightly soluble in water and freely soluble in alcohol. Erythromycin lactobionate occurs as white to slightly yellow crystals or powder. It may have a faint odor and is freely soluble in water and alcohol. Erythromycin may also be known as: eritromicina, and erythro-mycinum; many trade names are available. Storage/Stability/Compatibility Erythromycin (base) capsules and tablets should be stored in tight containers at room temperature (15-30°C). Erythromycin estolate preparations should be protected from light. T o retain palatability, the oral suspensions should be refrigerated. Erythromycin ethylsuccinate tablets and powder for oral sus-pension should be stored in tight containers at room temperature. The commercially available oral suspension should be stored in the refrigerator to preserve palatability. After dispensing, the oral sus-pensions are stable for at least 14 days at room temperature, but individual products may have longer labeled stabilities. Erythromycin lactobionate powder for injection should be stored at room temperature. For initial reconstitution (vials), only sterile water for injection should be used. After reconstitution, the drug is stable for 24 hours at room temperature and 2 weeks if refrigerated. T o prepare for administration via continuous or intermittent infu-sion, the drug is further diluted in 0. 9% sodium chloride, Lactated Ringer's, or Normosol-R. Other infusion solutions may be used, but ﬁrst must be buffered with 4% sodium bicarbonate injection (1 m L per 100 m L of solution). At p H's of <5. 5, the drug is unstable and loses potency rapidly. Many drugs are physically incompatible with erythromycin lactobionate; it is suggested to consult specialized ref-erences or a hospital pharmacist for more speciﬁc information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Erythromycin 100 mg/m L for IM Injection (with 2% butyl amin-obenzoate as a local anesthetic) in 100 m L vials; Gallimycin®-100 (Bimeda); (OTC). Approved for use in cattle, sheep, and swine. Milk withdrawal (when used as labeled) = 72 hours. Slaughter withdraw-al (when used as labeled) for cattle =14 days, sheep = 3 days, swine =7 days. There may also be erythromycin premixes alone and in combination with other drugs for use in swine and/or poultry. HUMAN-LABELED PRODUCTS: Erythromycin Base Delayed-release Tablets enteric-coated: 250 mg, 333 mg and 500 mg; Ery-Tab® (Abbott); (Rx) Erythromycin Base Tablets Film-coated: 250 mg, & 500 mg; Erythro-mycin Filmtabs® (Abbott); (Rx) Erythromycin Base Tablets with polymer coated particles: 333 mg and 500 mg; PCE Dispertab® (Abbott); (Rx) Erythromycin Base Delayed-release Capsules enteric-coated pellets: 250 mg; Eryc® (FH Faulding & Co. Ltd. ); generic; (Rx) Erythromycin Estolate Suspension: 125 mg (as base) per 5 m L in 473 m L and 250 mg (as base) per 5 m L in 473 m L; generic (Alpharma); (Rx) Erythromycin Stearate Film-coated tablets: 250 mg, 500 mg; Erythro-cin Stearate® (Abbott); (Rx) Erythromycin Ethylsuccinate Tablets: 400 mg; E. E. S. 400® (Abbott); generic; (Rx) Erythromycin Ethylsuccinate Powder for Oral Suspension: 200 mg per 5 m L when reconstituted in 60 m L (400 mg only), 100 m L, 200 m L and UD 5 m L; E. E. S. ® Granules (Abbott), Ery Ped® 200 and 400 (Abbott); (Rx) Erythromycin Ethylsuccinate Oral Suspension: 200 mg per 5 m L in 100, 480 m L; EES 200® (Abbott); generic; (Rx) Erythromycin Ethylsuccinate Oral Suspension: 400 mg per 5 m L in 100 & 480 m L; EES 400® (Abbott) (Rx); generic; (Rx) Erythromycin Ethylsuccinate Oral Suspension: 100 mg per 2. 5 m L in 50 m L; Ery Ped Drops® (Abbott); (Rx) Erythromycin Lactobionate Powder for Injection: 500 mg and 1 g (as lactobionate) in vials, piggyback vials and ADD-Vantage vials; Eyth-rocin® (Abbott); (Rx); generic; (Rx) Erythromycin & Sulﬁsoxazole Granules for Oral Suspension: eryth-romycin ethylsuccinate (equivalent to 200 mg erythromycin activity) and sulﬁsoxazole acetyl (equivalent to 600 mg sulﬁsoxazole) per 5 m L when reconstituted in 100 m L, 150 m L & 200 m L; Eryzole® (Alra); Pediazole® (Ross); generic; (Rx) T opical and ophthalmic preparations are also available. ESMOLOL HCL (ess-moe-lol) Brevibloc® BETA-1 BLOCKER Prescriber Highlights TT Ultra-short acting beta 1-blocker used IV for short-term treatment of SVT's or to determine if beta-blockers are effective for controlling arrhythmias TT Contraindications: Patients with overt cardiac failure, 2nd or 3rd degree AV block, sinus bradycardia, or in cardio-genic shock TT Caution: Patients with CHF, bronchoconstrictive lung dis-ease, or diabetes mellitus TT Adverse Effects: Hypotension & bradycardia are the ef-fects most likely seen Uses/Indications Esmolol may be used as test drug to indicate whether beta-blocker therapy is warranted as an antiarrhythmic agent, particularly in cats with hypertrophic cardiomyopathy, or as an infusion in the short-term treatment of supraventricular tachyarrhythmias (e. g., atrial ﬁbrillation/ﬂutter, sinus tachycardia). Pharmacology/Actions Esmolol primarily blocks both beta 1-adrenergic receptors in the myocardium. At clinically used doses, esmolol does not have any intrinsic sympathomimetic activity (ISA) and unlike propranolol, does not possess membrane-stabilizing effects (quinidine-like) or bronchoconstrictive effects. Cardiovascular effects secondary to es-molol include negative inotropic and chronotropic activity that can lead to reduced myocardial oxygen demand. Systolic and diastolic blood pressures are reduced at rest and during exercise. Esmolol's antiarrhythmic effect is thought to be due to its blockade of adren-ergic stimulation of cardiac pacemaker potentials. Esmolol increas-	pppbs.pdf
ESMOLOL HCL 359 es sinus cycle length, slows A V node conduction, and prolongs sinus node recovery time. Pharmacokinetics After IV injection esmolol is rapidly and widely distributed but not appreciably to the CNS, spleen or testes. The distribution half-life is about 2 minutes. Steady-state blood levels occur in about 5 min-utes if a loading dose was given or about 30 minutes if no load was given. It is unknown whether the drug crosses the placenta or enters milk. Esmolol is rapidly metabolized in the blood by esterases to a practically inactive metabolite. Renal or hepatic dysfunction do not appreciably alter elimination characteristics. T erminal half-life is about 10 minutes and duration of action after discontinuing IV infusion is usually about 20 minutes post-infusion in dogs. Contraindications/Precautions/Warnings Esmolol is contraindicated in patients with overt cardiac failure, 2nd or 3rd degree A V block, sinus bradycardia, or in cardiogenic shock. It should be used with caution (weigh beneﬁt vs. risk) in patients with CHF, bronchoconstrictive lung disease, or diabetes mellitus. Adverse Effects At usual doses adverse effects are uncommon and generally are an extension of the drug's pharmacologic effects. Hypotension (with resultant clinical signs) and bradycardia are the most likely ad-verse effects seen. These usually prove mild and transient in nature. Esmolol may mask certain clinical signs of developing hypoglyce-mia (such as increased heart rate or blood pressure). Reproductive/Nursing Safety Studies done in rats and rabbits demonstrated no teratogenic ef-fects at doses up to 3 times the maximum human maintenance dose (MHMD). Higher doses (8 times or more MHMD) demonstrated some maternal death and fetal resorption. It is unknown if esmolol is excreted in milk. Overdosage/Acute Toxicity The IV LD 50 in dogs is approximately 32 mg/kg. Dogs receiving 2 mg/kg per minute for one hour showed no adverse effects; doses of 3 mg/kg/minute for one hour produced ataxia and salivation and 4 mg/kg/minute for one hour caused muscular rigidity, tremors, sei-zures, ptosis, vomiting, hyperpnea, vocalizations, and prostration. These effects all resolved within 90 minutes of the end of infusion. Because of the short duration of action of the drug, discontinu-ation or dosage reduction may be all that is required; otherwise, symptomatic and supportive treatment may be initiated. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving esmolol and may be of signiﬁcance in veterinary patients: !TDIGOXIN : Esmolol may increase serum digoxin levels up to 20%, but these drugs have been used together safely and effectively !TMONOAMINE OXIDASE INHIBITORS : Concurrent use of monoamine oxidase inhibitors with esmolol is not recommended due to po-tential risk of hypertension !TMORPHINE : Titrate esmolol dosage carefully in patients also re-ceiving morphine as it may increase steady-state esmolol serum concentrations up to 50%. !TRESERPINE : May see additive effects (hypotension, bradycardia) if used with esmolol !TVASOCONSTRICTORS/INOTROPES (e. g., dopamine, epinephrine, norepi-nephrine ): If systemic vascular resistance is high, there is an in-crease risk for blocked cardiac contractility; esmolol is not rec-ommended to control SVT's in patients receiving these drugs !TVERAPAMIL : In humans, particularly with severe cardiomyopathy, cardiac arrest has occurred (rarely) Doses !TDOGS: For ultra-short acting beta blockade (for treating or assisting in treatment of ventricular arrhythmias): a) Can be administered two ways: 1) An initial loading dose of 0. 25-0. 5 mg/kg (250-500 mcg/kg) administered IV as slow bolus over 1-2 minutes, then followed by a constant rate in-fusion of 10-200 mcg/kg/minute; or 2) Start CRI at 10-200 mcg/kg/minute without the bolus loading dose. If no loading dose, maximal effect should occur in 10-20 minutes. Use of a loading dose and the high end of the infusion rate dose should only be used in dogs with normal cardiac func-tion. In dogs with severe dilated cardiomyopathy or severe mitral regurgitation do not give loading dose and start CRI at 10-20 mcg/kg/min and titrate upward every 10 minutes to an effective endpoint. (Kittleson 2006c) b) For SVTs: 0. 05-0. 1 mg/kg (50-100 mcg/kg) IV bolus over 2 minutes; repeat every 5 minutes to a maximum of 0. 5 mg/kg (500 mcg/kg). (Fine 2006), (Rush 2005b) c) Loading dose of 200-500 mcg/kg IV over 1 minute; followed by a constant rate IV infusion of 25-200 mcg/kg/minute (Ware 2000) d) Give incremental doses of 0. 05-0. 1 mg/kg boluses every 5 minutes to a maximum dose of 0. 5 mg/kg; or as an infusion of 50-200 micrograms/kg/min. If arrhythmia conversion does not occur, then other drugs with negative inotropic ef-fects (e. g., diltiazem or verapamil) may be given 30 minutes after esmolol administration. (Russell and Rush 1995) !TCATS: For ultra-short acting beta blockade for treating or assisting in treatment of ventricular arrhythmias, or in cats with HCM to determine if beta-blockers will reduce the dynamic left-ventric-ular outﬂow tract obstruction resulting from systolic anterior motion of the mitral valve: a) In cats with HCM: An initial loading dose of 0. 25-0. 5 mg/kg (250-500 mcg/kg) administered IV as slow bolus over 1-2 minutes, then followed by a constant rate infusion of 10-200 mcg/kg/minute. (Kittleson 2006c) b) Loading dose of 200-500 mcg/kg IV over 1 minute; followed by a constant rate IV infusion of 25-200 mcg/kg/minute (Ware 2000) Monitoring !TBlood Pressure !TECG !THeart Rate Client Information !TEsmolol should only be used in an in-patient setting where ap-propriate monitoring is available. Chemistry/Synonyms A short acting beta1-adrenergic blocker, esmolol occurs as white or off white crystalline powder. It is not as lipophilic as either labetolol or propranolol, but is comparable to acebutolol. 650 mg are soluble in one m L of water and 350 mg are soluble in one m L of alcohol. Esmolol HCl may also be known as ASL-8052, Brevibloc® or Miniblock®.	pppbs.pdf
360 ESTRADIOL CYPIONATE Storage/Stability/Compatibility The concentrate for injection should be stored at room tempera-ture; do not freeze and protect from excessive heat. It is a clear, colorless to light yellow solution. Expiration dates of 3 years are assigned after manufacture. After diluted to a concentration of 10 mg/m L esmolol HCl is stable (at refrigeration temperatures or room temperature) for at least 24 hours in commonly used IV solutions. Esmolol may be di-luted in standard D5, LRS or saline (or combinations thereof) IV ﬂuids. At this concentration it is reportedly physically compatible with digoxin, dopamine, fentanyl, lidocaine, morphine sulfate, ni-troglycerin, and nitroprusside. 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 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Esmolol HCl Injection: 10 mg/m L in 10 m L vials, 20 mg/m L in 5 m L vials and 100 m L bags, and 250 mg/m L in 10 m L amps; Brevibloc® (Baxter); generic; (Rx) ESTRADIOL CYPIONATE (ess-tra-dye-ole) ECP® HORMONAL A GENT (ESTROGEN) Prescriber Highlights TT Natural estrogen salt used primarily to induce estrus; has been used as an abortifacient (but rarely recommended today) TT Contraindications: Pregnancy (abortifacient, teratogen); the FDA has stated that the use of ECP in food animals is illegal TT Adverse Effects: In CATS & DOGS: bone marrow toxicity, cystic endometrial hyperplasia, pyometra; TT In male animals, feminization may occur; in females, signs of estrus may occur; TT In CATTLE: Prolonged estrus, genital irritation, decreased milk ﬂow, precocious development, & follicular cysts may develop TT Drug Interactions Uses/Indications For mares, indications for the use of estradiol include induction of estrus during the non-breeding or breeding seasons and to enhance the mare's uterine defense mechanism. Estradiol cypionate has his-torically been used as an abortifacient agent in cattle, cats and dogs. Estrogens are no longer recommended by most theriogenologists for use as an abortifacient in small animals. The FDA stated (April 5, 2006): “The use of ECP in food-producing animals is illegal, and manufacturing and compounding of ECP for such use is illegal. ” Pharmacology/Actions The most active endogenous estrogen, estradiol possesses the phar-macologic proﬁle expected of the estrogen class. Estrogens are necessary for the normal growth and development of the female sex organs and in some species contribute to the development and maintenance of secondary female sex characteristics. Estrogens cause increased cell height and secretions of the cervical mucosa, thickening of the vaginal mucosa, endometrial proliferation, and increased uterine tone. Estrogens have effects on the skeletal system. They increase cal-cium deposition, accelerate epiphyseal closure, and increase bone formation. Estrogens have a slight anabolic effect and can increase sodium and water retention. Estrogens affect the release of gonadotropins from the pituitary gland. This can cause inhibition of lactation, ovulation, and andro-gen secretion. Pharmacokinetics No speciﬁc information was located regarding the pharmacoki-netics of estradiol in veterinary species. In humans, estrogen in oil solutions after IM administration are absorbed promptly and ab-sorption continues over several days. Esteriﬁed estrogens (e. g., es-tradiol cypionate) have delayed absorption after IM administration. Estrogens are distributed throughout the body and accumulate in adipose tissue. Elimination of the steroidal estrogens occurs prin-cipally by hepatic metabolism. Estrogens and their metabolites are primarily excreted in the urine, but are also excreted into the bile where most is reabsorbed from the GI. Contraindications/Precautions/Warnings Estradiol is contraindicated during pregnancy as it can cause fetal malformations of the genitourinary system and induce bone mar-row depression in the fetus. Estradiol cypionate should not be used to treat estrogen-re-sponsive incontinence in small animals; other estrogens (DES, con-jugated estrogens) are less toxic. In cases of prolonged corpus luteum in cows, a thorough uterine exam should be completed to determine if endometritis or a fetus is present. Estradiol is reportedly very toxic (bone marrow) to ferrets. Adverse Effects Estrogens have been associated with severe adverse reactions in small animals. In cats and dogs, estrogens are considered toxic to the bone marrow and can cause blood dyscrasias. Blood dyscrasias are more prevalent in older animals and if higher dosages are used. Initially, a thrombocytosis and/or leukocytosis may be noted, but thrombocytopenia/leukopenias will gradually develop. Changes in a peripheral blood smear may be apparent within two weeks after estrogen administration. Chronic estrogen toxicity may be charac-terized by a normochromic, normocytic anemia, thrombocytope-nia, and neutropenia. Bone marrow depression may be transient and begin to resolve within 30-40 days or may persist or progress to a fatal aplastic anemia. Estrogens may cause cystic endometrial hyperplasia and pyo-metra. After therapy is initiated, an open-cervix pyometra may be noted 1-6 weeks after therapy. Estrogens may induce mammary neoplasia. When used chronically in male animals, feminization may occur. In females, signs of estrus may occur and persist for 7-10 days. In cattle, prolonged estrus, genital irritation, decreased milk-ﬂow, precocious development, and follicular cysts may develop af-ter estrogen therapy. These effects may be secondary to overdosage and dosage adjustment may reduce or eliminate them.	pppbs.pdf
ESTRADIOL CYPIONATE 361 Reproductive/Nursing Safety Estradiol is contraindicated during pregnancy. In humans, the FDA categorizes this drug as category X for use during pregnan-cy (Studies in animals or humans demonstrate fetal abnormalities or adverse reaction; reports indicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible beneﬁt. ) In a separate system evaluating the safety of drugs in canine and fe-line pregnancy (Papich 1989), this drug is categorized as in class: D (Contraindicated. These drugs have been shown to cause congenital malformations or embryotoxicity. ) Estrogens have been shown to decrease the quantity and quality of maternal milk. Overdosage/Acute Toxicity No reports of inadvertent acute overdosage in veterinary patients were located; see Adverse Effects above. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving estradiol and may be of signiﬁcance in veterinary patients: !TAZOLE ANTIFUNGALS (ﬂuconazole, itraconazole, ketoconazole ): May increase estrogen levels !TCORTICOSTEROIDS : Enhanced glucocorticoid effects may result if estrogens are used concomitantly with corticosteroid agents. It has been postulated that estrogens may either alter the protein binding of corticosteroids and/or decrease their metabolism; corticosteroid dosage adjustment may be necessary when estro-gen therapy is either started or discontinued !TMACROLIDE ANTIBIOTICS (erythromycin, clarithromycin ): May increase estrogen levels !TPHENOBARBITAL : May decrease estrogen activity if administered concomitantly !TRIFAMPIN : May decrease estrogen activity if administered con-comitantly !TST. JOHN'S WORT : May decrease estrogen activity if administered concomitantly !TWARFARIN : Oral anticoagulant activity may be decreased if estro-gens are administered concurrently; increases in anticoagulant dosage may be necessary if adding estrogens Laboratory Considerations !TEstrogens in combination with progestins ( e. g., oral contracep-tives) have been demonstrated in humans to increase thyroxine-binding globulin (TBG) with resultant increases in total circulating thyroid hormone. Decreased T 3 resin uptake also occurs, but free T4 levels are unaltered. It is unclear if estradiol affects these labo-ratory tests in veterinary patients. Doses !TDOGS: For pregnancy avoidance after mismating: Note : This drug is rarely used for this indication today. a) 0. 02 mg/kg (ECP) IM within 72 hours of mating (Burke 1986) b) 0. 044 mg/kg (ECP) IM once during 3-5 days of standing heat or within 72 hours of mismating (Woody 1988) c) 0. 044 mg/kg (ECP), not to exceed 1 mg total dose, IM once administered during estrus or early diestrus (Olson et al. 1986) !TCATS: For pregnancy avoidance after mismating: Note : This drug is rarely used for this indication today. a) 0. 125-0. 25 mg (ECP) IM within 40 hours of mating (Wildt 1986) b) 0. 125-0. 25 mg (ECP) IM within 3-5 days of coitus (Woody 1988) !TCATTLE: The FDA has stated that the use of ECP in food-producing ani-mals is illegal. !THORSES: For induction of estrus during the non-breeding season: a) 10 mg estradiol cypionate will result in estrus 2-3 days after treatment (Squires and Mc Kinnon 1987) For treatment of mares with estrogen-responsive incontinence: a) 4-10 mcg/kg estradiol cypionate IM daily for three days and then every other day. Some mares will improve, but does not “cure. ” (Schott II and Carr 2003) For induction of estrus in mares with “silent heat” during breed-ing season: a) 1 mg estradiol (Squires and Mc Kinnon 1987) T o enhance the mare's uterine defense mechanism: a) 1-2 mg estradiol daily for 3-5 days (Squires and Mc Kinnon 1987) Monitoring When therapy is either at high dosages or chronic, see adverse ef-fects for more information. Done at least monthly: !TPacked Cell Volumes (PCV) !TWhite blood cell counts (CBC) !TPlatelet counts; Baseline, one month after therapy, and repeated two months after cessation of therapy if abnormal !TLiver function tests Chemistry/Synonyms Estradiol is a naturally occurring steroidal estrogen. Estradiol cy-pionate is produced by esterifying estradiol with cyclopentanepro-pionic acid, and occurs as a white to practically white, crystalline powder. It is either odorless or may have a slight odor and has a melting range of 149-153°C. Less than 0. 1 mg/m L is soluble in wa-ter and 25 mg/m L is soluble in alcohol. Estradiol cypionate is spar-ingly soluble in vegetable oils. Estradiol may also be known as: beta-oestradiol, dihydrofolli-culin, dihydrotheelin, dihydroxyoestrin, estradiolum, NSC-9895, NSC-20293 (alpha-estradiol), and oestradiol; many trade names are available. Estradiol Cypionate may also be known as: oestradiol cyclopen-tylpropionate, oestradiol cypionate, Delestrogen®, Depo-Estradiol®, Depogen ®, Dura-Estrin®, ECP®, E-Cypionate®, Estra-D®, Es trace®, Estro-Cyp®, Estroject®, dep Gynogen®, Femtrace®, or Gynodiol®. Storage/Stability/Compatibility Estradiol cypionate should be stored in light-resistant containers at temperatures of less than 40°C, preferably at room temperature (15-30°C); avoid freezing. Commercially available injectable solutions of estradiol cypi-onate are sterile solutions in a vegetable oil (usually cottonseed oil); they may contain chlorobutanol as a preservative. It is not recommended to mix estradiol cypionate with other medications.	pppbs.pdf
362 ETHACRYNIC ACID Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: There are several estradiol-containing implants for use in beef cattle. HUMAN-LABELED PRODUCTS: Estradiol Cypionate in Oil for Injection: 5 mg/m L in 5 m L vials; De-po-Estradiol® (Pharmacia); (Rx) Estradiol Valerate in Oil for Injection: 10 mg/m L, 20 mg/m L & 40 mg/m L in 5 m L vials; Delestrogen® (Monarch); (Rx) Estradiol Tablets: 0. 45 mg, 0. 5 mg, 0. 9 mg, 1 mg, 1. 5 mg, 1. 8 mg and 2 mg micronized estradiol; Estrace® (Warner Chilcott), Gynodiol® (Fielding), Femtrace® (Warner Chilcott); generic; (Rx) ETHACRYNIC ACID ETHACRYNATE SODIUM (eth-a-krin-ik) Edecrin® LOOP DIURETIC Prescriber Highlights TT Rarely-used loop diuretic similar to furosemide; may have greater ototoxicity & GI effects than furosemide TT Contraindications: Patients with anuria, hypersensitivity, or seriously depleted electrolytes TT Caution: Patients with pre-existing electrolyte or water balance abnormalities, impaired hepatic function, & dia-betes mellitus TT Adverse Effects: Fluid & electrolyte abnormalities. Others include ototoxicity, GI distress, hematologic effects, weak-ness, & restlessness TT Drug Interactions Uses/Indications Ethacrynic acid is a loop diuretic that shares the same indications as furosemide (congestive cardiomyopathy, pulmonary edema, hy-percalcuric nephropathy, uremia, as adjunctive therapy in hyper-kalemia and, occasionally, as an antihypertensive agent). Its use has been largely supplanted in the armamentarium by furosemide for these indications. Ethacrynic acid may be useful in the treatment of nephrogenic diabetes insipidus as it may cause a paradoxical decrease in urine volume. Other uses include the adjunctive treatment of hypercal-cemia and to increase the excretion of bromide in the treatment of bromide toxicity. Pharmacology/Actions Ethacrynic acid reduces the absorption of electrolytes in the as-cending section of the loop of Henle, decreases the reabsorption of both sodium (to a much greater extent than the thiazides) and chloride, increases the excretion of potassium in the distal renal tu-bule, and directly effects electrolyte transport in the proximal tu-bule. The exact mechanisms of ethacrynic acid's effects have not been established. It has no effect on carbonic anhydrase nor does it antagonize aldosterone. Ethacrynic acid increases renal excretion of water, sodium, potassium, chloride, calcium, magnesium, hydro-gen, ammonium, and bicarbonate. Pharmacokinetics Ethacrynic acid is absorbed rapidly and nearly completely from the GI tract. It does not enter the CNS and accumulates in the liver. It is unknown if ethacrynic acid crosses the placenta or enters milk. Ethacrynic acid is metabolized in the liver and also secreted via the proximal tubules into the urine. Serum half-lives in humans aver-ages around one hour. Duration of effect is about 6-8 hours after oral dosing; about 2 hours after IV administration. Contraindications/Precautions/Warnings Ethacrynic acid is contraindicated in patients with anuria, are hy-persensitive to the drug, or have seriously depleted electrolytes. Ethacrynic acid is also contraindicated in human infants (safety not established). Ethacrynic acid should be used with caution in patients with pre-existing electrolyte or water balance abnormalities, impaired hepatic function (may precipitate hepatic coma), and diabetes mel-litus. Patients with conditions that may lead to electrolyte or wa-ter balance abnormalities (e. g., vomiting, diarrhea, etc. ) should be monitored carefully. Adverse Effects Ethacrynic acid may induce ﬂuid and electrolyte abnormalities. Pa-tients should be monitored for hydration status and electrolyte im-balances (especially potassium, calcium and sodium). Other poten-tial adverse effects include ototoxicity (especially in cats with high dose IV therapy), gastrointestinal disturbances, hematologic effects (anemia, leukopenia), weakness, and restlessness. Ethacrynic acid is thought to have a greater incidence of ototoxicity and GI effects than furosemide. Reproductive/Nursing Safety A study where pregnant dogs received 5 mg/kg daily demonstrated no teratogenic effects or effects on the pregnancy. It is unknown whether the drug enters milk. 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 stud-ies in pregnant women; or animal studies have shown an adverse ef-fect, 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 ethacrynic acid is distributed into milk. Overdosage/Acute Toxicity The LD 50 in dogs after oral administration is >1000 mg/kg; after IV injection >300 mg/kg. Chronic overdosing at 10 mg/kg for six months in dogs led to development of calciﬁcation and scarring of the renal parenchyma. Acute overdosage may cause electrolyte and water balance prob-lems, CNS effects (lethargy to coma and seizures) and cardiovascu-lar collapse. Treatment consists of emptying the gut after recent oral inges-tion, using standard protocols. Avoid giving concomitant cathartics as they may exacerbate the ﬂuid and electrolyte imbalances that can occur. Aggressively monitor and treat electrolyte and water balance abnormalities supportively. Additionally, monitor respiratory, CNS, and cardiovascular status; treat supportively and symptomatically, if necessary. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ethacrynic acid and may be of signiﬁcance in veterinary patients:	pppbs.pdf
ETHAMBUTOL HCL 363 T ! ACE INHIBITORS (e. g., enalapril, benazepril ): Increased risks for hy-potension, particularly in patients who are volume or sodium depleted secondary to diuretics T ! AMINOGLYCOSIDES (gentamicin, amikacin, etc. ): Increased risk for nephro-or ototoxicity T ! AMPHOTERICIN B: Loop diuretics may increase the risk for nephro-toxicity development; hypokalemia T ! CORTICOSTEROIDS : Increased risk for GI ulceration; hypokalemia T ! DIGOXIN : Ethacrynic acid-induced hypokalemia may increase the potential for digoxin toxicity T ! INSULIN : Ethacrynic acid may alter insulin requirements T ! MUSCLE RELAXANTS : Ethacrynic acid may inhibit the muscle re-laxation qualities of tubocurarine, but increase the effects of succinylcholine T ! PROBENECID : Can reduce the diuretic efﬁcacy of ethacrynic acid, and ethacrynic acid may reduce probenecid's uricosuric effects T ! SALICYLATES : Loop diuretics can reduce the excretion of salicylates T ! THEOPHYLLINE : Pharmacologic effects of theophylline may be en-hanced when used with ethacrynic acid Doses T ! DOGS & CAT S: a) 0. 2-0. 4 mg/kg IM or IV q4-12h (Allen, Pringle et al. 1993) Monitoring T ! Serum electrolytes, BUN, creatinine, glucose T ! Hydration status T ! Blood pressure, if indicated T ! Clinical signs of edema, patient weight, if indicated T ! Evaluation of ototoxicity, particularly with prolonged therapy or in cats Client Information T ! Recommend administering dosage with meals when possible. T ! Clients should contact veterinarian if clinical signs of water or electrolyte imbalance occur; excessive thirst, lethargy, lassitude, restlessness, oliguria, GI distress, or tachycardia Chemistry/Synonyms A loop diuretic, ethacrynic acid occurs as a white or nearly white, odorless or practically odorless crystalline powder. It is very slightly soluble in water and freely soluble in alcohol. Ethacrynic acid may also be known as etacrynic acid, acidum etacrynicum, etacrynsaure, MK-595, NSC-85791, Edecril®, Edecrin®, Reomax®, and Uregyt ®. Storage/Stability Ethacrynic acid tablets should be stored at room temperature in well-closed containers. An expiration date of 5 years is assigned at the time of manufacture. 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: Ethacrynic Acid Tablets: 25 mg, & 50 mg; Edecrin® (Merck); (Rx) Ethacrynate Sodium Powder for Injection: 50 mg ethacrynic sodium/50 m L vial for reconstitution; Edecrin® Sodium (Merck); (Rx) ETHAMBUTOL HCL (e-tham-byoo-tole) Myambutol®, Etibi® ORAL A NTIMYCOBACTERIAL ANTIBIOTIC Prescriber Highlights TT Can be used as an ingredient in an antimycobacterial “cocktail” for dogs, cats, birds TT Treating these infections is controversial because of po-tential public health risks associated with the infections TT Optic or neuro toxicity greatest concern Uses/Indications In combination with other antimycobacterial drugs, ethambutol may be useful in treating mycobacterial infections caused by M. bo-vis, M. tuberculosis, M. genavense, M. avium-intracellulare complex (MAC) in dogs or cats, particularly when the organism is resistant to treatment with other drug combinations (rifampin, enroﬂoxa-cin, azithromycin). In birds, ethambutol has been used in combina-tion with other agents for treating mycobacterial (e. g., M. avium) infections. Because of public health risks, particularly in the face of in-creased populations of immunocompromised people, treatment of mycobacterial (M. bovis, M. tuberculosis, etc. ) infections in domes-tic or captive animals is controversial. Pharmacology/Actions A synthetic, bacteriostatic, antimycobacterial agent, ethambutol's exact mechanism of action is not known. Ethambutol is only active against actively dividing mycobacteria. It enters mycobacterial cells and interferes with RNA synthesis. Ethambutol does not have appre-ciable activity against other bacteria or fungi. Resistance can occur and is thought to develop in a step-wise manner. Cross-resistance with other antimycobacterial agents has not been reported. Pharmacokinetics Pharmacokinetic values for cats or birds were not located. In dogs, ethambutol is reported to have a volume of distribution of 3. 8 L/kg, a total body clearance of 13. 2 m L/min/kg, and an elimination half-life of 4. 1 hours. Nephrectomized dogs had an elimination half-life of 5 hours. In humans, ethambutol is rapidly absorbed after PO adminis-tration and bioavailability is around 75%. The drug is distributed widely in the body, but CSF levels only range from 10-50% of those found in serum. Erythrocyte concentrations are about twice that of the serum and can serve as a depot for the drug. About 15% of ab-sorbed drug is hepatically metabolized to inactive metabolites. The majority of the drug is eliminated both by tubular secretion and glomerular ﬁltration as unchanged drug in the urine. Elimination half-life in humans with normal renal function is about 3-4 hours; up to 8 hours if renal function is impaired. Contraindications/Precautions/Warnings Ethambutol should not be used in patients with a history of prior hypersensitivity reactions to it. Patients with markedly reduced renal function may need dosage adjustment. Adverse Effects Well-described adverse effect proﬁles for ethambutol in dogs, cats or birds are not available. Because ethambutol is used in combination with other medications, adverse effects associated with treatment	pppbs.pdf
364 ETHAMBUTOL HCL Tmay not be a result of ethambutol. In pre-clinical studies, some dogs receiving ethambutol over prolonged periods developed non-dose related degenerative changes in the central nervous system. In toxicology studies, dogs receiving large, prolonged doses developed signs of myocardial toxicity and depigmentation of the tapetum lucidum of the eyes. However, doses as large as 400 mg/kg/day for 4 weeks in dogs demonstrated no signiﬁcant abnormalities in elec-troretinogram or visual evoked potential. In humans, optic neuritis (usually reversible after drug discontinuation) causing decreased visual acuity has been reported; routine ophthalmologic exams are recommended for humans taking this medication long-term. Reproductive/Nursing Safety Ethambutol crosses the placenta; fetal levels are reported to range from 30-75% of that found in maternal serum. Teratogenic ef-fects associated with ethambutol have not been reported in hu-mans, but studies in mice, rats, and rabbits given high doses yield-ed a variety of abnormalities in offspring. Although risks exist, most believe that ethambutol is relatively safe to use during hu-man pregnancy and untreated tuberculosis poses a much greater risk to the fetus. Ethambutol is excreted into milk in levels approximating those found in maternal serum. While no problems have been document-ed and it is most likely safe, risk to offspring cannot be ruled out. Overdosage/Acute Toxicity Very limited information exists. Acute overdoses of greater than 10 grams in humans have caused optic neuritis. Other adverse effects noted with human overdoses can include: CNS effects (confusion, visual hallucinations), abdominal pain, nausea, fever and headache; treatment is supportive. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ethambutol and may be of signiﬁcance in veterinary patients: !TALUMINUM-CONTAINING ANTACIDS : In humans, it has been docu-mented that co-administration can reduce oral absorption of ethambutol; it is suggested to separate dosing by at least 4 hours if both drugs are necessary Laboratory Considerations No speciﬁc concerns; in humans, increased serum uric acid levels have been noted Doses !TDOGS: a) For treatment of disseminated M. tuberculosis: Ethambutol: 10-25 mg/kg PO once daily, in combination with rifampin (5-10 mg/kg PO q12-24h; maximum of 600 mg/day) and isoniazid (10-20 mg/kg PO once daily; maximum of 300 mg/day). May also add pyrizinamide at 15-40 mg/kg PO once daily. Note : pyrizinamide is ineffective for M. bovis. Treatment must continue for more than 9 months. (Greene and Gunn-Moore 2006) !TCATS: a) For treatment of feline tuberculosis: Initial treatment phase with rifampin (10-20 mg/kg PO q12-24h); enroﬂoxa-cin (5 mg/kg PO q12-24h); azithromycin (5-10 mg/kg PO q12-24h) for the ﬁrst two months, then continuation phase (for approximately another 4 months) with rifampin and either enroﬂoxacin or azithromycin. If resistance devel-ops, rifampin, isoniazid (10-20 mg/kg PO once daily) and ethambutol (15 mg/kg PO once daily) may be considered. If only two drugs are required, suggest using only rifampin and isoniazid. (Hartmannn and Greene 2005) !TBIRDS: a) For treatment of M. avium infections in caged birds: Several protocols have been used, but controlled trials have not been performed. Combination therapy and treatment for 6-12 months is required. Protocol 1: Ciproﬂoxacin 20 mg/kg PO q12h or Enroﬂoxacin 15 mg/kg PO or IM ( Note : repeated IM injections can cause muscle necrosis) for 10 days; Clofazimine 1. 5 mg/kg PO once daily; Cycloserine 5 mg/kg PO q12h; and Ethambutol 20 mg/ kg PO q12h. Protocol 2: Clofazimine 6 mg/kg PO once daily; Ethambutol 30 mg/kg PO once daily; Rifampin 45 mg/kg PO once daily. Protocol 3: Ciproﬂoxacin 80 mg/kg PO once daily or Enro-ﬂoxacin 30 mg/kg PO once daily; Ethambutol 30 mg/kg PO once daily; Rifampin 45 mg/kg PO once daily or Rifabutin 15 mg/kg PO once daily. (Phalen 2006) b) For Avian mycobacteriosis: All are dosed PO once daily for 9-12 months: Rifabutin 45-55 mg/kg; Clarithromycin 60-85 mg/kg; Ethambutol 30-85 mg/kg; Enroﬂoxacin 20 mg/kg. (Flammer 2006) Monitoring !TClinical efﬁcacy !TWith long-term therapy, consider periodic monitoring of visual, liver, and renal function; CBC Client Information !TClients must be informed of the potential public health issues associated with mycobacterium infections and should be encour-aged to contact a physician, preferably an infectious disease spe-cialist for guidance !Treatment can be very prolonged (many months) and expensive !TMay be administered with or without food !TReport any changes noted with patient's eyes or vision to the vet-erinarian Chemistry/Synonyms Ethambutol HCl occurs as a white, crystalline powder that is freely soluble in water and soluble in alcohol. Ethambutol may also be known as: CL-40882, etambutol, or ethambutoli; there are many trade names for international products. Storage/Stability Ethambutol tablets should be stored below 40°C and preferably, be-tween 15-30°C in well-closed containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Ethambutol HCl Tablets: 100 mg, & 400 mg (scored); Myambutol® (X-Gen); (Rx)	pppbs.pdf
ETHANOL 365 ETHANOL ALCOHOL, ETHYL (eth-a-nol) Alcohol ANTIDOTE Prescriber Highlights TT Used for treatment of ethylene glycol or methanol toxicity TT Contraindications: None (above are life threatening) TT Adverse Effects: CNS depression, diuresis, pain, & infec-tion at the injection site. TT Avoid extravasation TT Monitor ﬂuid & electrolyte status, alcohol & toxin levels (if possible) Uses/Indications The principal use of ethanol in veterinary medicine is for the treat-ment of ethylene glycol or methanol toxicity. While fomepizole (4-methyl pyrazole) is now the treatment of choice for ethylene gly-col poisoning, alcohol is a readily available and an economical alter-native when patients present within a few hours after ingestion. Percutaneous injection of ethanol 95% has been used success-fully to treat feline hyperthyroidism. Ethyl alcohol has also been used in aerosol form as a mucoki-netic agent in horses. Pharmacology/Actions By competitively inhibiting alcohol dehydrogenase, alcohol can pre-vent the forma tion of ethylene glycol to its toxic metabolites (glyco-aldehyde, glycolate, glyoxalate, and oxalic acid). This allows the ethyl-ene glycol to be principally excreted in the urine unchanged. A similar scenario exists for the treatment of methanol poisoning. For alcohol to be effective, however, it must be given very early after ingestion; it is seldom useful if started 8 hours after a signiﬁcant ingestion. Pharmacokinetics Alcohol is well absorbed orally, but is administered intravenously for toxicity treatment. It rapidly distributes throughout the body and crosses the blood-brain barrier. Alcohol crosses the placenta. Contraindications/Precautions/Warnings Because ethylene glycol and methanol intoxications are life threat-ening, there are no absolute contraindications to ethanol's use for these indications. Use of ethanol with fomepizole is usually contraindicated; see drug interactions for more information. Adverse Effects The systemic adverse effects of alcohol are quite well known. The CNS depression and respiratory depression associated with the high levels used to treat ethylene glycol and methanol toxicity can con-fuse the clinical monitoring of these toxicities. Ethanol's affects on antidiuretic hormone may enhance diuresis. As both ethylene glycol and methanol may also cause diuresis, ﬂuid and electrolyte therapy requirements need to be monitored and managed. Hypocalcemia and metabolic acidosis may be noted and pulmonary edema can occur. Other adverse affects include pain and infection at the in-jection site and phlebitis. Extravasation should be watched for and avoided. When aerosolized in horses, irritation and bronchocon-striction may result. Reproductive/Nursing Safety Alcohol's safety during pregnancy has not been established for short-term use. Use only when necessary. In humans, the FDA cat-egorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Alcohol passes freely into milk in levels that approximate mater-nal serum levels, but it is unlikely to have negative effects on nurs-ing offspring. Overdosage/Acute Toxicity If clinical signs of overdosage occur, either slow the infusion or dis-continue temporarily. Alcohol blood levels may be used to monitor both efﬁcacy and toxicity of alcohol. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ethanol and may be of signiﬁcance in veterinary patients: T ! BROMOCRIPTINE : Alcohol may increase the severity of side effects seen with bromocriptine T ! CHARCOAL, ACTIVATED : Will inhibit absorption of orally admin-istered ethanol; do not use activated charcoal if administering ethanol orally for methanol or ethylene glycol intoxication T ! CNS DEPRESSANT DRUGS (e. g., barbiturates, benzodiazepines, phe-nothiazines, etc. ): Alcohol may cause additive CNS depression when used with other CNS depressant drugs T ! FOMEPIZOLE (4-MP ): Inhibits alcohol dehydrogenase; ethanol me-tabolism is reduced signiﬁcantly and alcohol poisoning (CNS depression, coma, death) can occur. Use together is generally not recommended, but if both drugs are used, monitoring of ethanol blood levels is mandatory. T ! INSULIN and other antidiabetic drugs : Alcohol may affect glucose metabolism and the actions of insulin or oral antidiabetic agents T ! A disulﬁram reaction (increased acetaldehyde with tachycardia, vomiting, weakness) may occur if alcohol is used concomitantly with the following drugs: cefoperazone, chlorpropamide, furazoli-done, metronidazole Doses T ! DOGS: For ethylene glycol poisoning: a) As a 20% solution, give 5. 5 m L/kg IV q4h for 5 treatments, then q6h for four additional treatments (Forrester and Lees 1994) b) Using a 5% solution, give 22 m L/kg IV every 4 hours for 24 hours, then every 6 hours for another 24 hours; alternatively give a constant rate IV infusion to run at 5. 5 m L/kg/hr (Firth 2000) T ! CATS: For ethylene glycol poisoning: a) As a 20% solution, give 5 m L/kg IV q6h for 5 treatments, then q8h for four additional treatments (Forrester and Lees 1994) b) Using a 5% solution, give a constant rate IV infusion to run at 5 m L/kg/hr (Firth 2000) Monitoring T ! Alcohol blood levels (and ethylene glycol or methanol levels). Note : In humans, blood ethanol levels should be maintained at 100 to 130 milligrams/deciliter (21. 7 to 28. 2 milli Moles/liter). It is safer to maintain a blood ethanol concentration greater than	pppbs.pdf
366 ETIDRONATE DISODIUM T T130 milligrams/deciliter than to have it fall below 100 milligrams/ deciliter. (POISINDEX® Managements, Thompson; MICROME-DEX® Healthcare Series, 2007) T ! Degree of CNS effect T ! Fluid/electrolyte status Client Information T ! Systemically administered alcohol should be given in a controlled clinical environment. Chemistry/Synonyms A transparent, colorless, volatile liquid having a characteristic odor and a burning taste, ethyl alcohol is miscible with water and many other solvents. Ethanol may also be known as aethanolum, alcool, grain alcohol, ethanolum, and ethyl alcohol. Storage/Stability/Compatibility/Preparation Alcohol should be protected from extreme heat or freezing. Do not use unless the solution is clear. Alcohol may precipitate many drugs; do not administer other medications in the alcohol infusion solu-tion unless compatibility is documented (consult specialized refer-ences or a hospital pharmacist for more speciﬁc information). Note : Since alcohol infusions are generally only used in veterinary medicine for the treatment of ethylene glycol/methanol toxicity and obtaining medical or laboratory grade alcohol or pharmaceutical grade products can be very difﬁcult in an emergency, veterinarians have often had to improvise. One method that has been successful, albeit not pharmaceutically elegant, is to use commercially available vodka (40%, 80 proof) diluted in an appropriate IV solution. T ! o make a 20% ethanol solution using 80 proof (40%) vodka: dilute with an equal volume (500 m L with 500 m L) of IV ﬂuids (e. g. ; LRS, Normosol-R). T ! o make a 5% solution using 80 proof (40%) vodka: add 125 m L of 80 proof (40%) vodka to 875 m L of IV ﬂuid (remove about 125 m L of ﬂuid from the bag). 100 proof (50%) vodka or 190 proof (95%) grain alcohol (“Everclear”) can also be used. Dilute as appropriate to make a 5-20% solution. Regardless of the product used, it is recommend-ed that an in-line ﬁlter be used for the IV. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Alcohol (Ethanol) in Dextrose Infusions: 5% Alcohol and 5% Dextrose in Water (450 Cal/L, 1114 m Osm/L) in 1000 m L; generic; (Rx) 5% Alcohol and 5% Dextrose in Water (450 Cal/L, 1125 m Osm/L) in 1000 m L; (Mc Gaw); (Rx) 10% Alcohol and 5% Dextrose in Water (720 Cal/L, 1995 m Osm/L) in 1000 m L; (Mc Gaw) (Rx) For information on obtaining tax-free alcohol for medicinal pur-poses, contact a regional ofﬁce of the Bureau of Alcohol, T obacco, and Firearms. ETIDRONATE DISODIUM (e-ti-droe-nate) Didronel® ORAL BISPHOSPHONATE BONE RESORPTION INHIBITOR Prescriber Highlights TT Biphosphonate that reduces calcium resorption from bone; used primarily to treat hypercalcemia associated with malignancy TT Contraindications: Treatment of hypercalcemia in pa-tients with severe renal function impairment TT Caution in patients with bone fractures, enterocolitis, car-diac failure, or moderate renal function impairment TT Adverse Effects: Potentially, diarrhea, nausea, or bone pain/tenderness TT Do not confuse etidronate with etretinate or etomidate TT Expense may be an issue Uses/Indications Etidronate is a ﬁrst generation bisphosphonate that may be use-ful for the treatment of severe hypercalcemia associated with neo-plastic disease. Its use in human medicine has been largely replaced with newer, more potent bisphosphonates that can be dosed less often or have fewer adverse effects. Etidronate is also indicated in humans for the treatment of Paget's disease and heterotopic ossiﬁ-cation (e. g., after total hip replacement). Pharmacology/Actions Etidronate's primary site of action is bone. It reduces normal and abnormal bone resorption. This effect can reduce hypercalcemia associated with malignant neoplasms. Etidronate can also increase serum phosphate concentrations, presumably by increasing the re-nal tubular reabsorption of phosphate. Some early studies in lab animals suggest that etidronate may inhibit the formation of bone metastases with some tumor types. Pharmacokinetics Oral absorption is poor and dose dependent. As little as 1% of a dose (smaller doses) may be absorbed; with higher doses, 6-10% may be absorbed. After oral dosing, the drug is rapidly cleared from blood and 50% of the drug absorbed goes into bone. At usual doses, it appears that etidronate does not cross the placenta. Duration of effect may be very prolonged. In humans, effects have persisted for up to one year after discontinuation in patients with Paget's disease. Effects for hypercalcemia may last for 11 days. Absorbed etidronate is excreted unchanged by the kidneys. Approximately 50% of the absorbed dose is excreted within 24 hours; the remainder is chemisorbed to bone and then slowly eliminated. Contraindications/Precautions/Warnings Etidronate is considered contraindicated for the treatment of hy-percalcemia in patients with renal function impairment (serum creatinines >5 mg/d L). Risk vs. beneﬁt should be carefully consid-ered in patients with bone fractures (delays healing), enterocolitis (higher risk of diarrhea), cardiac failure (especially with parenteral etidronate as patients may not tolerate the extra ﬂuid load), or those with renal function impairment (serum creatinines 2. 5-5 mg/d L). Do not confuse etidronate with etretinate or etomidate.	pppbs.pdf
ETODOLAC 367 Adverse Effects Adverse effects are not well described in small animals. In humans, diarrhea, nausea (with higher oral doses), and bone pain/tender-ness are most the likely adverse effects reported. Increases in serum creatinine are possible. Reproductive/Nursing Safety Etidronate's safety during pregnancy has not been established. Rabbits given oral doses 5X those recommended in humans, dem-onstrated no overt problems with offspring. Rats, given very large doses IV, showed skeletal malformations. In humans, the FDA cat-egorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) It is unknown if the drug enters milk. Overdosage/Acute Toxicity Very little information is available at this time. Overdoses may re-sult in hypocalcemia (ECG changes may occur), bleeding problems (secondary to rapid chelation of calcium) and proximal renal tu-bule damage. Use standard gut emptying protocols after oral ingestion when warranted. IV calcium administration (e. g., calcium gluconate) may be used to reverse hypocalcemia. Intensive monitoring is suggested. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving etidronate and may be of signiﬁcance in veterinary patients: T ! ANTACIDS, DIARY PRODUCTS, MINERAL SUPPLEMENTS, and medica-tions containing iron, magnesium, calcium or aluminum : Absorption of oral etidronate may be inhibited; separate etidronate doses from these substances by at least two hours. Laboratory Considerations T ! Etidronate may interfere with bone uptake of technetium Tc 99m medronate or technetium Tc 99m oxidronate Doses T ! DOGS: For severe hypercalcemia associated with neoplastic disease: a) 5 mg/kg/day PO (Papich 1992); (Gaschen 2000) b) 5-20 mg/kg/day PO (Ward 1999) c) 5-15 mg/kg daily to twice daily PO; for moderate to severe hypercalcemia (Chew, Schenck et al. 2003) T ! CATS: For severe hypercalcemia associated with neoplastic disease: a) 10 mg/kg/day PO (Papich 1992) b) 5-20 mg/kg/day PO (Ward 1999) Monitoring T ! Serum calcium T ! Serum protein Client Information T ! Recommended to give dose to animal that has an empty stomach. T ! If anorexia or vomiting occur, notify veterinarian. Chemistry/Synonyms An analog of pyrophosphate, etidronate disodium (also known as EHDP, Na2EHDP, or sodium etidronate) is a biphosphonate agent that occurs as a white powder and is freely soluble in water. Unlike pyrophosphate, etidronate is resistant to enzymatic degradation in the gut. Etidronate disodium may also be known as: EHDP, disodium etidronate, etidronate disodium, Anfozan®, Bonemass®, Didronate®, Didronel®, Difosfen®, Diphos®, Dralen®, Dronate-OS®, Etidrate®, Etidron®, Etiplus®, Feminoﬂex®, Ostedron®, Osteodidronel, Osteum®, Ostogene®, Ostopor®, Somaﬂex®, and Sviroxit®. Storage/Stability Store tablets in tight containers at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Etidronate Disodium Tablets: 200 mg, & 400 mg; Didronel® (Procter & Gamble Pharm. ); Etidronate Disodium (Genpharm); (Rx) ETODOLAC (ee-toe-doe-lak) Eto Gesic®, Lodine® NON-STEROIDAL A NTIINFLA MMATORY AGENT Prescriber Highlights TT NSAID (oral) used in dogs, relatively few adverse effects & labeled for once daily TT Contraindications: Hypersensitivity TT Caution: Patients with preexisting or occult GI, hepatic, renal, cardiovascular, or hematologic abnormalities TT Safe use not established for dogs less than 12 months of age or in breeding, pregnant, or lactating dogs TT Adverse Effects: Vomiting, diarrhea, lethargy, hypopro-teinemia; keratoconjunctivitis sicca possible TT Drug interactions Uses/Indications Etodolac is labeled for the management of pain and inﬂammation associated with osteoarthritis in dogs. It may ﬁnd uses, however, for a variety of conditions where pain and/or inﬂammation should be treated. Pharmacology/Actions Like other NSAIDs, etodolac has analgesic, antiinﬂammatory, and antipyretic activity. Etodolac appears to be more selective for inhi-bition of cyclooxygenase-2 than cyclooxygenase-1. This means that the drug should possess greater inhibition of the prostaglandins in-volved with pain and inﬂammation than those involved with cyto-protection of the GI tract and renal tissue. Etodolac is also thought to inhibit macrophage chemotaxis, which may explain some of its antiinﬂammatory activity. In horses, etodolac does not exhibit much COX-2 selectivity. Pharmacokinetics The S(+) enantiomer is thought to provide the bulk of the phar-macologic activity, but the drug is supplied as a racemic mixture. Pharmacokinetic studies that measure both forms as one are not very relevant clinically. After oral administration to healthy dogs, etodolac is rapidly and nearly completely absorbed. The presence of food may alter the rate, but not the extent, of absorption. Peak serum levels occur about 2 hours post dosing. Etodolac is highly	pppbs.pdf
368 ETODOLAC bound to serum proteins. The drug is primarily excreted via the bile into the feces. Glucuronide conjugates have been detected in the bile but not the urine. Elimination half-life in dogs varies depend-ing whether food is present in the gut, which may affect the rate of enterohepatic circulation of the drug. These values range from about 8 hours (fasted) to 12 hours (non-fasted). In horses, etodolac has an oral bioavailability of about 77%. After IV dosing, volume of distribution was 0. 29 L/kg and the clear-ance was 235 m L/hr/kg. Elimination half-life (after IV dosing) was approximately 2. 5-3 hours. Contraindications/Precautions/Warnings Etodolac is contraindicated in dogs previously found to be hyper-sensitive to it. It should be used with caution in dogs with preex-isting or occult GI, hepatic, cardiovascular, or hematologic abnor-malities as NSAIDs may exacerbate these conditions. Patients may be more susceptible to renal injury from etodolac if they are dehy-drated, on diuretics, or have preexisting renal, hepatic, or cardiovas-cular dysfunction. Safety of etodolac has not been established in dogs less than 12 months of age. Adverse Effects In clinical ﬁeld studies, etodolac's primary adverse effect was vomit-ing/regurgitation, reported in about 5% of dogs tested. Diarrhea, lethargy, and hypoproteinemia were also reported in a small num-ber of dogs. Urticaria, behavioral changes, and inappetence were reported in less than 1% of dogs treated. It must be remembered, however, that as the drug is used in many more dogs for signiﬁcant periods, additional adverse effects may surface. Etodolac may decrease total serum T4 in some dogs. Clinical sig-niﬁcance is unclear. Etodolac appears to have less impact on clotting times than oth-er canine-approved NSAIDs. Cases have been reported of dogs developing keratoconjunctivi-tis sicca (KCS) after receiving etodolac treatment. Incidence rate is unknown at this time. Potentially, hepatotoxicity and/or nephrotoxicity are possible. The manufacturer warns to terminate therapy if inappetence, vomiting, fecal abnormalities, or anemia are observed. Reproductive/Nursing Safety Safe use has not been established in breeding, pregnant, or lactat-ing dogs; use only when the beneﬁts clearly outweigh the potential risks in these animals. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Most NSAIDs are excreted in milk; use with caution. Overdosage/Acute Toxicity Limited information is available, but in a safety study where dogs were given 40 mg/kg/day (2. 7X) GI ulcers, weight loss, emesis and local occult blood were noted. Doses of 80 mg/kg/day (5. 3X), caused 6 of 8 dogs to either die or become moribund secondary to GI ulceration. It should be noted that these were not single dose overdoses. However, they demonstrate that there is a relatively nar-row therapeutic window for the drug in dogs and that doses should be carefully determined (i. e., do not confuse mg/kg dosages with mg/lb). There were 34 exposures to etodolac reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) during 2005-2006. In these cases 24 cases were dogs that showed no clini-cal signs and 10 were cats with 2 showing clinical signs. Common ﬁndings in these cats are recorded in decreasing frequency includ-ing acute renal failure, anorexia, collapse, hyperkalemia and hyper-salivation. This medication is a NSAID. As with any NSAID, overdosage can lead 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 monitor etodolac's use with other drugs, especially those that are also highly protein bound. It also recommends close monitoring, or to avoid using etodolac with any other ulcerogenic drugs (e. g., corti-costeroids, other NSAIDs ). The following drug interactions have either been reported or are theoretical in humans or animals receiving etodolac and may be of signiﬁcance in veterinary patients: !TACE INHIBITORS (enalapril, benazepril, etc. ): Etodolac may reduce the antihypertensive effects of ACE inhibitors !TASPIRIN : When aspirin is used concurrently with etodolac, plasma levels of etodolac could decrease and an increased likelihood of GI adverse effects (blood loss) could occur; concomitant admin-istration of aspirin with etodolac cannot be recommended !TCYCLOSPORINE : Etodolac may increase cyclosporine blood levels and increase the risk for nephrotoxicity !TDIGOXIN : Etodolac may increase serum levels of digoxin. Use with caution in patients with severe cardiac failure !TFUROSEMIDE & OTHER DIURETICS : Etodolac may reduce the saluretic and diuretic effects of furosemide !TMETHOTREXATE : Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate; use together with caution !TNEPHROTOXIC AGENTS (e. g., amphotericin B, aminoglycosides, cispl-atin, etc. ): Potential for increased risk of nephrotoxicity if used with NSAIDs !TPROBENECID : May cause a signiﬁcant increase in serum levels and half-life of etodolac !TWARFARIN : Etodolac may increase the risk for bleeding Laboratory Considerations !TEtodolac may cause false-positive determinations of urine bilirubin. !TEtodolac therapy may alter thyroid function tests and their interpre-tation; falsely low values may occur in dogs receiving etodolac. Doses !TDOGS: a) For treatment of pain and inﬂammation associated with os-teoarthritis: 10-15 mg/kg PO once daily. Dogs less than 5 kg cannot be accurately dosed with Eto Gesic®. Adjust dose to obtain satisfactory response, but do not exceed 15 mg/kg. For long-term therapy, reduce dose level to minimum effective dosage. (Package Insert; Eto Gesic®—Fort Dodge) b) 5-15 mg/kg PO once daily (Hardie 2000) Monitoring !TBaseline (especially in geriatric dogs or dogs with chronic diseas-es or those where prolonged treatment is likely): physical exam, CBC, Serum chemistry panel (including liver and renal function tests), UA. It is recommended to reassess liver enzymes at one	pppbs.pdf
ETOMIDATE 369 week of therapy. Should elevation occur, recommend discontinu-ing the drug T ! Clinical efﬁcacy T ! Signs of potential adverse reactions: inappetence, diarrhea, mucoid feces, vomiting, melena, polyuria/polydipsia, anemia, jaundice, lethargy, tear production, behavior changes, ataxia, or seizures T ! Chronic therapy: Consider repeating CBC, UA, and serum chem-istries on an ongoing basis. Client information T ! Give the client written information on the proper use and moni-toring for etodolac Chemistry/Synonyms An indole acetic acid derivative non-steroidal antiinﬂammatory agent (NSAID), etodolac occurs as a white, crystalline compound that is insoluble in water, but soluble in alcohol or DMSO. Etodolac has a chirally active center with a corresponding S (+) enantiomer and an R (-) enantiomer. The commercially available product is supplied as a racemic mixture of the forms. Etodolac may also be known as: AY-24236, etodolacum, etodolic acid, Acudor®, Articulan®, Dualgan®, Eccoxolac®, Edolan®, Elderin®, Eto Gesic®, Etonox®, Etopan®, Flancox®, Hypen ®, Lodot®, Lonine®, Metazin®, Sodolac®, Todolac®, Ultradol®, and Zedolac®. Storage/Stability The commercially available veterinary tablets should be stored at controlled room temperature (15-30°C). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Etodolac Scored Tablets: 150 mg and 300 mg in bottles of 30 and 90; Eto Gesic® (Fort Dodge); (Rx). Approved for use in dogs. Do not use in cats. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Etodolac Tablets: 200 mg, 300 mg, 400 mg, 500 mg tablets and 400 mg, 500 mg and 600 mg extended release tablets; generic; (Rx) ETOMIDATE (ee-toe-mi-date) Amidate® INJECTA BLE ANESTHETIC Prescriber Highlights TT Injectable non-barbiturate anesthetic agent that may be useful as an alternative to thiopental or propofol for induction, particularly in patients with preexisting cardiac dysfunction, head trauma, or that are critically ill TT Not a controlled substance TT Relatively expensive, especially in large dogs Uses/Indications Etomidate may be useful as an alternative to thiopental or propofol for anesthetic induction in small animals, particularly in patients with preexisting cardiac dysfunction, head trauma, or that are criti-cally ill. Pharmacology/Actions The exact mechanism of action of etomidate is not well deﬁned. Etomidate causes minimal hemodynamic changes and little effect on the cardiovascular system when compared to other injectable anesthetic agents. At usual doses, etomidate has little effect on re-spiratory rate or rhythm. Etomidate decreases cerebral blood ﬂow and oxygen consumption. It usually lowers intraocular pressure and causes slight decreases in intracranial pressure. The reported therapeutic index (toxic dose/therapeutic dose) for etomidate is 16. Therapeutic indexes for propofol and thiopen-tal are 3 and 5 respectively. Pharmacokinetics No speciﬁc information on the pharmacokinetics of etomidate in domesticated animals was located. In humans, after intravenous injection etomidate is rapidly distributed into the CNS and then rapidly cleared from the brain back into systemic tissues. Duration of hypnosis is short (3-5 minutes) and dependent upon dose. Recovery from anesthesia appears to be as fast as with thiopental, but slower than propofol. Etomidate is 75% bound to plasma pro-teins. The drug is rapidly metabolized in the liver primarily via hy-drolysis or glucuronidation to inactive metabolites. The majority of the drug and metabolites are excreted into the urine with the remainder into the bile and feces. Elimination half-life ranges from 1. 25-5 hours. Contraindications/Precautions/Warnings Etomidate is contraindicated in patients known to be hypersensi-tive to it. Etomidate can inhibit adrenocortical function; it should not be used for purposes other than induction, and with caution in pa-tients whose adrenocortical function is impaired. Exogenous glu-cocorticoid administration should be considered in severely com-promised animals. Etomidate does not provide any analgesia. Limited studies in patients with impaired hepatic or renal func-tion have shown that elimination half-lives may be signiﬁcantly in-creased in these patients. Adverse Effects Common adverse effects include pain at intravenous injection site, skeletal muscle movements (myoclonus), eye movements, and post-operative retching. Preanesthetic medications and a benzodi-azepine (diazepam, midazolam) just prior to etomidate can mini-mize these effects. Some hemolysis may occur due to the propylene glycol content of the injection. Some anesthesiologists recommend injecting eto-midate into a running IV line to decrease the pain associated with injection and, potentially, reduce hemolysis. While etomidate causes minimal cardiopulmonary depression, a brief period of hypoventilation and decreased arterial blood pres-sure can occur after administration. Apnea, laryngospasm, hiccups, hyperventilation, hypoventila-tion, hypertension, hypotension, lactic acidosis, arrhythmias, and postoperative vomiting have all been reported in human patients that have received the drug. Seizures have been reported in a few human patients receiving etomidate; this adverse effect may be re-duced if an opiate premed is ﬁrst administered. Reproductive/Nursing Safety In humans, the FDA categorizes etomidate 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).	pppbs.pdf
370 EUTHANASIA AGENTS WITH PENTOBARBITAL Etomidate has caused embryocidal effects in rats and maternal tox-icity in rabbits and rats. Some etomidate is excreted into maternal milk; use with caution in nursing patients. Overdosage/Acute Toxicity Acute overdoses would be expected to cause enhanced pharma-cologic effects of the drug. Treatment would be supportive (i. e., mechanical ventilation), until the effects of the medication are diminished. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving etomidate and may be of signiﬁcance in veterinary patients: T ! CNS/RESPIRATORY DEPRESSANTS (e. g., barbiturates, opiates, anes-thetics, etc. ): Additive pharmacological effects can occur if eto-midate is used concurrently with other drugs that can depress CNS or respiratory function T ! VERAPAMIL : Has been associated with potentiating the anesthetic and respiratory depressant effects of etomidate Laboratory Considerations No speciﬁc laboratory interactions or considerations located. Doses T ! DOGS & CAT S: a) As an induction agent: etomidate 1 mg/kg IV plus diazepam 0. 5 mg/kg IV (Cornell 2004) b) As an induction agent: 1-2 mg/kg rapidly IV (Heath 2003) c) As an induction agent: 0. 5-2 mg/kg IV. Pre-medication is highly recommended to reduce incidence of side effects (myoclonus, vomiting). Alternatively or additionally, eto-midate may be given with a benzodiazepine. Because of its effects on cortisol, administration of a physiologic dose of dexamethasone or another short-acting glucocorticoid prior to etomidate is suggested. (Mama 2002a) T ! FERRETS: a) As an induction agent in the cardiovascular unstable patient: etomidate 1-2 mg/kg IV after diazepam (0. 5 mg/kg IV) (Lichtenberger 2006a) T ! SMALL MAMMALS: a) Rabbits: As an induction agent in the cardiovascular unstable patient: etomidate 1-2 mg/kg IV after diazepam (0. 5 mg/kg IV) (Lichtenberger 2006a) Monitoring As per any anesthetic agent: T ! Level of consciousness T ! Respiration rate and depth T ! Cardiovascular function Client Information T ! Etomidate is a potent sedative-hypnotic that should only be used by professionals in a setting where adequate patient monitoring is available. Chemistry/Synonyms An injectable, carboxylic imidazole anesthetic, etomidate occurs as a white or almost white powder. It is very slightly soluble in water and freely soluble in alcohol. The commercially available injection has a p H of 8. 1, contains 35% propylene glycol, and is hyperosmo-lar (4640 mosm/l). Etomidate may also be known as: R-16659, Amidate®, Hypnomidate®, Radenarcon®, or Sibul®. Storage/Stability Unless otherwise labeled, store etomidate injection at room tem-perature and protect from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Etomidate Injection: 2 mg/m L in 10 m L, 20 m L amps and 20 m L Ab-boject syringes; Amidate® (Hospira); (Rx) Etretinate—see Acitretin EUTHANASIA AGENTS WITH PENTOBARBITAL (yoo-thon-ayzh-ya; pen-toe-barb-i-tal) For therapeutic uses (other than euthanasia) of pentobarbital, see the main pentobarbital monograph for this agent. The sections on chemis-try, storage, pharmacokinetics, overdosage, drug interactions, and moni-toring parameters can be found in the main pentobarbital monograph. Prescriber Highlights TT Used for humane euthanasia for animals not to be used for food TT Store so that it will not be confused with therapeutic agents; keep out of reach of children TT Use care in handling ﬁlled syringes & dispose of used injection equipment properly TT Avoid any contact with open wounds or accidental injection TT Tranquilizing agent may be necessary when the animal is in pain or agitated TT Renderers may not accept carcasses euthanized with pentobarbital Uses/Indications For rapid, humane euthanasia in animals not intended for food purposes. Individual products may be approved for use in speciﬁc species. “The advantages of using barbiturates for euthanasia in small animals far outweigh the disadvantages. Intravenous injection of a barbituric acid derivative is the preferred method for euthanasia of dogs, cats, other small animals, and horses. Intraperitoneal injec-tion may be used in situations when an intravenous injection would be distressful or even dangerous. Intracardiac injection must only be used if the animal is heavily sedated, unconscious, or anesthe-tized. ” (A VMA Guidelines on Euthanasia, 2007) Pharmacology/Actions Pentobarbital causes death by severely depressing the medullary respiratory and vasomotor centers when administered at high doses. Cardiac activity may persist for several minutes following administration.	pppbs.pdf
FAMCICLOVIR 371 Phenytoin is added to Beuthanasia®-D Special ( Schering) for its added cardiac depressant effects and to denature the compounds from a Class-II controlled substance to Class-III drugs. Contraindications/Precautions/Warnings Must not be used in animals to be used for food purposes (hu-man or animal consumption). Should be stored in such a manner that these products will not be confused with therapeutic agents. Extreme care in handling ﬁlled syringes and proper disposal of used injection equipment must be undertaken. Avoid any contact with open wounds or accidental injection. Keep out of reach of children. Prior use of a tranquilizing agent may be necessary when the animal is in pain or agitated. Adverse Effects Minor muscle twitching may occur after injection. Death may be delayed or not accomplished if injection given perivascularly. Doses Because different products have different concentrations, please re-fer to the information provided with the product in use. T ! DOGS: a) Pentobarbital sodium (as a single agent): Approximately 120 mg/kg for the ﬁrst 4. 5 kg of body weight, and 60 mg/kg for every 4. 5 kg of body weight thereafter. Preferably administer IV. b) Pentobarbital sodium with phenytoin (Beuthanasia®-D Spe-cial): 1 m L for each 4. 5 kg of body weight. T ! CATS: a) Pentobarbital sodium (as a single agent): Approximately 120 mg/kg for the ﬁrst 4. 5 kg of body weight, and 60 mg/kg for every 4. 5 kg of body weight thereafter. Administer IV. b) Pentobarbital sodium with phenytoin: (Beuthanasia®-D Spe-cial): 1 m L for each 4. 5 kg of body weight (not approved for use in this species) T ! LARGE ANIMALS: Note : must not be used in animals to be consumed by either humans or other animals. a) Depending on product concentration, most animals require 10-15 m L per 100 pounds of body weight. Monitoring T ! Respiratory rate T ! Cardiac rate T ! Corneal reﬂex Client Information T ! Must be administered by an individual familiar with its use. T ! Animals must be restrained during administration. T ! Inform clients observing euthanasia that animal may give a ter-minal gasp after becoming unconscious. Dosage Forms/Regulatory Status See other pentobarbital dosage forms under the main pentobar-bital monograph for lower concentration products that are used therapeutically. VETERINARY-LABELED PRODUCTS: Pentobarbital Sodium 390 mg/m L & Phenytoin Sodium 50 mg/m L for Injection (Euthanasia) in 100 m L vials; Beuthanasia®-D Special (Schering-Plough); Euthasol® (Virbac); Euthanasia-III® Solution (Med-Pharmex); Somnasol® (Butler); (Rx, C-III). Approved for use in dogs. Pentobarbital Sodium Powder: 392 mg/m L when constituted with 250 m L of water. Fatal-Plus® Pow-der (Vortech), Pentasol® Powder (Virbac); (Rx, C-II) Approved for use in animals regardless of species. Pentobarbital Sodium for Injection (Euthanasia): 260 mg/m L: Sleepaway® (Fort Dodge) 26%: in 100 m L bottles; (Rx, C-II). Approved for use in dogs and cats. 324 mg/m L: SP5® (Vedco) in 100 m L vials; (Rx, C-II). Approved for use in dogs and cats. 389 mg/m L: Socumb-6gr® (Butler), Somlethol® (Webster), SP6® (Ve-dco); 100 m L & 250 m L vials; (Rx, C-II). Approved for use in dogs and cats. 390 mg/m L: Fatal-Plus® Solution (Vortech); in 250 m L vials (Rx, C-II). Approved for use in animals regardless of species. HUMAN-LABELED PRODUCTS: None FAMCICLOVIR (fam-sye-klow-veer) Famvir® ANTIVIRAL (HERPES) Prescriber Highlights TT May be effective in treating feline herpes (FHV-1) infections TT Limited experience and information available in using this medication in cats TT Appears to be well tolerated when used short-term (2-3 weeks) Uses/Indications Famciclovir may be of beneﬁt in treating feline herpes infections. Pharmacology/Actions Famciclovir is rapidly converted in vivo to penciclovir. In cells in-fected with susceptible Herpes virus or varicella zoster virus, viral thymidine kinase phosphorylates penciclovir to penciclovir mono-phosphate. Cellular kinases further convert this compound to pen-ciclovir triphosphate which inhibits herpes virus DNA polymerase via competition with deoxyguanosine triphosphate, thereby selec-tively inhibiting herpes viral DNA synthesis. Viral resistance can occur by mutation. Pharmacokinetics In cats, after oral administration of famciclovir (62. 5 mg), penci-clovir peak levels were less than the in vitro inhibitory concentra-tion 50 (IC-50) for FHV-1. It is postulated that cats either absorb famciclovir or convert it to penciclovir poorly and that they will likely require higher doses than other species. (Thomasy, Maggs et al. 2006) In humans, famciclovir is well absorbed after oral administra-tion, but undergoes extensive ﬁrst pass metabolism (not by CYP enzymes). Food can decrease peak levels, but does not signiﬁcantly impact clinical efﬁcacy. Penciclovir (active metabolite) is only mar-ginally bound to plasma proteins. In humans, penciclovir elimina-tion half-life is about 2-3 hours; excretion is primarily via renal mechanisms. Intracellular half-lives of penciclovir in infected cells are signiﬁcantly longer.	pppbs.pdf
372 FAMOTIDINE TContraindications/Precautions/Warnings Famciclovir is contraindicated in patients known to be hypersensi-tive to it or penciclovir. It should be used with caution (and dosage adjustment) in pa-tients with renal dysfunction. In humans patients with Cr Cl <40 m L/min, dosage adjustments are recommended. Adverse Effects Adverse effects in cats are not well documented, but the drug ap-pears to be tolerated quite well when used for up to 3 weeks. In humans, famciclovir can cause nausea, vomiting, diarrhea, and headache. Neutropenia has been reported and renal failure can occur, particularly when doses are not adjusted in patients with re-nal dysfunction. Reproductive/Nursing Safety In laboratory animals, doses of up to 1,000 mg/kg/day did not cause any observed effects on developing embryos or fetuses. In humans, the FDA categorizes this drug as category B for use during preg-nancy (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 preg-nancy, and there is no evidence of risk in later trimesters. ) Famciclovir (as penciclovir) is excreted in the milk of rats. It is unclear if there is any clinical signiﬁcance for nursing offspring. Overdosage/Acute Toxicity Little information is available. Supportive treatment has been rec-ommended. Penciclovir can be removed by hemodialysis. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving famciclovir and may be of signiﬁcance in veterinary patients: T ! PROBENECID : Can reduce the amount of penciclovir excreted by the kidneys, increase penciclovir plasma levels can occur Laboratory Considerations No concerns noted Doses T ! CATS: For feline herpes virus (FHV-1): a) For adjunctive treatment of FHV-1 rhinotracheitis: 31. 25 mg (G of one 125 mg tablet) PO q12h for 14 days. Has not been evaluated for long-term therapy. (Lappin 2007) b) For chronic, recurrent and/or severe herpes viral infection: Dose range is variable! Kittens: Jth of one 125 mg tablet PO once daily (q24h) for 2 weeks; adult cats: G of one 250 mg tablet once daily (q24h) for 3 weeks. (Diehl 2007b) c) G of one 125 mg tablet PO twice daily (q12h) for 10-14 days; may continue once daily for up to 30 days. (Ramsey 2006) d) For adjunctive treatment (with interferon and lysine) of her-pes virus-associated ulcerative facial dermatitis & stomatitis: 125 mg PO q12h. (Hillier 2006c) Monitoring T ! Clinical efﬁcacy T ! Adverse effects (most likely GI) T ! Consider occasional CBC's and creatinine to monitor for neutro-penia or renal dysfunction if using the drug chronically Client Information T ! May be administered with food T ! here is limited experience with this drug in cats, report any un-usual effects to the veterinarian Chemistry/Synonyms A prodrug, famciclovir is a purine-derived, synthetic, acyclic purine nucleoside analog. Famciclovir may also be known as A V 42810, BRL 42810, famci-clovirum, or by the trade name Famvir®. Storage/Stability Famciclovir tablets should be stored at room temperature (15-30°C). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Famciclovir Tablets (ﬁlm-coated) 125 mg, 250 mg, & 500 mg: Fam-vir® (Novartis); generic; (Rx) FAMOTIDINE (fa-moe-ti-deen) Pepcid® H2-RECEPTOR ANTAGONIST Prescriber Highlights TT H2-receptor antagonist used to reduce GI acid production TT Longer duration of action & fewer drug interactions than cimetidine TT Contraindications: Hypersensitivity to H2 blockers TT Caution: Patients with cardiac disease, signiﬁcantly impaired hepatic or renal function; (consider dosage reduction) TT Adverse Effects: Too rapid IV infusion may cause brady-cardia. Potentially: GI effects, headache, or dry mouth or skin, intravascular hemolysis when given IV to cats Uses/Indications In veterinary medicine, famotidine may be useful for the treat-ment and/or prophylaxis of gastric, abomasal and duodenal ulcers, uremic gastritis, stress-related or drug-induced erosive gastritis, esophagitis, duodenal gastric reﬂux, and esophageal reﬂux. Famotidine has fewer drug interactions and activity may persist longer than cimetidine. Pharmacology/Actions At the H 2 receptors of the parietal cells, famotidine competitively inhibits histamine, thereby reducing gastric acid output both dur-ing basal conditions and when stimulated by food, pentagastrin, histamine or insulin. Gastric emptying time, pancreatic or biliary secretion, and lower esophageal pressures are not altered by famo-tidine. By decreasing the amount of gastric juice produced, H 2-blockers also decreases the amount of pepsin secreted. Pharmacokinetics Famotidine is not completely absorbed after oral administration, but undergoes only minimal ﬁrst-pass metabolism. In humans, sys-temic bioavailability is about 40-50%. Distribution characteristics are not well described. In rats, the drug concentrates in the liver,	pppbs.pdf
FAMOTIDINE 373 pancreas, kidney and submandibular gland. Only about 15-20% is bound to plasma proteins. In rats, the drug does not cross the blood brain barrier or the placenta. It is distributed into milk. When the drug is administered orally, about N is excreted unchanged in the urine and the remainder primarily metabolized in the liver and then excreted in the urine. After intravenous dosing, about 2/3's of a dose is excreted unchanged. The pharmacokinetics of famotidine, ranitidine, and cimetidine have been investigated in horses. (Duran and Ravis 1993) After a single IV dosage, elimination half-lives of cimetidine, ranitidine, and famotidine all were in the 2-3 hour range and were not signiﬁcantly different. Of the three drugs tested, famotidine had a larger volume of distribution (4. 28 L/kg) than either cimetidine (1. 14 L/kg) or raniti-dine (2. 04 L/kg). Bioavailability of each of the drugs was low; famoti-dine (13%), ranitidine (13. 5%) and cimetidine (30%). Contraindications/Precautions/Warnings Famotidine is contraindicated in patients with known hypersensi-tivity to the drug. Famotidine should be used cautiously in geriatric patients and patients with signiﬁcantly impaired hepatic or renal function. Consider dosage reduction in patients with signiﬁcant renal dys-function. Famotidine may have negative inotropic effects and have some cardioarrhythmogenic properties. Use with caution in pa-tients with cardiac disease. Adverse Effects T oo rapid IV infusion may cause bradycardia. Other H2-blockers have been demonstrated to be relatively safe and exhibit minimal adverse effects. Potential adverse effects (documented in humans) that could be seen include GI effects (anorexia, vomiting, diarrhea), headache, or dry mouth or skin. Rarely, agranulocytosis may de-velop particularly when used concomitantly with other drugs that can cause bone marrow depression. While some clinicians routinely use famotidine intravenously in cats, there have been anecdotal reports of famotidine causing intra-vascular hemolysis when given intravenously to cats. It is believed this is probably an idiosyncratic reaction that occurs in a small per-centage of cats treated. Reproductive/Nursing Safety In lab animal studies, famotidine demonstrated no detectable harm to offspring. Large doses could affect the mother's food intake and weight gain during pregnancy that could indirectly be harmful. Use in pregnancy when potential beneﬁts outweigh the risks. In rats, nursing from mothers receiving very high doses of famoti-dine, transient decreases in weight gain occurred. 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. ) Famotidine is excreted in the milk of rats. It is unclear if there is any clinical signiﬁcance for nursing offspring with H2-blockers in milk. Overdosage/Acute Toxicity The minimum acute lethal dose in dogs is reported to be >2 grams/ kg for oral doses and approximately 300 mg/kg for intravenous doses. IV doses in dogs ranging from 5-200 mg/kg IV caused: vomiting, restlessness, mucous membrane pallor and redness of the mouth and ears. Higher doses caused hypotension, tachycardia and collapse. Because of this wide margin of safety associated with the drug, most overdoses should require only monitoring. In massive oral overdoses, gut-emptying protocols should be considered and sup-portive therapy initiated when warranted. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving famotidine and may be of signiﬁcance in veterinary patients: !TAZOLE ANTIFUNGALS (ketoconazole, itraconazole, ﬂuconazole ): By raising gastric p H, famotidine may decrease the absorption of these agents; if both drugs are required, administer the azole one hour prior to famotidine !TCEFPODOXIME, CEFUROXIME : Famotidine may decrease the absorp-tion of these cephalosporins; taking with food may alleviate this effect !TIRON S ALTS (ORAL ): Famotidine may decrease the absorption of oral iron; administer iron at least one hour prior to famotidine Unlike cimetidine or ranitidine, famotidine does not appear to inhibit hepatic cytochrome P-450 enzyme systems and dosage ad-justments of other drugs (e. g., warfarin, theophylline, diazepam, procainamide, phenytoin) that are metabolized by this metabolic pathway should usually not be required. Laboratory Considerations !THistamine 2-blockers may antagonize the effects of histamine and pentagastrin in the evaluation gastric acid secretion. !TAfter using allergen extract skin tests, histamine 2 antagonists may inhibit histamine responses. It is recommended that hista-mine 2 blockers be discontinued at least 24 hours before perform-ing either of these tests. Doses !TDOGS: T o reduce gastric acid production: a) 0. 5 mg/kg PO, SC, IM, IV q12-24 hours (Matz 1995) b) 0. 5-1 mg/kg PO or IV once or twice daily (Johnson, Sherd-ing et al. 1994) c) 0. 1-0. 2 mg/kg PO q8h (Zerbe and Washabau 2000) d) 0. 55-1. 1 mg/kg PO q24h (or every 12 hours if there is se-vere esophagitis) for 2-3 weeks in dogs with acute reﬂex esophagitis (Tams 2003a) e) For adjunctive treatment (to prevent/treat gastric ulcers) of mast cell tumors: 0. 5 mg/kg once daily (route not speciﬁed). (Garrett 2006) f) For adjunctive treatment of GI effects (anorexia, nausea, vomiting) associated with chronic kidney disease: 0. 5 mg/ kg PO once daily (q24h) Effective evidence grade: 3. (Polzin 2005b) !TCATS: Note : See the warning (in the adverse effects section) about IV use in cats. T o reduce gastric acid production: a) 0. 5 mg/kg PO, SC, IM, IV q12-24 hours (Matz 1995) b) 0. 5 mg/kg PO or parenterally once daily (Trepanier 1999) c) 0. 55-1. 1 mg/kg PO q24h (or every 12 hours if there is severe esophagitis) for 2-3 weeks in cats with acute reﬂex esophagi-tis (Tams 2003a) For adjunctive treatment of GI effects (anorexia, nausea, vomit-ing) associated with chronic progressive renal disease: a) 1 mg/kg PO once daily (q24h) (Wolf 2006b)	pppbs.pdf
374 FATTY ACIDS, ESSENTIAL Tb) 0. 5-1 mg/kg PO once or twice daily (q12-24h) (Zoran 2006a) T ! FERRETS: a) For stress induced ulcers: 0. 25-0. 5 mg/kg PO, IV once daily (Williams 2000) b) In combination with antibiotics for Helicobacter treatment: 0. 25-0. 5 mg/kg PO, IV q24h (Fisher 2005) T ! SMALL MAMMALS: Rabbits: For stress induced ulcer prevention once critically ill animal has stabilized: a) 1 mg/kg IV once daily (q24h) (Johnston 2006) T ! HORSES: (Note : ARCI UCGFS Class 5 Drug) As an adjunct in ulcer treatment: a) IV doses: 0. 23 mg/kg, IV q8h or 0. 35 mg/kg IV q12h. Oral doses: 1. 88 mg/kg, PO q8h or 2. 8 mg/kg PO q12h (Du-ran and Ravis 1993) Monitoring T ! Clinical efﬁcacy (dependent on reason for use); monitored by decrease in symptomatology, endoscopic examination, blood in feces, etc. T ! Adverse effects, if noted Client Information T ! o maximize the beneﬁt of this medication, it must be adminis-tered as prescribed by the veterinarian T ! Clinical signs may reoccur if dosages are missed Chemistry/Synonyms An H 2-receptor antagonist, famotidine occurs as a white to pale yellow, crystalline powder. It is odorless, but has a bitter taste. 740 micrograms are soluble in one m L of water. Famotidine may also be known as: famotidinum, L-643341, MK-208, and YM-11170; many trade names are available. Storage/Stability/Compatibility Tablets should be stored in well-closed, light-resistant containers at room temperature. Tablets are assigned an expiration date of 30 months after date of manufacture. The powder for oral suspension should be stored in tight con-tainers at temperatures less than 40°C. After reconstitution, the re-sultant suspension is stable for 30 days when stored at temperatures less than 30°C. ; do not freeze. Famotidine injection should be stored in the refrigerator (2-8°C). It is physically compatible with most commonly used IV infusion solutions and is stable for 48 hours at room temperature when diluted in these solutions. 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: Famotidine Tablets (plain, ﬁlm-coated & orally disintegrating) & Gelcaps: 10 mg (regular & chewable), (OTC), 20 mg, & 40 mg; Pep-cid®, Pepcid AC® Maximum Strength and Pepcid RPD® (Merck); (Rx); Pepcid AC® (J & J Merck); generic; (Rx & OTC)) Famotidine Powder for Oral Suspension: 8 mg/m L when reconsti-tuted in 400 mg bottles; Pepcid® (Merck); (Rx) Famotidine Injection: 10 mg/m L in 1 and 2 m L single dose vials and 4 m L, 20 m L and 50 m L multidose vials (may contain mannitol or ben-zyl alcohol); 20 mg/50 m L premixed (regular & preservative free) in 50 m L single-dose Galaxy containers; Pepcid® (Merck); generic; (Rx) FATTY ACIDS, ESSENTIAL/ OMEGA FISH OIL/ VEGETABLE OIL NUTRITIONAL Prescriber Highlights TT Used for treatment of dogs with pruritus associated with atopy, idiopathic seborrhea; in cats for pruritus associ-ated with miliary dermatitis & eosinophilic granuloma complex TT May also be useful in other species & for other disease states TT Safety in pregnancy not established; use caution in pa-tients with coagulopathies TT Adverse Effects: High doses may cause GI distress; rarely some dogs may become lethargic or more pruritic Uses/Indications These products are generally indicated for the treatment of pruritus associated with atopy and idiopathic seborrhea. In cats, they can be used for treating pruritus in the adjunctive treatment of miliary dermatitis and eosinophilic granuloma complex. Fatty acids may improve coat quality and be helpful for adjunctive therapy for ar-thropathies such as hip dysplasia. When used for pruritus, signiﬁcant therapeutic effects may be noted in only 25-50% of patients treated and require 2-3 months of treatment before evaluating efﬁcacy. Antihistamine and fatty acid therapy may be synergistic for treatment of pruritus. Polyunsaturated fatty acids, particularly the omega-3's may prove to be useful for a variety of conditions, including renal fail-ure, arthritis (both degenerative and autoimmune), cardiovascu-lar disease (hypercoagulable states), and some neoplastic diseases. Further studies are required to document any clinical beneﬁts for veterinary use, however. Pharmacology/Actions The exact pharmacologic actions of these products are not well described; particularly in light of the combination nature of the commercial products being marketed, it is difﬁcult to ascertain which compounds may be responsible for their proposed efﬁcacy. The particular therapeutic beneﬁts and ratios of omega-3 versus omega-6 fatty acids are still being debated. Fish oils affect arachidonic acid levels in plasma lipids and plate-let membranes. They may affect production of inﬂammatory pros-taglandins in the body, thereby reducing inﬂammation and pruri-tus. Linolenic or linoleic acids may be used as essential fatty acid sources which are necessary for normal skin and haircoats. Contraindications/Precautions/Warnings Because of potential affects on bleeding times, use with caution in patients with coagulation disorders or those receiving anticoagulant medications. Use with caution in patients with non-insulin depen-dent diabetes as omega-3 fatty acids have impaired insulin secre-tion with resultant increased glucose levels in humans with type-2	pppbs.pdf
FELBAMATE 375 diabetes. Fatty acids should be used with caution in dogs that have had previous bouts with pancreatitis or protracted diarrhea. Adverse Effects At high dosages, GI disturbances (e. g., vomiting, diarrhea) may be seen. Rarely, some dogs become lethargic or more pruritic. In hu-man patients, increased bleeding times and decreased platelet ag-gregation have been noted with use of ﬁsh oils; use with caution in patients with coagulopathies. Reproductive/Nursing Safety Safe use in pregnancy has not been established; these products are not recommended for use in pregnant human patients. Use cau-tiously in veterinary patients. Overdosage/Acute Toxicity With products containing vitamin A, acute toxicosis may result af-ter accidental overdoses. Contact a poison control center for ad-ditional information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving fatty acids/ﬁsh oils and may be of signiﬁcance in veterinary patients: T ! ANTICOAGULANTS : Because of potential affects on bleeding times, use with caution in patients receiving anticoagulant medications such as aspirin, warfarin, or heparin Doses T ! DOGS & CAT S: Because of the unique nature of each commercially available product, see the actual label directions of that product for spe-ciﬁc dosage recommendations. a) A few published clinical articles suggest that (for pruritus in dogs) a beneﬁcial dose for eicosapentanoic acid (EPA) is around 22 mg/kg /day. (White 2003a) Monitoring T ! Efﬁcacy T ! Adverse effects Chemistry/Synonyms/Storage/Stability/Compatibility The commercially available veterinary products generally contain a combination of ﬁsh oil (eicosapentanoic and docosahexanoic ac-ids) and vegetable oil (gamma linolenic acid) that serve as essential fatty acids. They may also contain vitamin E (d-alpha tocopherol) and vitamin A. The oral capsules should be stored in tight containers and pro-tected from heat (cool, dry place). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: There are many combination products available without prescription having various trade names, including (partial listing): Dermapet Ei-cosderm®, Dermapet OFA plus EZ-C Caps®, F. A. Caps®, F. A. Caps ES®, Omega EFA® Capsules, Omega EFA® Capsules XS, Performer® OFA Gel Capsules Extra Strength, etc. HUMAN-LABELED PRODUCTS: There are many ﬁsh oil or ﬂaxseed oil capsules available without pre-scription having various trade names. Febantel— S ee the product Drontal® Plus listed in the Praziquantel and Pyrantel monographs FELBAMATE (fell-ba-mate) Felbatol® ANTICONVULSANT Prescriber Highlights TT 3rd line antiseizure medication for dogs TT Appears relatively safe to use in dogs, but because of limited use, adverse effect proﬁle may be incomplete TT Cost & accessibility may be issues Uses/Indications Felbamate is an anticonvulsant agent that may useful for treating seizure disorders (especially complex partial seizures) in dogs. A potential advantage of felbamate therapy is that when used alone or in combination with phenobarbital and/or bromides, it does not appear to cause additive sedation. Pharmacology/Actions Felbamate's anticonvulsant activity is thought to be due its ability to reduce excitatory neurotransmission; its exact mechanism is un-known, but it is believed to increase activation of sodium chan-nels thereby decreasing sustained high-frequency ﬁring of action potentials. Pharmacokinetics Felbamate is well absorbed after oral administration in dogs. Felbamate is both excreted unchanged and as metabolites in the urine (about 50:50). The half-life in dogs may range from 5-14 hours. Because the drug can induce liver enzyme induction, half-lives may decrease with time and dosages may need adjustment. Contraindications/Precautions/Warnings Felbamate is contraindicated in patients hypersensitive to it or oth-er carbamates (meprobamate). In humans, felbamate should not be used in patients with a history of blood dyscrasias or hepatic dys-function. In dogs, however, these are probably only cautions since dogs who require felbamate are often close to euthanasia due to the refractoriness of their conditions and a lack of evidence that felbamate causes liver toxicity in dogs. Adverse Effects Potential adverse reactions in the dog include liver enzyme induc-tion, tremor, limb rigidity, salivation, restlessness and agitation (at high doses). In humans, aplastic anemia and hepatic necrosis have been noted and could be a factor in canine medicine. There ap-parently have not been any case reports yet of aplastic anemia in dogs, but blood dyscrasias (thrombocytopenia, lymphopenia, and leukopenia) have been reported. Sedation, and vomiting/nausea have been reported in dogs, but usually in those receiving other an-ticonvulsants as well. Reproductive/Nursing Safety Although no overt teratogenicity has been documented, felbamate should only be used during pregnancy when its potential beneﬁts outweigh its potential risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate stud-ies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) The drug is excreted into maternal milk, but adverse conse-quences to nursing puppies appear remote.	pppbs.pdf
376 FENBENDAZOLE T TOverdosage/Acute Toxicity Limited information is available. One human subject taking 12 grams over 12 hours only developed mild gastric distress and a slightly increased heart rate. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving felbamate and may be of signiﬁcance in veterinary patients: T ! PHENOBARBITAL : When felbamate is added to patients taking phe-nobarbital it may cause increases in phenobarbital levels. When phenobarbital is added to patients taking felbamate, felbamate levels may decrease. The same effect can occur with phenytoin. T ! VALPROATE : Felbamate can cause increases in valproic acid levels Doses T ! DOGS: For seizures: a) As a third choice antiepileptic agent: 15-65 mg/kg PO q8h. Steady state reached after 4th oral dose. Monitor CBC and liver function tests as you would for phenobarbital. Thera-peutic serum concentration reported to be 15-100 mcg/m L. (Quesnel 2000) b) For patients on phenobarb and bromides (both in therapeu-tic range) and seizure activity unchanged or having intoler-able side effects with this combination: If intolerable side ef-fects, do levels and decrease the dose of the one that is in the high end of the range. Then add felbamate at 5-20 mg/kg PO three times daily. (Neer 2000) c) In dogs refractory to phenobarbital and bromides: Felbamate initial dose of 15 mg/kg PO q8h. May increase the dose in 15 mg/kg increments every 2 weeks until seizures are controlled. Dosages as high as 70 mg/kg, q8h may be necessary and be tolerated by some dogs. (Thomas 2000) Monitoring T ! here is some controversy about monitoring felbamate use in dogs, probably since there is such limited experience with its use. Some clinicians state that liver function tests and CBC's should be regularly assessed (q2-3 months). Others state that the drug is very safe in dogs and that monitoring does not appear to be necessary. Clearly, if the dog is receiving other drugs (especially phenobarbital), monitoring is essential. T ! herapeutic drug levels for felbamate in dogs are not truly known, but appear to be in the 25-100 mcg/m L range. The usefulness of monitoring serum levels is questionable at this point. Client Information T ! Clients must understand the importance of giving doses as pre-scribed. Because of its short half-life, three times daily adminis-tration is routinely administered to adequately judge the efﬁcacy of this drug. T ! Because felbamate use in dogs has been limited, the adverse effect proﬁle and possible incidence of serious effects (liver, blood) is not truly known. Chemistry/Synonyms Felbamate is a unique dicarbamate anticonvulsant agent, that is slightly soluble in water. Felbamate may also be known by as: AD-03055, W-554, Felbamyl®, Felbatol®, Taloxa®, and Taloxa®. Storage/Stability/Compatibility Felbamate preparations should be stored at room temperature. The suspension should be shaken well before use. 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: Felbamate Tablets: 400 mg, & 600 mg; Felbatol® (Wallace Labs); (Rx) Felbamate Suspension: 120 mg/m L in 240 and 960 m L: Felbatol® (Wallace Labs); (Rx) FENBENDAZOLE (fen-ben-da-zole) Panacur®, Safe-Guard® ANTIPARASITIC AGENT Prescriber Highlights TT Anthelmintic useful for a variety of parasites in dogs, cats, cattle, horses, swine, etc TT Adverse Effects: Antigen release by dying parasites may occur; particularly at high dosages; vomiting may occur infrequently in dogs or cats Uses/Indications Fenbendazole is indicated (labeled) for the removal of the following parasites in dogs: ascarids (Toxocara canis, T. leonina), Hookworms (Ancylostoma caninum, Uncinaria stenocephala), whipworms (Trichuris vulpis), and tapeworms (Taenia pisiformis). It is not ef-fective against Dipylidium caninum. Fenbendazole has also been used clinically to treat Capillaria aerophilia, Filaroides hirthi, and Paragonimus kellicotti infections in dogs. Fenbendazole is indicated (labeled) for the removal of the fol-lowing parasites in cattle: Adult forms of: Haemonchus contortus, Ostertagia ostertagi, Trichostrongylus axei, Bunostomum phleboto-mum, Nematodirus helvetianus, Cooperia spp., Trichostrongylus colubriformis, Oesophagostomum radiatum, and Dictyocaulus viva-parus. It is also effective against most immature stages of the above listed parasites. Although not approved, it has good activity against Moniezia spp., and arrested 4th stage forms of Ostertagia ostertagi. Fenbendazole is indicated (labeled) for the removal of the fol-lowing parasites in horses: large strongyles (S. edentatus, S. equi-nus, S. vulgaris), small strongyles (Cyathostomum spp., Cylicocylus spp., Cylicostephanus spp., Triodontophorus spp. ), and pinworms (Oxyuris equi). Fenbendazole is indicated (labeled) for the removal of the follow-ing parasites in swine: large roundworms (Ascaris suum),lungworms (Metastrongylus pair), nodular worms (Oesphagostomum dentatum, O. quadrispinolatum), small stomach worms (Hyostrongylus rubi-dus), whipworms (Trichuris suis), and kidney worms (Stephanurus dentatus; both mature and immature). Although not approved, fenbendazole has been used in cats, sheep, goats, pet birds, and llamas. See Dosage section for more in-formation.	pppbs.pdf
FENBENDAZOLE 377 Pharmacology/Actions Benzimidazole antiparasitic agents have a broad spectrum of activ-ity against a variety of pathogenic internal parasites. In susceptible parasites, their mechanism of action is believed due to disrupting intracellular microtubular transport systems by binding selectively and damaging tubulin, preventing tubulin polymerization, and in-hibiting microtubule formation. Benzimidazoles also act at higher concentrations to disrupt metabolic pathways within the helminth, and inhibit metabolic enzymes, including malate dehydrogenase and fumarate reductase. Pharmacokinetics Fenbendazole is only marginally absorbed after oral administra-tion. After oral dosing in calves and horses, peak blood levels of 0. 11 micrograms/m L and 0. 07 micrograms/m L, respectively, were measured. Absorbed fenbendazole is metabolized (and vice-versa) to the active compound, oxfendazole (sulfoxide) and the sulfone. In sheep, cattle, and pigs, 44-50% of a dose of fenbendazole is ex-creted unchanged in the feces, and <1% in the urine. Contraindications/Precautions/Warnings Fenbendazole is not approved for use in horses intended for food purposes. Adverse Effects At usual doses, fenbendazole generally does not cause any adverse effects. Hypersensitivity reactions secondary to antigen release by dying parasites may occur, particularly at high dosages. Vomiting may infrequently occur in dogs or cats receiving fenbendazole. Pancytopenia has been reported in one dog. Single doses (even at exaggerated doses) are not effective in dogs and cats; must treat for 3 days. Reproductive/Nursing Safety Fenbendazole is considered safe to use in pregnant bitches and is generally considered safe to use in pregnancy for all species. In a 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/Toxicity Fenbendazole is apparently well tolerated at doses up to 100X recom mended. The LD 50 in laboratory animals exceeds 10 grams/ kg when administered PO. It is unlikely an acute overdosage would lead to clinical signs. Drug Interactions !TBROMSALAN FLUKICIDES (dibromsalan, tribromsalan ; not available in the USA): Oxfendazole or fenbendazole should not be given con-currently with the bromsalan ﬂukicides; abortions in cattle and death in sheep have been reported after using these compounds together Doses !TDOGS: For susceptible ascarids, hookworms, whipworms, and tape-worms (Taenia spp. only): a) 50 mg/kg, PO for 3 consecutive days (Package insert; Panacur®—Hoechst), (Cornelius and Roberson 1986) b) 55 mg/kg, PO for 3 days (5 days for Taenia) (Chiapella 1988), (Reinemeyer 1985) T o prevent transplacental and transmammary transmission of somatic T. canis and A. caninum: a) 50 mg/kg PO once daily from the 40th day of gestation to the 14th day of lactation. (Kazacos 2002) For Capillaria plica: a) 50 mg/kg once daily for 3 days; repeat a single 50 mg/kg dose 3 weeks later (T odd, Paul, and Di Pietro 1985) b) 50 mg/kg, PO daily for 3-10 days (Brown and Prestwood 1986) For Capillaria aerophilia: a) 25-50 mg/kg q12h for 10-14 days (Hawkins, Ettinger, and Suter 1989); (Hawkins 2000) b) 50 mg/kg PO once daily for 10-14 days (Reinemeyer 1995) For Filaroides hirthi: a) 50 mg/kg, PO once daily for 14 days. Symptoms may worsen during therapy, presumably due to a reaction when the worm dies. (Hawkins, Ettinger, and Suter 1989) b) 50 mg/kg PO once daily for 10-14 days (Reinemeyer 1995) For Paragonimus kellicotti: a) 25-50 mg/kg PO twice daily for 10-14 days (T odd, Paul, and Di Pietro 1985); (Hawkins 2000) b) 50 mg/kg PO once daily for 10-14 days (Reinemeyer 1995) c) 50 mg/kg, PO once daily for 3 consecutive days; repeat in 2-3 weeks and again in 2 months (De Novo 1988) For Crenosoma vulpis: a) 50 mg/kg PO once daily for 3 days (Reinemeyer 1995); (Hawkins 2000) For Giardia: a) 50 mg/kg PO once daily for 3 days (Barr and Bowman 1994); (Greene and Watson 1998) b) 25 mg/kg PO q12h for 3-7 days (Lappin 2000) For Eucoleus boehmi: a) 50 mg/kg PO once daily for 10-14 days; improvement may only be temporary (Reinemeyer 1995) !TCATS, DOMESTIC: For susceptible ascarids, hookworms, strongyloides, and tape-worms (Taenia spp. only): a) 50 mg/kg, PO for 5 days (Dimski 1989) For lungworms (Aelurostrongylus abstrusus): a) 25-50 mg/kg q12h for 10-14 days (Hawkins, Ettinger, and Suter 1989); (Hawkins 2000) b) 50 mg/kg, PO for 10 days (Pechman 1989) c) 20 mg/kg PO once daily for 5 days; repeat in 5 days (Rein-emeyer 1995) For lungworms (Capillaria aerophilia): a) 50 mg/kg, PO for 10 days (Pechman 1989) b) 50 mg/kg PO once daily for 10-14 days (Reinemeyer 1995) For Capillaria feliscati: a) 25 mg/kg, twice daily PO for 3-10 days (Brown and Prest-wood 1986) b) 25 mg/kg, PO q12h for 10 days (Brown and Barsanti 1989) For Paragonimus kellicotti: a) 25-50 mg/kg PO twice daily for 10-14 days (Hawkins 2000) b) 50 mg/kg PO once daily for 10-14 days (Reinemeyer 1995) For Eurytrema procyonis (pancreatic ﬂuke): a) 30 mg/kg, PO daily for 6 days (Steiner and Williams 2000) For Giardia: a) In young kittens: 50 mg/kg PO (using the suspension) once a day for 3-5 days (Tams 1999) b) 50 mg/kg PO q24h for 3-5 days (Vasilopulos 2006)	pppbs.pdf
378 FENBENDAZOLE !TCATS, LARGE (EXOTIC): For labeled parasites: a) 10 mg/kg PO once daily for 3 consecutive days. (Label infor-mation; Panacur® 22. 25 Granules—Intervet) !TBEARS (URSIDAE): For labeled parasites: a) 10 mg/kg PO once daily for 3 consecutive days. (Label infor-mation; Panacur® 22. 25 Granules—Intervet) !TSMALL MAMMALS/RODENTS: a) For pinworms in mice, rats, hamsters, gerbils and rabbits: 50 mg/kg PO once (Burke 1999) b) For Giardia in Chinchillas: 25 mg/kg PO once a day for 3 days (Hayes 2000) c) Mice, Rats, Gerbils, Hamsters, Guinea pigs, Chinchillas: 20-50 mg/kg PO once daily for 5 days (Higher dose is for Giardia) (Adamcak and Otten 2000) !TCATTLE: For removal/control of Haemonchus contortus, Ostertagia ostert-agi, Trichostrongylus axei, Bunostomum phlebotomum, Nemato-dirus helvetianus, Cooperia spp., Trichostrongylus colubriformis, Oesophagostomum radiatum, and Dictyocaulus vivaparus: a) 5 mg/kg, PO (Paul 1986) b) 7. 5 mg/kg, PO (Roberson 1988b) c) 4 mg/kg PO; under conditions of continuous exposure to parasites, animals may need to be retreated after 4-6 weeks, (Label information Panacur® Paste—Intervet) For Moniezia spp., and arrested 4th stage forms of Ostertagia os-tertagi: a) 10 mg/kg, PO (Paul 1986), (Roberson 1988b) For giardiasis in calves: a) 15 mg/kg PO for 3 successive days and then moved to a pen that was thoroughly cleaned and disinfected with 10% am-monia. (Claerebout 2006) !THORSES: For susceptible parasites: a) For control of large and small strongyles, and pinworms in adult horses: 5 mg/kg PO; For foals and weanlings (less than 18 months of age) where ascarids are a common problem: 10 mg/kg PO; For control of encysted early 3rd stage, late 3rd stage and 4th stage cyathostome larvae and 4th stage Strongylus vulgaris larvae) 10 mg/kg PO for 5 consecutive days. (Label informa-tion Panacur® Paste—Intervet) For treatment of migrating large strongyles: a) 50 mg/kg PO for 3 consecutive days, or 10 mg/kg for 5 con-secutive days (Herd 1987) For mucosal stage of small strongyles: a) 7. 5-10 mg/kg PO once daily for 5 days; a single dose of 30 mg/kg is effective against older encysted stages (Lyons and Drudge 2000) !TSWINE: For susceptible parasites: a) 5 mg/kg PO; 3 mg/kg in feed for 3 days; 10 mg/kg for ascarids (Roberson 1988b) b) For whipworms in potbellied pigs: 9 mg/kg PO for days (Braun 1995) !TSHEEP & GOATS: For susceptible parasites: a) 5 mg/kg in feed for 3 days (Roberson 1988b) !TLLAMAS: For susceptible parasites: a) 10-15 mg/kg PO (as paste or suspension) (Fowler 1989) b) 5-10 mg/kg PO for 1-3 days. Fenbendazole and ivermectin are the most effective and safest anthelmintics for use in lla-mas. (Cheney and Allen 1989) !TBIRDS: a) For Ascarids: 10-50 mg/kg PO once; repeat in 10 days. Do not use during molt (may cause stunted feathers) or while nesting. For ﬂukes or microﬁlaria: 10-50 mg/kg PO once daily for 3 days For Capillaria: 10-50 mg/kg PO once daily for 5 days. Is not effective against gizzard worms in ﬁnches. (Clubb 1986) b) For nematodes, some trematodes: 10-50 mg/kg PO once daily for 3-5 days; 20-100 mg/kg oral single dose range; 125 mg/L of drinking water for 5 days (50 mg/L for 5 days in ﬁnches); or 100 mg/kg of feed for 5 days. Not recommend-ed to be used in breeding season during molting. (Marshall 1993) c) Ratites: 15 mg/kg PO once daily for 3 days. Has efﬁcacy against ostrich tapeworm. (Houttuynia struthionus) (Jenson 1998) !TREPTILES: For susceptible infections: a) For most species: 50-100 mg/kg PO once; repeat in 2-3 weeks; very effective against Strongyloides. (Gauvin 1993) Chemistry/Synonyms A benzimidazole anthelmintic, fenbendazole occurs as a white, crystalline powder. It is only slightly soluble in water. Fenbendazole may also be known as: Hoe-881V, Panacur®, and Safe-Guard®. Storage/Stability Fenbendazole products should be stored at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Fenbendazole Granules: 222 mg/gram (22. 2%) in 0. 18 oz and 1 g, 2 g, 4 g packets and 1 lb jars; Panacur® Granules 22. 2% (Intervet); (Rx); Safeguard® Canine Dewormer (Intervet), (OTC). Approved for use in dogs, large exotic cats (lions, etc. ), and bears (black bears, polar bears, etc. ) Fenbendazole Granules: 222 mg/gram (22. 2%); Panacur® Granules 22. 2% (Intervet). (OTC). Approved for use in horses not intended for food. Fenbendazole Suspension: 100 mg/m L (10%); available in both equine and bovine labeled products; Panacur® Suspension (Intervet); (Rx). Approved for use in horses (not intended for food) and cattle Slaughter withdrawal = 8 days (cattle). Safe-Guard® Suspension (In-tervet); (OTC). Approved for use in beef and dairy cattle. Slaughter withdrawal at labeled doses = 8 days Fenbendazole Paste: 100 mg/gram (10%); available in both equine and bovine labeled products and sizes. Panacur® Paste (Intervet); (OTC). Approved for use in horses (not intended for food) and cattle. Slaughter withdrawal at labeled doses = 8 days (cattle). Safe Guard® Paste (Intervet); (OTC). Approved for use in horses not intended for food and cattle. Slaughter withdrawal at labeled doses = 8 days; no milk withdrawal time at labeled doses.	pppbs.pdf
FENTANYL 379 Fenbendazole Type B Medicated Feed Safe-Guard® EZ Scoop Swine Dewormer (Intervet) (OTC). 1. 8% Fenbendazole No slaughter withdrawal time required at labeled doses Safe-Guard® 0. 96% Scoop Dewormer (Intervet); (OTC). Approved for use in cattle. No milk withdrawal time; slaughter withdrawal time at labeled doses = 13 days Fenbendazole Type C Medicated Feed Safe-Guard® Free-choice Cattle Dewormer (Intervet); (OTC); 0. 50% Fenbendazole (2. 27 g/lb). Approved for use in beef and dairy cattle. No milk withdrawal time. Safe-Guard® 35% Salt Free-choice Cattle Dewormer (Intervet); (OTC); 1. 9 g/lb Fenbendazole. Approved for use in dairy and beef cattle. Slaughter withdrawal time at labeled doses = 13 days; no milk withdrawal time. Fenbendazole Pellets Safe-Guard® 0. 5% Cattle Top Dress (Intervet); (OTC). At labeled dose, slaughter withdrawal time = 13 days; no milk withdrawal pe-riod at labeled doses Safe-Guard® 1. 96% Scoop Dewormer Mini Pellets (Intervet); (OTC). Approved for use in beef and dairy cattle. No milk withdrawal time at labeled doses; slaughter withdrawal time at labeled doses = 13 days Fenbendazole Premix 20% Type A (200 mg/gram) Safe-Guard® Premix (Intervet); (OTC). Approved for use in swine, growing turkeys, dairy and beef cattle, zoo and wildlife animals. Slaughter withdrawal for cattle = 13 days; no milk withdrawal time. Slaughter withdrawal for swine at labeled doses = none. Wildlife animal slaughter (hunting) withdrawal = 14 days at labeled doses. HUMAN-LABELED PRODUCTS: None FENTANYL, TRANSDERMAL FENTANYL CITRATE (fen-ta-nil) Sublimaze®, Duragesic® OPIATE Prescriber Highlights TT Class-II opiate analgesic used parenterally & transder-mally in small animals TT Contraindications: Use extreme caution when additional respiratory, or CNS depression would be deleterious TT Use caution in geriatric, very ill or debilitated patients & those with a preexisting respiratory problem TT Adverse Effects: Dose related respiratory, CNS & circula-tory depression (bradycardia); also, rashes at the patch site, urine retention, constipation, dysphoria, or agitation TT Do NOT cut patches; dispose of properly TT Lab values (amylase, lipase) may be altered Uses/Indications In veterinary medicine, fentanyl injection and transdermal patch-es are used primarily in dogs and cats and have been shown to be useful for the adjunctive control of postoperative pain and in the control of severe pain associated with chronic pain, dull pain, and non-speciﬁc, widespread pain (e. g., associated with cancer, pan-creatitis, aortic thromboemboli, peritonitis, etc. ). Perioperative in-jectable fentanyl can also reduce the requirements for inhalational anesthetics during surgery, which can be particularly advantageous in patients with compromised cardiac function. Transdermal fen-tanyl has been clinically effective overall and has not demonstrated substantial adverse effects. In humans, signiﬁcant respiratory depression with use of the patches after surgery has precluded post-operative use, but this has not been a signiﬁcant problem in veterinary medicine. Pharmacology/Actions Fentanyl is a mu opiate agonist. Mu receptors are found primarily in the pain regulating areas of the brain. They are thought to con-tribute to the analgesia, euphoria, respiratory depression, physical dependence, miosis, and hypothermic actions of opiates. Receptors for opiate analgesics are found in high concentrations in the limbic system, spinal cord, thalamus, hypothalamus, striatum, and mid-brain. They are also found in tissues such as the gastrointestinal tract, urinary tract, and in other smooth muscle. The pharmacology of the opiate agonists is discussed in more detail in the monograph, Narcotic (opiate) Agonist Analgesics. Pharmacokinetics When used via a single dose IV injection, fentanyl has a relatively short duration of effect (15-30 minutes. ) When administered to dogs as 10 mcg/kg IV bolus, fentanyl rap-idly distributes and exhibits a large volume of distribution (5 L/kg). The terminal elimination half life is about 45 minutes; total clear-ance is 78 m L/min/kg. After a 10 mcg/kg bolus, dogs administered a constant rate intravenous infusion of 10 mg/kg/hr were able to maintain blood levels around 1 ng/m L (the assumed—but not veri-ﬁed therapeutic analgesic level). (Sano, Nishimura et al. 2006) Half-life after IV administration in cats is approximately 2. 5 hours. There have been limited pharmacokinetic studies performed with transdermal fentanyl patches in dogs, cats, and horses. While therapeutic levels of fentanyl are attained, there is a signiﬁcant in-terpatient variability with both the time to achieve therapeutic lev-els and the levels themselves. Cats tend to achieve therapeutic levels faster than do dogs; in dogs, the patch should be applied 24 hours in advance of need if possible; minimum of 12 hours pre-need. Most cats attain therapeutic beneﬁt in about 6 hours after application. While applied, duration of action persists for at least 72 hours (usu-ally for at least 104 hours). Duration of action is generally longer in cats than in dogs. For continued use, patches may need to changed every 48 hours in dogs or horses. In horses, fentanyl patches are rapidly absorbed with therapeutic levels (1 ng/m L?) achieved in about 6 hours after application and persists for 48+ hours. Contraindications/Precautions/Warnings Fentanyl is contraindicated in patients with known hypersensitivity to it or any component of the product (including the adhesive for the patch). Because of its potency, fentanyl injection should be used only by professionals familiar with its use in circumstances where patients can be adequately monitored and supported. Use cautiously with other CNS depressants. Dosages of other opiates may need to be reduced when given with fentanyl trans-dermal, particularly several hours after application of the patch. Transdermal fentanyl should be used cautiously in geriatric, very ill or debilitated patients and those with a preexisting respiratory problem. Febrile patients may have increased absorption of fenta-nyl and will require increased monitoring.	pppbs.pdf
380 FENTANYL Patches must not be cut. Do not allow applied fentanyl patch to be exposed to exogenous heat sources (heating pads, etc. ). Increased drug release and absorption have occurred with fatal results. Adverse Effects Dose related respiratory, CNS and circulatory depression (brady-cardia) are the primary adverse effects with fentanyl injection. Dogs and cats appear less prone, but not immune to opiate-induced re-spiratory depression, than are humans. Respiratory depression and bradycardia associated with fentanyl patches are the most concerning adverse effects, but incidence of these effects have not been widespread thus far when used alone (without other opiates or other respiratory and cardiodepressant medications). Rashes at the patch site have been reported and should they occur, the patch should be removed; if an additional patch is warranted, a different site should be chosen. Urine reten-tion and constipation may occur. Consider removing patch in pa-tients developing a fever after application, as fentanyl absorption may increase. Some patients exhibit dysphoria or agitation after application; acepromazine or other mild tranquilizer may alleviate dysphoria. Reproductive/Nursing Safety Safe use in pregnancy has not been established. In humans, the FDA categorizes fentanyl as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) 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. ) Most narcotic agonist analgesics are excreted into milk, but ef-fects on nursing offspring may not be signiﬁcant. Overdosage/Acute Toxicity Overdosage may produce profound respiratory and/or CNS depres-sion in most species. Newborns may be more susceptible to these effects than adult animals. Other toxic effects may include cardio-vascular collapse, tremors, neck rigidity, and seizures. Naloxone is the agent of choice in treating respiratory depression. In massive overdoses, naloxone doses may need to be repeated; animals should be closely observed as naloxone's effects sometimes diminish before sub-toxic levels of fentanyl are attained. Mechanical respiratory support should also be considered in cases of severe respiratory depression. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving fentanyl and may be of signiﬁcance in veterinary patients: !TAZOLE ANTIFUNGALS (ketoconazole, itraconazole, ﬂuconazole ): May inhibit fentanyl metabolism !TCNS DEPRESSANTS, OTHER : Additive CNS effects possible !TDIURETICS : Opiates may decrease efﬁcacy in CHF patients !TMACROLIDE ANTIBIOTICS (erythromycin, clarithromycin ): May inhibit fentanyl metabolism !TMONOAMINE OXIDASE INHIBITORS (e. g., amitraz, and possibly selegi-line): Severe and unpredictable opiate potentiation may be seen; not recommended (in humans) if MAO inhibitor has been used within 14 days) !TMUSCLE RELAXANTS, SKELETAL : Fentanyl may enhance neuromus-cular blockade !TNITROUS OXIDE : High fentanyl doses may cause cardiovascular de-pression !TPHENOBARBITAL, PHENYTOIN : May increase the metabolism of fentanyl !TRIFAMPIN : May increase the metabolism of fentanyl !TTRICYCLIC ANTIDEPRESSANTS (clomipramine, amitriptyline, etc. ): Fen-tanyl may exacerbate the effects of tricyclic antidepressants !TWARFARIN : Opiates may potentiate anticoagulant activity Laboratory Considerations !TAs they may increase biliary tract pressure, opiates can increase plasma amylase and lipase values up to 24 hours following their administration. Doses !TDOGS: Fentanyl Injectable: a) For perioperative pain: The combination of a 10 mcg/kg loading dose IV followed by a CRI of 10 mcg/kg/hour in-vestigated in this study might be a guideline for a CRI dose of fentanyl during general anesthesia to provide analgesia in dogs. (Sano, Nishimura et al. 2006) b) Loading dose: 2-5 mcg/kg IV, followed by a CRI at 2-5 mcg/ kg/hr for pain management; CRI at 10-45 mcg/kg/hr for surgical analgesia. (Wagner 2002) c) For perioperative pain: 5-10 mcg/kg/hr IV or CRI (Tran-quilli 2003) d) For induction: 0. 001-0. 005 mg/kg IV. For MAC reduction during general anesthesia: 10-45 mcg/kg/hr CRI. (Mama 2002b) Fentanyl Transdermal: Note : There is signiﬁcant interpatient variability on the response of the transdermal product. When used as the primary analgesic for post-operative pain, application prior to surgery is advised as many hours may be required for “therapeutic” levels to be achieved. Generally in dogs = 12-24 hours may be necessary; cats = 6-24 hours; and horses = 6+ hours. The following dosage regimen has been used at the University of Minnesota Veterinary Medical Center and is adapted from information provided by Dr. Lynelle Graham: Choose your patient carefully, realizing that the fentanyl patch alone may not provide sufﬁcient analgesia. Fentanyl patches are effective for relief of chronic pain, dull pain and non-speciﬁc, widespread pain (peritonitis, pancreatitis, cancer, aortic throm-boemboli, declaws, etc. ) In the face of acute surgical pain or se-vere traumatic pain (fractures, thoracotomies, HBC/traumatic injuries/head trauma), analgesia provided by a fentanyl patch tends to be inadequate. Therefore, the patch should be used as an adjunctive measure for pain relief in these patients. If the patient is febrile, do not use fentanyl patch.	pppbs.pdf
FENTANYL 381 Choose your Patch Size: PATIENT DOSE (PATCH SIZE) FENTANYL CONTENT Small Dogs (<5kg) 25 mcg/hr or 12. 5 mcg/ 2. 5 mg; and Cats hr 1. 25 mg Dogs: 5-10 kg 25 mcg/hr 2. 5 mg Dogs: 10-20 kg 50 mcg/hr 5 mg Dogs: 20-30 kg 75 mcg/hr 7. 5 mg Dogs: >30 kg 100 mcg/hr 10 mg Horses: 350-500 kg 2 x 100 mcg/hr 20 mg Pigs: 17-25 kg 50-100 mcg/hr 5-10 mg Sheep 1-3 x 50 mcg/hr 5-15 mg Goats 50 mcg/hr 5 mg Rabbits 25 mcg/hr 2. 5 mg (**These patients can be dosed with H of a 25 mcg/hr patch, i. e., only half of the membrane is exposed to the patient's skin (cover the other half with tape); DO NOT CUT the patch in half, as this will alter the drug releasing membrane and al-low evaporation of the fentanyl-containing alcohol-cellulose gel. Current research suggests dosing with a whole 25 mcg/hr patch in otherwise healthy patients of this size (i. e., fractures, declaws). However, in order to avoid sedation, “half-patch” dosing may be desired for pediatric, geriatric, and systemi-cally ill cats and very small dogs, but this is controversial. Choose your location: DOG: Thorax, inguinal area, metatarsal/carpal ar-eas, base of tail (dorsal or lateral cervical area has been used, but leashes must not be placed around the neck if fentanyl patches are in place) CAT: Lateral thorax, inguinal area, metatarsal/carpal areas; base of tail (the cervical area is NOT rec-ommended, as the patch tends not to remain on) HORSE: Neck, antebrachium PIG, RABBIT: Lateral thorax SHEEP, GOAT: Abdomen, cervical area Note : Direct patch contact with heating pads can signiﬁcantly increase fentanyl absorption and risk toxicity. The patch should be kept dry; be aware of potential surgical clip sites. 1) Clip close, but don't shave, the site. DO NOT use depilatory agents in preparation of the site. Clip at least a 1 cm margin around the patch. 2) Wipe the site with a damp cloth and allow the skin to dry. This step is absolutely necessary, or patch will not stick to the skin. DO NOT wipe the area with alcohol or surgical scrub solution. Alcohol and surgical scrubs may “de-fat” the skin and alter drug absorption. 3) Place the patch on the skin and hold it in place with the palm of your hand for 2-3 minutes. The heat of your hand will help the adhesive bond to the skin. Failure to perform this step will allow the patch to fall off. If patch is not fully ad-hered to the skin, fentanyl will not be absorbed properly. 4) Cover the patch with a light bandage or clear adhesive ban-dage (i. e., Bioclusive®, Johnson and Johnson, Arlington, TX). If you choose to use Bioclusive®, apply the fentanyl patch as described above. Spray around the perimeter and over the patch with medical adhesive spray (Medical Adhesive®, Hol-lister, Libertyville, IL). Place the Bioclusive® over the site and press it down ﬁrmly. Be sure to clip an area large enough so that the Bioclusive® can adhere to the patch and the skin. If the Bioclusive® can only adhere to the patch and fur, without good adherence to skin, the patch will tend to peel up and dislodge. 5) Label the site with the size of patch (25, 50, 75 or 100 mcg/ hr) and the date and time the patch was placed. Patches have shown to release effective fentanyl levels for up to ﬁve days in cats, three days in dogs and two days in horses. Potentially, the patches could be left longer, especially in dogs; this deci-sion can be made by the attending clinician. 6) Potential side effects include bradycardia, respiratory depres-sion, urinary retention, and constipation. All patients with fentanyl patches should be monitored accordingly. If a pa-tient with a patch develops a fever, consider patch removal. If the patch is left in place, the patient must be closely moni-tored since the rate of fentanyl absorption may increase. 7) Person applying or removing the patch must gently, but thoroughly rinse their hands with water to remove any drug residue. Soap, cleansers or solvents should not be used. Sur-gical gloves may be worn to place or remove patches, as skin contact does occur when handling the adhesive edges. 8) Dispose of used patches in a safe and effective manner. !TCATS: Fentanyl Injectable: a) For perioperative pain: 2-3 mcg/kg IV plus 2-3 mcg/kg/ hour IV infusion (Pascoe 2000) b) Loading dose: 1-3 mcg/kg IV, followed by a CRI at 1-4 mcg/ kg/hr for pain management; CRI at 10-30 mcg/kg/hr for surgical analgesia. (Wagner 2002) c) For perioperative pain: 2. 5-5 mcg/kg/hr IV or CRI (Tran-quilli 2003) d) For induction: 0. 001-0. 002 mg/kg IV. For MAC reduction during general anesthesia: 10-20 mcg/kg/hr CRI. (Mama 2002b) Fentanyl Transdermal: See above in dog dose section !TFERRETS: Fentanyl Injectable: a) Pre-op dose: 5-10 mcg/kg IV; Intra-operatively: CRI at 10-20 mcg/kg/hr with a ketamine CRI (0. 3-0. 4 mg/kg/ hr); Post-operatively: 2-5 mcg/kg/hr with a ketamine CRI. (Lichtenberger 2006c) !TRABBITS/RODENTS/SMALL MAMMALS: Fentanyl Injectable: a) For perioperative pain: 5-20 mcg/kg IV bolus (30-60 min-ute duration; causes sedation and respiratory depression) (Ivey and Morrisey 2000) Fentanyl Transdermal: a) Rabbits for postoperative analgesia: H small patch (25 mcg/ hr) per medium sized rabbit (3 kg) every 3 days. Do not cut patch (Ivey and Morrisey 2000) b) Rabbits: See above in dog dose section !THORSES: (Note : ARCI UCGFS Class 1 Drug) Fentanyl Transdermal: See a bove in dog dose section !TSHEEP, GOATS & SWINE: Fentanyl Transdermal: See above in dog dose section	pppbs.pdf
382 FERROUS SULFATE Monitoring T ! Analgesic efﬁcacy T ! Heart rate and respiratory rate Client Information T ! Fentanyl injection should be used only by professionals familiar with its use in a setting where adequate monitoring can occur. T ! Fentanyl Patches: Explain carefully to clients how to apply (if ap-plicable), remove and dispose of patches. Consider making ap-plication, removal, and disposal an outpatient procedure, thereby bypassing concerns with clients. T ! Should accidental human skin contact occur with the patch, wash with water only (no soap, etc. ). Use cautiously in house-holds where young children or animals could remove and ingest or be exposed to patches. Chemistry/Synonyms Fentanyl citrate, a very potent opiate agonist, occurs as a white, crystalline powder. It is sparingly soluble in water and soluble in alcohol. It is odorless and tasteless (not recommended for taste test because of extreme potency) with a p K a of 8. 3 and a melting point between 147°-152°C. Fentanyl and fentanyl citrate may also be known as: fentanylum, fentanyli citras, Mc N-JR-4263-49, phentanyl citrate, R-4263, Actiq®, Fenodid®, Fenta-Hameln®, Fentabbott®, Fentanest®, Fentax®, Fentora®, Haldid®, Ionsys®, Leptanal®, Naﬂuvent®, Sintenyl®, Sublimaze®, Tanyl®, and Trofentyl®. Storage/Stability/Compatibility Fentanyl transdermal patches should be stored at temperatures less than 25°C and applied immediately after removing from the indi-vidually sealed package. Do not cut patches. The transmucosal (buccal) tablets should be stored at room temperature; do not refrigerate or freeze. Fentanyl injection should be stored protected from light. It is hydrolyzed in an acidic solution. The injection is compatible with normal saline and D5W. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 1 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Fentanyl Buccal Tablets: 100 mcg, 200 mcg, 400 mcg, 600 mcg, & 800 mcg with mannitol in color-coded blister packs; Fentora® (Cepha-lon); (Rx, C-II) Fentanyl Injectable: 0. 05 mg/m L (50 mcg/m L) in 2, 5, 10, and 20 m L amps; 30 m L and 50 m L vials; preservative free in 2, 5, 10 m L, & 20 m L amps; Sublimaze® (Akorn); generic; (Rx, C-II) Fentanyl Transdermal System: 1. 25 (5 cm 2; 12. 5 mcg/hr ); 2. 5 to 2. 75 (6. 25-10 cm 2; 25 mcg/hr ); 2. 5 to 5. 5 (12. 5-20 cm 2; 50 mcg/hr ); 7. 5 to 8. 25 (18. 75-30 cm 2; 75 mcg/hr ); 10 to 11 (25-40 cm 2; 100 mcg/hr ); Duragesic®-12,-25,-50,-75 and-100 (Janssen); generic; (Rx, C-II) Fentanyl Iontophoretic Transdermal System: 40 mcg/dose fentanyl hydrochloride (equivalent to 44. 4 mcg of fentanyl) delivered over a 10-minute period upon each activation of the dose button; Each system contains fentanyl hydrochloride 10. 8 mg; Ionsys® (Ortho-Mc Neil); (Rx; C-II) Fentanyl Transmucosal System: Lozenges on a stick: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg and 1600 mcg (as base); Actiq® (Cephalon); generic; (Rx, C-II) All fentanyl products are Class-II controlled substances. FERROUS SULFATE (fer-us sul-fayte) Fer-In-Sol®, Feosol® NUTRITIONAL/HEMATINIC Prescriber Highlights TT Oral iron supplement for the treatment of iron-deﬁciency anemias TT Contraindications: Patients with hemosiderosis, hemo-chromatosis, hemolytic anemias, or known hypersensitiv-ity; some consider it contraindicated with GI ulcers TT Adverse Effects: With non-toxic doses, mild gastrointesti-nal upset TT May be very toxic (life threatening) if OD'd Uses/Indications While iron is a necessary trace element in all hemoglobin-utilizing animals, the use of therapeutic dosages of ferrous sulfate (or other oral iron) preparations in veterinary medicine is limited primarily to the treatment of iron-deﬁciency anemias in dogs (usually due to chronic blood loss), and as adjunctive therapy in cats when receiv-ing epoetin (erythropoietin) therapy. Injectable iron products are usually used in the treatment of iron deﬁciency anemias associated with newborn animals. Pharmacology/Actions Iron is necessary for myoglobin and hemoglobin in the transport and utilization of oxygen. While neither stimulating erythropoiesis nor correcting hemoglobin abnormalities not caused by iron de-ﬁciency, iron administration does correct both physical signs and decreased hemoglobin levels secondary to iron deﬁciency. Ionized iron is a component in the enzymes cytochrome oxi-dase, succinic dehydrogenase, and xanthine oxidase. Pharmacokinetics Oral absorption of iron salts is complex and determined by a va-riety of factors including diet, iron stores present, degree of eryth-ropoiesis, and dose. Iron is thought to be absorbed throughout the GI tract, but is most absorbed in the duodenum and proximal jeju-num. Food in the GI tract may reduce the amount absorbed. After absorption, the ferrous iron is immediately bound to transferrin, transported to the bone marrow and eventually incor-porated into hemoglobin. Iron metabolism occurs in a nearly closed system. Because iron liberated by the destruction of hemoglobin is reused by the body and only small amounts are lost by the body via hair and nail growth, normal skin desquamation and GI tract sloughing, normal dietary intake usually is sufﬁcient to maintain iron homeostasis.	pppbs.pdf
FERROUS SULFATE 383 Contraindications/Precautions/Warnings Ferrous sulfate (or other oral iron products) are considered con-traindicated in patients with hemosiderosis, hemochromatosis, hemolytic anemias, or known hypersensitivity to any component of the product. Because of the GI irritating properties of the drugs, oral iron products are considered contraindicated by some clini-cians in patients with GI ulcerative diseases. Adverse Effects Adverse effects associated with non-toxic doses are usually limited to mild gastrointestinal upset. Division of the daily dosage may re-duce this effect, but dosage reduction may also be necessary in some animals. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category A for use dur-ing pregnancy (Adequate studies in pregnant women have not dem-onstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Overdosage/Acute Toxicity Ingestion of iron containing products may result in serious toxic-ity. While lethal doses are not readily available in domestic species, as little as 400 mg (of elemental iron) is potentially fatal in a child. Initial clinical signs of acute iron poisoning usually present with an acute onset of gastrointestinal irritation and distress (vomiting— possibly hemorrhagic, abdominal pain, diarrhea). The onset of these effects may be seen within 30 minutes of ingestion, but can be delayed for several hours. Peripheral vascular collapse may rapidly follow with clinical signs of depression, weak and/or rapid pulse, hypotension, cyanosis, ataxia, and coma possible. Some patients do not exhibit this phase of toxicity and may be asymptomatic for 12-48 hours after ingestion, when another critical phase may oc-cur. This phase may be exhibited by pulmonary edema, vasomo-tor collapse, cyanosis, pulmonary edema, fulminant hepatic failure, coma and death. Animals that survive this phase may exhibit long-term sequelae, including gastric scarring and contraction and have persistent digestive disturbances. Because an acute onset of gastroenteritis may be associated with a multitude of causes, diagnosis of iron intoxication may be dif-ﬁcult unless the animal has been observed ingesting the product or physical evidence suggests ingestion. Ferrous sulfate (and glucon-ate) tablets are radiopaque and often can be observed on abdomi-nal radiographs. Serum iron levels and total iron binding capacity (TIBC) may also be helpful in determining the diagnosis, but must be done on an emergency basis to have any clinical beneﬁt. Treatment of iron intoxication must be handled as an emergen-cy. In humans who have ingested 10 mg/kg or more of elemental iron within 4 hours of presentation, the stomach is emptied, pref-erably using gastric lavage with a large bore tube to remove tablet fragments. It is generally recommended to avoid using emetics in patients who already have had episodes of hemorrhagic vomiting. These patients are lavaged using tepid water or 1-5% sodium bi-carbonate solution. In dogs, one author (Mount 1989), has recommended using oral milk of magnesia to help bind the drug, administering apomor-phine if appropriate to help dislodge tablets, and to instill a gastric lavage slurry of 50% sodium bicarbonate with a portion left in the stomach. Deferoxamine is useful in chelating iron that has been ab-sorbed. See that monograph for further information. In addition to chelation therapy, other supportive measures may be necessary including treatment of acidosis, prophylactic antibi-otics, oxygen, treatment for shock, coagulation abnormalities, sei-zures, and/or hyperthermia. After the acute phases have resolved, dietary evaluation and management may be required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ferrous sulfate and may be of signiﬁcance in veterinary patients: !TANTACIDS : May bind to iron and decrease oral absorption; admin-ister at least two hours apart !TCALCIUM (ORAL ): May bind to iron and decrease oral absorption; administer at least two hours apart !TCHLORAMPHENICOL : Because chloramphenicol may delay the re-sponse to iron administration, avoid using chloramphenicol in patients with iron deﬁciency anemia !TFLUOROQUINOLONES (enroﬂoxacin, etc. ): Iron may reduce the ab-sorption of oral ﬂuoroquinolones; administer at least two hours apart !TH2-RECEPTOR ANTAGONISTS (e. g., ranitidine, famotidine, etc. ): In-creased gastric p H may decrease iron absorption !TPENICILLAMINE : Iron can decrease the efﬁcacy of penicillamine, probably by decreasing its absorption; if both drugs are required, space doses of the two drugs as far apart as possible !TPROTON-PUMP INHIBITORS (e. g., omeprazole ): Increased gastric p H may decrease iron absorption !TTETRACYCLINES : Oral iron preparations can bind to orally admin-istered tetracyclines, thereby decreasing the absorption of both compounds !TTHYROXINE : Iron may reduce the absorption of oral thyroxine; ad-minister at least two hours apart !TVITAMIN C : May enhance the absorption of iron Laboratory Considerations !TLarge doses of oral iron can color the feces black and cause false-positives with the guaiac test for occult blood in the feces. !TIron does not usually affect the benzidine test for occult blood. Doses CAUTION: Unless otherwise noted, doses are for ferrous sulfate (regular—not dried). Dosing of oral iron products can be confus-ing; some authors state doses in terms of the iron salt and some state doses in terms of elemental iron. For the doses below, assume that the doses are for ferrous sulfate and not elemental iron, unless speciﬁed. !TDOGS: For iron deﬁciency anemia: a) 60-300 mg PO per day for 2 weeks or more (Adams 1988a) b) First correct underlying cause of blood loss, then give ferrous sulfate at 100-300 mg per day (total dose) PO. Absorption is enhanced if administered 1 hour before or several hours after feeding. Reduce dosage if GI side effects occur. (Harvey, French, and Meyer 1982) For patients to be treated with epoetin (erythropoietin): a) 100-300 mg (total dose) PO per day (Cowgill 2002); (Vaden 2006b) !TCATS: For iron deﬁciency anemia: a) 50-100 mg PO once daily (Kirk 1986), (Morgan 1988) b) 30-200 mg PO per day for 2 weeks or more (Adams 1988a) For patients to be treated with epoetin (erythropoietin): a) 50-100 mg (total dose) PO per day. Many cats do not toler-ate oral iron therapy and are better treated with iron dextran at 50 mg IM q3-4 weeks. (Cowgill 2002) b) 5-50 mg per cat PO once daily (Di Bartola and Chew 2006a) c) 50-100 mg per cat PO once daily (Vaden 2006b)	pppbs.pdf
384 FILGRASTIM T ! CATTLE: As a hematinic: a) 8-15 g PO per day for 2 weeks or more (Adams 1988a) T ! HORSES: As a hematinic: a) 2-8 g PO per day for 2 weeks or more (Adams 1988a) T ! SWINE: As a hematinic: a) 0. 5-2 g PO per day for 2 weeks or more (Adams 1988a) T ! SHEEP: As a hematinic: a) 0. 5-2 g PO per day for 2 weeks or more (Adams 1988a) Monitoring T ! Efﬁcacy; adverse effects: a) Hemograms b) Serum iron and total iron binding capacity, if necessary. Normal serum iron values for dogs and cats are reported as 80-180 micrograms/dl and 70-140 micrograms/dl, respec-tively. T otal iron binding for dogs and cats are reported as 280-340 micrograms/dl and 270-400 micrograms/dl, re-spectively. (Morgan 1988). Serum transferrin saturation can estimated by dividing serum iron by total iron binding ca-pacity. Client Information T ! Because of the potential for serious toxicity when overdoses of oral iron-containing products are ingested by either children or animals, these products should be kept well out of reach of chil-dren and pets. Chemistry/Synonyms An orally available iron supplement, ferrous sulfate occurs as odor-less, pale-bluish-green, crystals or granules having a saline, styptic taste. In dry air the drug is efﬂorescent. If exposed to moisture or moist air, the drug is rapidly oxidized to a brownish-yellow ferric compound that should not be used medicinally. Exposure to light or an alkaline medium will enhance the conversion from the fer-rous to ferric state. Ferrous sulfate is available commercially in two forms, a “regu-lar” and a “dried” form. Regular ferrous sulfate contains 7 molecules of water of hydration and is freely soluble in water and insoluble in alcohol. Ferrous sulfate contains approximately 200 mg of elemen-tal iron per gram. Dried ferrous sulfate consists primarily of the monohydrate with some tetrahydrate. It is slowly soluble in water and insoluble in water. Dried ferrous sulfate contains 300 mg of elemental iron per gram. Ferrous sulfate, dried may also be known as ferrous sulfate, exsiccated. Ferrous sulfate may also be known as: eisen(II)-sulfat, ferreux (sulfate), ferrosi sulfas heptahydricus, ferrous sulphate, ferrum sulfuricum oxydulatum, iron (II) sulphate heptahydrate, iron sul-phate; many trade names are available. Storage/Stability Unless otherwise instructed, store ferrous sulfate preparations in tight, light-resistant containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: No veterinary-approved products containing only ferrous sulfate could be located, but there are many multivitamin with iron contain-ing products available. HUMAN-LABELED PRODUCTS: Ferrous Sulfate Tablets: 325 mg (65 mg iron); Feosol® (Glaxo Smith-Kline); Fero Sul® (Major); generic; (OTC) Ferrous Sulfate Elixir/Liquid: 220 mg/5m L (44 mg iron/5ml) in 473 m L, 300 mg/5 m L (60 mg iron/5ml) in 5 m L; Feosol® (Smith Kline Beecham); generic; (OTC) Ferrous Sulfate Drops: 75 mg/0. 6 m L (15 mg iron/0. 6 m L) in 50 m L; Fer-In-Sol® (Mead Johnson Nutritionals); Fer-Gen-Sol® (Goldline); generic; (OTC) Ferrous Sulfate, Dried (exsiccated) Tablets: 200 mg (65 mg iron) & 300 mg (60 mg iron); Feosol® (Glaxo Smith Kline); Feratab® (Upsher-Smith); generic (Rugby); (OTC) Ferrous Sulfate, Dried (exsiccated) Tablets, Slow-Release: 160 mg (50 mg iron); Slow FE® (Ciba); Slow Release Iron® (Cardinal Health);(OTC) FILGRASTIM (GRANULOCYTE COLONY STIMULATING FACTOR; GCSF) (ﬁll-grass-stim) Neupogen® CYTOKINE HEMATOPOIETIC AGENT Prescriber Highlights TT Cytokine that in the bone marrow primarily increases the proliferation, differentiation, & activation of progenitor cells in the neutrophil-granulocyte line TT Human origin product; antibodies may form that can cause prolonged neutropenia TT Treatment is very expensive Uses/Indications Filgrastim may be of beneﬁt in treating neutropenias in dogs or cats when the intrinsic response to endogenously produced cytok-ines is thought to be inadequate and there is evidence that there are precursors in the bone marrow available. Because of the drug's cost and lack of good evidence for its efﬁcacy in reducing mortality ver-sus using antibiotic therapy alone, its use in small animal medicine is somewhat controversial. Pharmacology/Actions Filgrastim is a hematopoietic agent that primarily affects the bone marrow to increase the proliferation, differentiation, and activa-tion of progenitor cells in the neutrophil-granulocyte line. While derived from human DNA, the product is not species speciﬁc and also affects canine and feline bone marrow. Pharmacokinetics After subcutaneous injection, ﬁlgrastim is rapidly absorbed and distributed with highest concentrations found in the bone mar-row, liver, kidneys and adrenal glands. It is unknown if it crosses the blood-brain barrier, placenta, or enters maternal milk. The elimina-tion pathways of ﬁlgrastim are still under investigation.	pppbs.pdf
FINASTERIDE 385 Contraindications/Precautions/Warnings Filgrastim is contraindicated in patients hypersensitive to it. Dogs or cats that have developed antibodies to ﬁlgrastim with resultant neutropenia should probably not receive it in the future. Adverse Effects Because the human DNA origin product can be immunogenic to dogs and cats, some patients may develop severe neutropenia by mounting an immune response against both endogenously pro-duced and exogenously administered G-CSF. Studies in cats have demonstrated that short pulse doses of 3-5 days at the time of neu-tropenia may be safe and minimize the development of neutrophil neutralizing antibodies. Preliminary studies using canine origin G-CSF have not demonstrated autoantibody formation in either dogs or cats. Additionally, there are concerns that exogenously administered ﬁlgrastim can elicit undesirable responses in other tissues, includ-ing causing myeloﬁbrosis and medullary histiocytosis. Occasionally irritation at the injection site may occur. Bone pain, splenomegaly, and hypotension have been reported in humans. Reproductive/Nursing Safety Adverse effects in females and offspring have been demonstrated after ﬁlgrastim was administered to pregnant laboratory animals at high dosages. T o interpret this data for use in a clinical setting is difﬁcult, but ﬁlgrastim should be used in pregnant females only when the beneﬁts of treating outweigh the potential risks. 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. ) It is not known whether ﬁlgrastim is excreted in milk, but it is unlikely to pose signiﬁcant risk to nursing offspring. Overdosage/Acute Toxicity Limited information is available. Because of the expense of the drug and its apparent limited acute toxic potential, clinically signiﬁcant overdoses are unlikely. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ﬁlgrastim and may be of signiﬁcance in veterinary patients: T ! ANTINEOPLASTICS : While ﬁlgrastim was developed primarily to prevent the neutropenias associated with some chemotherapeu-tic agents, some controversy exists about using ﬁlgrastim within 24 hours of a dose of antineoplastic agents that target rapidly proliferating cells; generally, in human medicine, use is avoided within 24 hours of such antineoplastics Doses Note : T o avoid the development of autoantibody formation, most clinicians using this agent recommend using ﬁlgrastim in dogs or cats using a “pulse” therapy of no more than 5 days in duration. T ! DOGS: a) For adjunctive therapy of neutropenia (secondary to drug induced aplastic pancytopenia): 5 mcg/kg SC daily (Ruiz de Gopegui and Feldman 2000) b) For neutropenia: 1-5 mcg/kg SC daily (Ritt and Modiano 1999) T ! CATS: a) For neutropenia secondary to drug toxicity, infectious dis-eases, Fe LV-associated cyclic neutropenia or idiopathic causes: 5 mcg/kg SC twice daily. Cost and/or development of antibodies usually limit usefulness to a few weeks, but often it is effective for acute or life-threatening neutropenia. (Levy 2000) b) For neutropenia: 1-5 mcg/kg SC daily (Ritt and Modiano 1999) c) For adjunctive therapy of neutropenia: 5 mcg/kg SC daily until neutrophil count exceeds 3,000/mcl for 2 days (Levy 2002) Monitoring T ! CBC with platelets, routinely Client Information T ! Clients should be briefed on the cost of this agent as well as the possibility that it may cause antibodies to form against endoge-nously produced G-CSF, thereby causing a potentially life threat-ening neutropenia. Chemistry/Synonyms Prepared via recombinant DNA technology from human DNA, ﬁl-grastim is a single chain polypeptide containing 175 amino acids with a molecular weight of about 18,800 daltons. The commercially available injection occurs as a clear solution; buffered to a p H of 4. Filgrastim may also be known as: granulocyte colony-stimulat-ing factor, G-CSF, recombinant methionyl human GCS-F, r-met H-u G-CSF, Filgen®, Gran®, Granulen®, Granulokine®, Neulasta®, Neupogen®, and Neutromax®. Storage/Stability/Compatibility Injection should be stored in the refrigerator (2-8°C). Do not freeze or shake contents of vial. The drug should never be diluted with saline as a precipitate may form. If necessary it may be diluted into 5% dextrose for injection, but if diluted to concentrations be-tween 5 and 15 mcg/m L, it is recommended that albumin be added to the solution to a concentration of 2 mg/m L to reduce adsorption to plastic IV tubing. It is not recommended to dilute to a concentra-tion of less than 5 mcg/m L. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Filgrastim Injection: 300 mcg/m L preservative free in 1 m L and 1. 6 m L single dose vials; 300 mcg/0. 5 m L preservative free in 0. 5 m L and 0. 8 m L preﬁlled syringes; Neupogen® (Amgen); (Rx) FINASTERIDE (ﬁn-as-te-ride) Proscar®, Propecia® 5-ALPHA-REDUCTASE INHIBITOR Prescriber Highlights TT 5-alpha-reductase inhibitor potentially useful for dogs with benign prostatic hypertrophy & ferrets with adrenal disease TT Contraindications: Hypersensitivity to ﬁnasteride; sexually developing animals TT Caution: Patients with signiﬁcant hepatic impairment TT Adverse Effects: Potentially may cause some minor sexual side effects TT Expense may be an issue	pppbs.pdf
386 FIROCOXIB Uses/Indications Finasteride may be useful in treating the benign prostatic hypertro-phy in canine patients. Because of the drug's relative expense and the long duration of therapy required to see a response, its useful-ness may be limited in veterinary medicine. It may also be useful in the adjunctive treatment of adrenal dis-ease in ferrets. Pharmacology/Actions Finasteride speciﬁcally and totally inhibits 5-alpha-reductase. This enzyme is responsible for metabolizing testosterone to dihydrotes-tosterone (DHT) in the prostate, liver and skin. DHT is a potent androgen and is the primary hormone responsible for the develop-ment of the prostate. Pharmacokinetics Finasteride is absorbed after oral administration and in humans about 65% is bioavailable. The presence of food does not affect absorption. It is distributed across the blood-brain barrier and is found in seminal ﬂuid. In humans, about 90% is bound to plasma proteins. Finasteride is metabolized in the liver and the half-life is about 6 hours. Metabolites are excreted in the urine and feces. In humans, a single daily dose suppresses DHT concentrations for 24 hours. Contraindications/Precautions/Warnings Finasteride is contraindicated in patients hypersensitive to it. It should be used with caution in patients with signiﬁcant hepatic im-pairment as metabolism of the drug may be reduced. Finasteride should be used in males only; do not use in sexually developing animals. Adverse Effects One study done in dogs reported no adverse effects or irreversibility of effects after treating for 21 weeks at 1 mg/kg. The adverse effects reported in humans have been very limited, mild and transient. Decreased libido, decreased ejaculate volume, and impotence have been reported. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category X for use during pregnancy (Studies in animals or humans demonstrate fetal abnormalities or adverse reaction; reports indicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible beneﬁt. ) Finasteride is not indicated for use in females. It is not known whether ﬁnasteride is excreted in milk. Overdosage/Acute Toxicity Limited information is available; gastrointestinal effects may be noted. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ﬁnasteride and may be of signiﬁcance in veterinary patients: T ! ANTICHOLINERGIC DRUGS : May precipitate or aggravate urinary re-tention thereby negating the effects of the drug when used for BPH Doses T ! DOGS: a) For benign prostatic hyperplasia: 0. 1-0. 5 mg/kg once daily PO; for a 10-50 kg dog, one 5 mg tablet daily (Root Kustritz and Klausner 2000); (Kamolpatana, Johnston et al. 1998), (Bartges 2006c) b) For dogs <15 kg: 1. 5 mg (approx. N of a 5 mg tablet); for dogs 15-30 kg = 2. 5 mg (H tablet); for dogs >30 kg = 5 mg (one tablet). Given PO daily. (Romagnoli 2006b) T ! FERRETS: a) For adjunctive treatment of adrenal disease: 5 mg (total dose) tablet once daily (Johnson 2006b) Monitoring T ! Efﬁcacy: Prostate exam Client Information T ! Clients should understand that therapy might be prolonged be-fore efﬁcacy can be determined and regular dosing compliance is mandatory. Once the drug is stopped, the prostate will start growing again. T ! Pregnant women should be advised to guard against exposure to this drug as it may cause birth defects. Chemistry/Synonyms Finasteride is a 4-azasteroid synthetic drug that inhibits 5 alpha-dihydroreductase (DH), and has a molecular weight of 372. 55. Finasteride may also be known as: ﬁnasteridum, MK-0906, and MK-906; many trade names are available. Storage/Stability Store tablets below 30°C in tight containers and protected from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Finasteride Oral Tablets: 1 mg and 5 mg; Proscar®, Propecia® (Mer-ck); generic; (Rx) Fipronil — S ee the listing in the Dermatological Agents, Topical Appendix FIROCOXIB (feer-oh-koks-ib) Previcox®, Equioxx® ORAL COX-2 INHIBITOR NSAID Prescriber Highlights TT Oral COX-2 NSAID labeled for the control of pain & inﬂammation associated with osteoarthritis in dogs & horses TT Adverse effect proﬁle not fully determined; in DOGS: GI effects (vomiting, anorexia) most likely, but serious effects are possible TT Adverse effects in HORSES include mouth ulcers, facial skin lesions, excitation (rare)	pppbs.pdf
FIROCOXIB 387 Uses/Indications Firocoxib is indicated in dogs and horses for the control of pain and inﬂammation associated with osteoarthritis. A chewable tablet form for dogs and an oral paste for horses are available. Like other NSAIDs, ﬁrocoxib can be useful for treating fever, pain, and/or inﬂammation associated with other conditions, post-surgery, trauma, etc. Firocoxib may also be useful in other species, but information is scant regarding its safety and efﬁcacy. One study in cats (Mc Cann, Rickes et al. 2005) evaluating ﬁrocoxib in experimentally induced pyrexia, demonstrated that the drug was effective after a single oral dose in preventing or attenuating pyrexia at all doses studied (0. 75-3 mg/kg). Pharmacology/Actions Firocoxib is a coxib-class, nonsteroidal antiinﬂammatory drug (NSAID). It is believed to predominantly inhibit cyclooxygenase-2 (COX-2) and spare COX-1 at therapeutic dosages. This theoreti-cally would inhibit production of the prostaglandins that contrib-ute to pain and inﬂammation (COX-2) and spare those that main-tain normal gastrointestinal, platelet and renal function (COX-1). However, COX-1 and COX-2 inhibition studies are done in vitro and do not necessarily correlate perfectly with clinical effects seen in actual patients. Pharmacokinetics In dogs, ﬁrocoxib absorption after oral dosing varies among indi-viduals. Oral bioavailability with the chewable tablets, on average, is about 38%. Food will delay, but not affect the amount absorbed. Peak levels occur about 1 hour after dosing if fasted, and 5 hours if the patient is fed. Volume of distribution at steady state is about 3 L/kg; it is 96% bound to plasma proteins. Biotransformation occurs predominantly via dealkylation and glucuronidation in the liver; elimination is principally in the bile and feces. Elimination half-life in dogs is approximately 6-8 hours. In horses, oral availability after administering the paste is ap-proximately 79%. Peak levels occur 4-12 hours after dosing. Volume of distribution at steady state is about 1. 7 L/kg and it is 98% bound to plasma proteins. Biotransformation in horses occurs primarily via decyclopropylmethylation and then glucuronidation. Metabolites are primarily excreted in the urine. Elimination half-life is approximately 30-40 hours. Pharmacokinetics of ﬁrocoxib have only been reported in two cats studied (Mc Cann, Rickes et al. 2005). Oral bioavailability after administering an oral suspension was about 60% and the volume of distribution, between 2-3 L/kg. Elimination half-life in the two cats studied averaged about 10 hours. Contraindications/Precautions/Warnings Firocoxib should not be used in animals hypersensitive to it or oth-er NSAIDs. The drug should be used with caution and enhanced monitoring in patients with preexisting renal, hepatic or cardio-vascular dysfunction, and those that are dehydrated, hypovolemic, hypotensive, or on concomitant diuretic therapy. Because geriatric patients have reduced renal function and ﬁrocoxib is often used for osteoarthritis in this patient population, ongoing monitoring for adverse effects is mandatory. Because all NSAIDs can potentially cause GI toxicity, ﬁrocoxib is relatively contraindicated in dogs with active GI ulcerative condi-tions. As it may affect platelet function, it is relatively contraindi-cated in patients with bleeding disorders or thrombocytopenia. The safety of ﬁrocoxib in horses less than one year old has not been established. A chronic dosing (5 mg/kg for 6 months) study performed in puppies 10-13 weeks old, showed subclinical periportal hepatic fatty changes in half the dogs studied. Higher doses (15-25 mg/ kg; 3-5X) in this age range caused increased rates of hepatic fatty changes; some dogs died or were euthanized due to moribund con-ditions. The manufacturer states in the package insert: “Use of this product at doses above the recommended 5 mg/kg in puppies less than 7 months old has been associated with serious adverse reac-tions, including death” and “... this product cannot be accurately dosed in dogs weighing less than seven pounds in body weight. ” The labeling in the UK states that it should not be used in dogs “less than 10 weeks of age. ” If changing from one NSAID to another in dogs for reasons of efﬁcacy, consider a washout period between agents. While the actu-al length of time between agents is controversial and opinions vary widely, often a 24-hour washout period between COX-2 selective agents is recommended. Recommendations for washout periods before starting a COX-2 selective agent after using a non-selective agent or aspirin are usually much longer (72 hours-1 week). Adverse Effects Because ﬁrocoxib is a relatively new product, its adverse effect pro-ﬁle in dogs is yet to be fully determined. In pre-approval studies (128 dogs treated), vomiting and decreased appetite/anorexia were the most common adverse effects noted with an approximate inci-dence rate of 4% and 2%, respectively. In the FDA 's CVM Cumulative Adverse Drug Experiences (ADE) Summaries Report (through 12/06/2006) for ﬁrocoxib in dogs, the most prevalent ADE reported was vomiting. On the list of 10 most reported ADE's for ﬁrocoxib, the second most reported event was anorexia. Other effects on this list included: diarrhea, increases in BUN, creatinine, alkaline phosphatase and ALT, depression/leth-argy, and ataxia. Melena, GI ulcers, bloody vomiting and GI per-foration were included within the 25 most reported events listed. It should be noted that this data reﬂects voluntary reporting to the FDA and does not reﬂect actual incidence rates, nor is causation necessarily proven. In pre-approval studies done in horses treated for 14 days, di-arrhea/loose stools were seen in about 2%. Excitation was rarely (<1%) detected. In safety studies, oral lesions/ulcers were seen in some horses after dosages of 1-5X were given. Reproductive/Nursing Safety Information on the safety of ﬁrocoxib in breeding, pregnant or lac-tating dogs or horses is not available. Studies performed in preg-nant rabbits at dosages approximating those given to dogs, demon-strated maternotoxic and fetotoxic effects. Overdosage/Acute Toxicity Limited information is available for acute overdoses in animals. The reported oral LD 50 for rats is > 2 grams per kg. Should an overdose occur, contacting an animal poison control center or the manufacturer (1-877-217-3543) is highly recommended. Use of gut emptying protocols and supportive treatment (IV ﬂuids, oral su-cralfate, etc. ) may be useful in managing the case. Drug Interactions In the package insert for Previcox, the manufacturer states the fol-lowing ( Note : bold mine—Plumb): “As a class, cyclooxygenase in-hibitory NSAIDs may be associated with renal and gastrointestinal toxicity. Sensitivity to drug-associated adverse events varies with the individual patient. Patients at greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with existing renal, cardiovascular, and/or hepatic dysfunction. Concurrent administration of potentially nephrotoxic drugs should be carefully approached. NSAIDs may inhibit the prostaglandins that maintain normal homeostatic function. Such antiprostaglan-	pppbs.pdf
388 FLAVOXATE HCL Tdin effects may result in clinically signiﬁcant disease in patients with underlying or pre-existing disease that has not been previ-ously diagnosed. Since many NSAIDs possess the potential to pro-duce gastrointestinal ulcerations, concomitant use with other an-tiinﬂammatory drugs, such as NSAIDs or corticosteroids, should be avoided or closely monitored. The concomitant use of protein bound drugs with PREVICOX™ Chewable Tablets has not been studied in dogs. Commonly used protein-bound drugs include cardiac, anticon-vulsant, and behavioral medications. The inﬂuence of concomitant drugs that may inhibit the metabolism of PREVICOX™ Chewable Tablets has not been evaluated. ” Drug interactions reported in humans taking NSAIDS, that may be of signiﬁcance in veterinary patients receiving ﬁrocoxib include: T ! ACE INHIBITORS (e. g., enalapril, benazepril ): Some NSAIDs can re-duce effects on blood pressure T ! ASPIRIN : May increase the risk of gastrointestinal toxicity (e. g., ul-ceration, bleeding, vomiting, diarrhea) T ! CORTICOSTEROIDS (e. g., prednisone ): May increase the risk of gastrointestinal toxicity (e. g., ulceration, bleeding, vomiting, diarrhea) T ! DIGOXIN : NSAIDS may increase serum levels T ! FLUCONAZOLE : Administration has increased plasma levels of cele-coxib in humans and potentially could also affect ﬁrocoxib levels in dogs T ! FUROSEMIDE : NSAIDs may reduce the saluretic and diuretic effects T ! HIGHLY PROTEIN BOUND DRUGS (phenytoin, valproic acid, oral antico-agulants, other antiinﬂammatory agents, salicylates, sulfonamides, sulfonylurea antidiabetic agents ): As ﬁrocoxib is highly bound to plasma proteins (95-98%), it may displace other highly bound drugs or these agents could displace ﬁrocoxib. Increased serum levels, duration of actions and toxicity could occur. T ! METHOTREXATE : Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate ; use together with extreme caution T ! NEPHROTOXIC DRUGS (e. g., furosemide, aminoglycosides, amphotericin B, etc. ): May enhance the risk of nephrotoxicity development Laboratory Considerations No speciﬁc laboratory concerns; see Monitoring Doses T ! DOGS: For the control of pain and inﬂammation associated with os-teoarthritis (labeled indication): a) 5 mg/kg (2. 27 mg/lb) PO once daily. Dosage should be calcu-lated in half tablet increments and can be administered with or without food. (Package insert; Previcox ®—Merial) T ! CATS: Caution: While ﬁrocoxib may ultimately be shown to be safe for use in cats, supporting information (or FDA approval) is not currently available for it to be recommended. T ! HORSES: For the control of pain and inﬂammation associated with os-teoarthritis (labeled indication): a) 0. 1 mg/kg (0. 45 mg/lb) body weight PO daily for up to 14 days (Package insert; Equioxx®—Merial) Monitoring T ! Baseline and periodic physical exam including clinical efﬁcacy and adverse effect queries T ! Baseline and periodic: CBC, liver function, renal function, and electrolytes; urinalysis Client Information T ! he manufacturer provides a client hand-out that is recom-mended to be distributed each time the drug is dispensed T ! May be administered with or without food T ! Contact veterinarian if any of the following occur in dogs: vom-iting, decreased appetite/weight loss, diarrhea or loose stools, changes in behavior or activity, changes in water consumption or urination, or yellowing of whites of eyes or mucous membranes T ! For horses, contact veterinarian if patient develops ulcers or sores on tongue or in mouth, sores or lesions on facial skin or lips, di-arrhea/loose stools, changes in behavior/activity, changes in feed or water consumption, or yellowing of whites of eyes or mucous membranes Chemistry/Synonyms Firocoxib occurs a white crystalline powder. Firocoxib may also be known as: 3-(cyclopropylmethoxy)-5, 5-dimethyl-4-(4-methylsulfonyl) phenylfuran-2(5H)-on or ML-1,785,713, Equioxx®, and Previcox®. Storage/Stability/Compatibility Commercially available tablets and oral paste should be stored at room temperature (15-30°C); brief excursions are permitted up to 40°C (104°F). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Firocoxib Chewable Tablets (scored): 57 mg, & 227 mg; Previcox® (Merial); (Rx). Approved for use in dogs. Firocoxib Oral Paste: 0. 82% w/w (8. 2 mg ﬁrocoxib per gram of paste) in a 6. 93 gram oral syringe (total of 56. 8 mg of ﬁrocoxib per syringe); Equioxx® (Merial); (Rx). HUMAN-LABELED PRODUCTS: None Fish Oil— See Fatty Acids FLAVOXATE HCL (ﬂa-vox-ate) Urispas® PARASYMPAT HETIC BLOCKER; URINARY ANTISPASMODIC Prescriber Highlights TT Alternative medication to treat with detrusor hyper-spasticity (hyperactive bladder; urge incontinence) in dogs TT Not commonly used; little information available on veteri-nary use TT Most likely adverse effect is weakness Uses/Indications Flovoxate may be considered for treating dogs with detrusor hyper-spasticity (hyperactive bladder, urge incontinence). Pharmacology/Actions Flavoxate has direct smooth muscle relaxing properties and anti-muscarinic effects.	pppbs.pdf
FLORFENICOL 389 Pharmacokinetics No information was located for dogs or cats. In humans, the drug's onset of action is within an hour with peak effects at around 2 hours post dose. 57% of a dose is excreted in the urine within 24 hours. Contraindications/Precautions/Warnings Flavoxate is contraindicated in human patients with pyloric or duo-denal obstruction, obstructive intestinal lesions or ileus, achalasia, GI hemorrhage or obstructive uropathies of the lower urinary tract. It is to be given with caution in patients with suspected glaucoma. Adverse Effects Weakness is the most likely adverse effect seen in dogs treated with ﬂavoxate. Reproductive/Nursing Safety In laboratory animals, doses of up to 34X (human dose) demon-strated no harm to fetuses or impaired fertility. In humans, gluca-gon is designated by the FDA as a category B drug (Animal studies have not 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 demonstrat-ed a risk to the fetus during the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) It is not known whether this drug is excreted into milk. Use with caution in nursing mothers. Overdosage/Acute Toxicity The approximate oral LD-50 for rats and mice are 4300 mg/kg and 1800 mg/kg respectively. Drug Interactions No signiﬁcant drug interactions with ﬂavoxate were located; how-ever, concomitant use with other anticholinergic drugs may cause ad-ditive effects. Laboratory Considerations No concerns noted Doses T ! DOGS: T o decrease urinary bladder contractility: a) 100-200 mg (per dog) PO q6-8h (Bartges 2006a) Monitoring T ! Clinical efﬁcacy T ! Adverse effects (most likely GI) T ! Consider occasional CBC's and creatinine to monitor for neutro-penia or renal dysfunction if using the drug chronically Client Information T ! May cause weakness or changes in activity level in treated dogs; if these become a problem, contact veterinarian Chemistry/Synonyms Flavoxate HCl occurs as a white or almost white crystalline powder. It is slightly soluble in water or alcohol. Flavoxate may also be known as ﬂavoxato, AK 123, or Rec 7-0040. A common trade name is Urispas®. Storage/Stability Flavoxate tablets should be stored at room temperature (15-30°C). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Flavoxate HCl Tablets (ﬁlm-coated) 100 mg: Urispas® (Ortho-Mc-Neil), generic (Global); (Rx) FLORFENICOL (ﬂor-fen-i-col) Nu Flor® ANTIBIOTIC Prescriber Highlights TT Broad spectrum antibiotic approved for use in cattle, swine, & ﬁsh, but may be useful in other species (e. g., dogs, cats) TT Contraindications: Do not give IV, to veal calves or cattle of breeding age (per manufacturer) TT Adverse Effects: Cattle: Anorexia, decreased water con-sumption, diarrhea, injection site reactions (may result in trim loss); IM injection may be painful in small animals TT Slaughter withdrawals depend upon route of administra-tion (IM shorter than SC) Uses/Indications The drug is approved for use in cattle only (in the USA) for the treatment of bovine respiratory disease (BRD) associated with Pasteurella haemolytica, Pasteurella multocida, and Haemophilus somnus. Because ﬂorfenicol has activity against a wide range of micro-organisms (e. g., Mycoplasma), it may be useful for treating other infections in cattle (or other species) as well, but speciﬁc data is limited. Pharmacology/Actions Like chloramphenicol, ﬂorfenicol is a broad-spectrum antibiotic that has activity against many bacteria. It acts by binding to the 50S ribosome, thereby inhibiting bacterial protein synthesis. Pharmacokinetics After IM injection in cattle, approximately 79% of the dose is bio-available. The drug appears to be well distributed throughout the body, including achievement of therapeutic levels in the CSF. In cattle, the volume of distribution is about 0. 7 L/kg and only about 13% is bound to serum proteins. Mean serum half-life is 18 hours, but wide interpatient variation exists. In dogs, ﬂorfenicol is absorbed poorly after subcutaneous injec-tion and has an elimination half-life of less than 5 hours. PO ad-ministration results in good bioavailability (95%), but is eliminated rapidly (elimination half-life 1. 25 hours). Cats, however, have high absorption of a 100 mg/m L solution when either given IM or orally and have an elimination half-life of less than 5 hours. Times above an MIC of 2 mg/m L were 12 hours (IM) and 18 hours (PO); and an MIC of 8 mg/m L were 10 hours (IM) and 6 hours (PO), respectively, in cats. Contraindications/Precautions/Warnings No contraindications are listed in the package insert, but see resi-due warnings (in Dosage forms) and reproductive safety (below). Caution : Do not give this drug IV.	pppbs.pdf
390 FLORFENICOL Adverse Effects Noted transient adverse reactions in cattle include anorexia, de-creased water consumption, or diarrhea. Injection site reactions can occur that may result in trim loss. Reactions may be more severe if injected at sites other than the neck. When used in other species (mammals), gastrointestinal effects, including severe diarrheas are potentially possible. Reproductive/Nursing Safety Safety or effects when used in breeding cattle or swine, during pregnancy, or during lactation are unknown and the manufacturer states that the drug is not for use in cattle of breeding age or in swine intended for breeding. Overdosage/Acute Toxicity In toxicology studies where feeder calves were injected with up to 10X the recommended dosage, the adverse effects noted above were seen, plus increased serum enzymes. These effects were generally transient in nature. Long-term (43 day) standard dosage studies showed a transient decrease in feed consumption, but no long-term negative effects were noted. Drug Interactions No speciﬁc drug interactions for ﬂorfenicol were located, but the drug may behave similarly to chloramphenicol. If so, ﬂorfenicol could antagonize the bactericidal activity of the penicillins or amino-glycosides. This antagonism has not been demonstrated in vivo, and these drug combinations have been used successfully many times clinically. Other antibiotics that bind to the 50S ribosomal subunit of susceptible bacteria ( erythromycin, clindamycin, lincomycin, tylosin, etc. ) may potentially antagonize the activity of chloramphenicol or vice versa, but the clinical signiﬁcance of this potential inter-action has not been determined. For other drug interactions that ﬂorfenicol may share with chloramphenicol, see the monograph for chloramphenicol or refer to other drug information resources. Doses !TCATTLE: a) For treatment of BRD: 20 mg/kg IM (in neck muscle only); repeat in 48 hours. Alternatively, a single 40 mg/kg SC dose (in neck) may be used. Note : 20 mg/kg equates to 3 m L of the injection per 100 lb. of body weight. Do not exceed 10 m L per injection site. (Package Insert; Nuﬂor® —Schering Plough) !TDOGS: a) For susceptible systemic (bacterial or rickettsial) infec-tions when myelotoxic potential (in humans or animals) of chloramphenicol is to be avoided: 20 mg/kg IM q8h for 3-5 days. (Greene, Hartmannn et al. 2006) !TCATS: a) For susceptible systemic infections (bacterial or rickettsial) infections when myelotoxic potential (in humans or ani-mals) of chloramphenicol is to be avoided: 22 mg/kg IM, PO q12h for 3-5 days ( Note : Oral dosage form not available, but solution given orally to experimental cats was well absorbed) (Greene, Hartmannn et al. 2006) !TSHEEP & GOATS: a) For respiratory disease complex in kids: 20 mg/kg a day (route not speciﬁed; assume IM) for 2 days (de la Concha 2002) !TSWINE: a) For swine respiratory disease: In water at a concentration of 400 mg/gallon (100 ppm). Use as only source of drinking water for 5 days. For bulk tank add one gallon concentrate to 128 gallons of water; for proportioner set to 1:128 (0. 8%). (Label information; Nu Flor® Concentrate Solution—Scher-ing-Plough) Monitoring !TClinical efﬁcacy !TInjection site reactions Client Information !TResidue Warnings: When administered as labeled, cattle slaugh-ter withdrawal is 28 days post injection if using the IM route; 38 days after the SC route. Swine (in drinking water) = 16 days. !TNot to be used in female dairy cattle 20 months of age or older. !TA withdrawal period has not been established in preruminating calves. Do not use in calves to be processed for veal. !TDo not give IV. Chemistry/Synonyms A ﬂuorinated analog of thiamphenicol, ﬂorfenicol is commercially available as light yellow to straw-colored injectable solution also containing n-ethyl-2-pyrolidone, propylene glycol, and polyethyl-ene glycol. Florfenicol may also be known as Sch-25298 and Nu Flor®. Storage/Stability Florfenicol injection should be stored between 2°-30°C (36°-86-°F). The oral solution (swine) should be stored between 2°-26°C (36°-77°F) Dosage Forms/Regulatory Status/Withdrawal Times VETERINARY-LABELED PRODUCTS: Florfenicol Injection: 300 mg/m L in 100 m L, 250 m L and 500 m L multi-dose vials; Nu Flor® (Schering-Plough); (Rx). Approved for use in cattle; see residue warnings above. Slaughter withdrawal (at labeled dosages) = 28 days (IM treatment), 38 days (subcutaneous treatment). Do not use in female dairy cattle 20 months of age or older. A withdrawal period has not been established in preruminating calves. Do not use in calves to be processed for veal. Florfenicol 2. 3% (23 mg/m L) Concentrate Solution in 2. 2 btls; Nu-Flor® Concentrate Solution (Schering-Plough); (Rx). Approved for use in swine; Slaughter withdrawal (at labeled dosages) = 16 days. There are ﬂorfenicol products for addition to catﬁsh or salmonid feeds (Aquaﬂor®) and to feed for swine. HUMAN-LABELED PRODUCTS: None	pppbs.pdf
FLUCONAZOLE 391 FLUCONAZOLE (ﬂoo-kon-a-zole) Diﬂucan® ANTIFUNGAL Prescriber Highlights TT Oral or parenteral antifungal particularly useful for CNS infections TT Caution: Renal failure (dosage adjustment needed), preg-nancy (safety not established), hepatic failure TT Adverse Effects: Occasional GI effects (inappetence) in cats or dogs; in humans: headache &, rarely, increased liver enzymes & hepatic toxicity TT Expensive, but price is decreasing now that it is available as a generic TT Drug Interactions Uses/Indications Fluconazole may have use in veterinary medicine in the treatment of systemic mycoses, including cryptococcal meningitis, blasto-mycosis, and histoplasmosis. It may also be useful for superﬁcial candidiasis or dermatophytosis. Because of the drug's unique phar-macokinetic qualities, it is probably more useful in treating CNS infections or fungal urinary tract infections than other azole de-rivatives. Fluconazole does not have appreciable effects (unlike ke-toconazole) on hormone synthesis and may have fewer side effects than ketoconazole in small animals. Pharmacology/Actions Fluconazole is a fungistatic triazole compound. Triazole-derivative agents, like the imidazoles (clotrimazole, ketoconazole, etc. ), pre-sumably act by altering the cellular membranes of susceptible fungi, thereby increasing membrane permeability and allowing leakage of cellular contents and impaired uptake of purine and pyrimidine precursors. Fluconazole has efﬁcacy against a variety of pathogenic fungi including yeasts and dermatophytes. In vivo studies using lab-oratory models have shown that ﬂuconazole has fungistatic activity against some strains of Candida, Cryptococcus, Histoplasma, and Blastomyces. In vivo studies of efﬁcacy against Aspergillus strains have been conﬂicting. Pharmacokinetics Fluconazole is rapidly and nearly completely absorbed (90%) after oral administration. Gastric p H or the presence of food, do not ap-preciably alter ﬂuconazole's oral bioavailability. It has low protein binding and is widely distributed throughout the body and pen-etrates well into the CSF, eye, and peritoneal ﬂuid. Fluconazole is eliminated primarily via the kidneys and achieves high concentra-tions in the urine. In humans, ﬂuconazole's serum half-life is about 30 hours in patients with normal renal function. Because of it's long half-life, ﬂuconazole does not reach steady state plasma levels for 6-14 days after beginning therapy, unless loading doses are given. Patients with impaired renal function may have half-lives extended signiﬁcantly and dosage adjustment may be required. Contraindications/Precautions/Warnings Fluconazole should not be used in patients hypersensitive to it or other azole antifungal agents. In patients with hepatic impairment it should be used only when the potential beneﬁts outweigh the risks. Because ﬂuconazole is eliminated primarily by the kidneys, ﬂuconazole doses or dosing intervals may need to be adjusted in patients with renal impairment. Fluconazole is reportedly toxic to budgerigars. Adverse Effects There is limited experience with this drug in domestic animals. Thus far, it appears to be safe to use in dogs and cats. Occasionally, inappetence may be reported. In humans, the side effects have been generally limited to oc-casional GI effects (vomiting, diarrhea, anorexia/nausea) and headache. Rarely, increased liver enzymes and hepatic toxicity, ex-foliative skin disorders, and thrombocytopenia have been reported in humans. Thrombocytopenia has not been reported thus far in animals. Reproductive/Nursing Safety Safety during pregnancy has not been established and it is not rec-ommended for use in pregnant animals unless the beneﬁts 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 reproduction studies and no adequate studies in humans. ) Fluconazole is excreted in milk at concentrations similar to plas-ma. Use with caution in nursing dams. Overdosage/Acute Toxicity There is very limited information on the acute toxicity of ﬂucona-zole. Rats and mice survived doses of 1 g/kg, but died within several days after receiving 1-2 g/kg. Rats and mice receiving very high dosages demonstrated respiratory depression, salivation, lacrima-tion, urinary incontinence, and cyanosis. If a massive overdose occurs, consider gut emptying and give supportive therapy as re-quired. Fluconazole may be removed by hemodialysis or peritoneal dialysis. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ﬂuconazole and may be of signiﬁcance in veterinary patients: T ! AMPHOTERICIN B : Lab animal studies have shown that ﬂuconazole used concomitantly with amphotericin B may be antagonistic against Aspergillus or Candida; the clinical importance of these ﬁndings is not yet clear T ! BUSPIRONE : Plasma concentrations may be elevated T ! CISAPRIDE : Fluconazole may increase cisapride levels and the pos-sibility for toxicity T ! CORTICOSTEROIDS : Fluconazole may inhibit the metabolism of corticosteroid; potential for increased adverse effects T ! CYCLOPHOSPHAMIDE : Fluconazole may inhibit the metabolism of cyclophosphamide and its metabolites; potential for increased toxicity T ! CYCLOSPORINE : Increased cyclosporine levels T ! DIURETICS, THIAZIDES : Increased ﬂuconazole concentrations T ! FENTANYL/ALFENTANIL : Fluconazole may increase fentanyl levels T ! MIDAZOLAM : Increased midazolam levels and effects T ! NSAID s: Fluconazole may increase plasma levels; increased risk for adverse effects T ! RIFAMPIN : May decrease ﬂuconazole efﬁcacy; ﬂuconazole may in-crease rifampin levels T ! THEOPH YLLINE/AMINOPH YLLINE : Increased theophylline concentrations	pppbs.pdf
392 FLUCONAZOLE !TTRICYCLIC ANTIDEPRESSANTS (clomipramine, amitriptyline, etc. ): Flu-conazole may exacerbate the effects of tricyclic antidepressants !TSULFONYLUREA ANTIDIABETIC AGENTS (e. g., glipizide, glyburide ): Flu-conazole may increase levels; hypoglycemia possible !TVINCRISTINE/VINBLASTINE : Fluconazole may inhibit vinca alkaloid metabolism !TWARFARIN : Fluconazole may cause increased prothrombin times in patients receiving warfarin or other coumarin anticoagulants Doses !TDOGS: a) General dosing guidelines: Give twice calculated daily dose for the ﬁrst day of treatment; give for 2-3 days if rapidly advancing or severe disseminated mycosis. Give IV solution over 1-2 hours. For cryptococcosis, candidiasis, systemic mycoses, nasal aspergillosis: 2. 5-5 mg/kg PO or IV q12-24h for 56-84 days. Often treat neurologic ocular cryptococcosis for at least 12 weeks or 2 weeks after CSF exam shows resolution of in-ﬂammation and antigen test results on serum and CSF are negative. For fungal meningitis: 5-8 mg/kg PO or IV q12h OR 8-12 mg/kg PO or IV once daily (q24h) for 56-84 days; For urinary candidiasis: 5-10 mg/kg PO q24h for 21-42 days; For urinary Candida glabrata infection: 12 mg/kg PO once daily for 21-42 days. (Greene, Hartmannn et al. 2006) b) For cryptococcosis: 5 mg/kg PO once or twice daily. Treat-ment should continue for at least 2 months beyond resolu-tion of clinical signs. (Taboada 2000) c) For blastomycosis: 5 mg/kg PO q12h for 60 days For cryptococcosis: 5-15 mg/kg PO q12-24h for 6-10 months (Lemarie 2003b) d) For treatment of Malassezia (may be safer than itraconazole or ketoconazole in dogs with hepatic disease): 5 mg/kg PO once daily. (Thomas 2005b) e) For systemic treatment of Malassezia dermatitis: 5-10 mg/ kg PO once daily to once a week. (Ihrke 2006) f) For systemic treatment of Malassezia dermatitis: 2-5 mg/kg PO once daily (q24h). (Beale and Murphy 2006) !TCATS: a) General dosing guidelines: Give twice calculated daily dose for the ﬁrst day of treatment; give for 2-3 days if rapidly ad-vancing or severe disseminated mycosis. For cryptococcosis or other systemic infections, treatment should continue until antigen testing results of blood or CSF are negative, this is usually at least 2 months beyond clinical resolution (mean time of 8 months treatment). For nasal or dermal cryptococcosis: 5-10 mg/kg PO q12-24h, or 10 mg/kg PO q24h; for most infections, 50 mg/ cat PO once daily achieves adequate therapeutic levels. For CNS, intraocular, or multisystemic cryptococcosis: 50-100 mg/cat PO or IV q12h. Often treat neurologic ocu-lar cryptococcosis for at least 12 weeks or 2 weeks after CSF exam shows resolution of inﬂammation and antigen test re-sults on serum and CSF are negative. For CNS, intraocular or multisystemic mycoses: 50 mg/cat PO once daily (q24h); (Greene, Hartmannn et al. 2006) b) For cryptococcosis: 50 mg PO twice daily. Treatment should continue for 1 month beyond resolution of clinical signs. (Legendre 1995) c) For cryptococcosis: 50 mg PO twice daily. Treatment should continue for at least 2 months beyond resolution of clinical signs. (Taboada 2000) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: 25-43 mg/kg slow IV q12h (Ivey and Morrisey 2000) !TBIRDS: a) As an alternate treatment of aspergillosis: 5-10 mg/kg PO once daily for up to 6 weeks, with or after amphotericin B (Oglesbee and Bishop 1994) Monitoring !TClinical Efﬁcacy !TWith long-term therapy, occasional liver function tests are rec-ommended Client Information !TCost of this drug may be an issue. Fluconazole therapy may be prolonged (several weeks to months) and an average dosage in a cat (50 mg twice a day) may be very expensive !TCompliance with treatment recommendations must be stressed. !THave clients report any potential adverse effects. Chemistry/Synonyms A synthetic triazole antifungal agent, ﬂuconazole occurs as a white crystalline powder. It is slightly soluble (8 mg/m L) in water. Fluconazole may also be known as UK-49858; many trade names are available. Storage/Stability/Compatibility Fluconazole tablets should be stored at temperatures less than 30°C in tight containers. Fluconazole injection should be stored at temperatures from 5-30°C (5-25°C for the Viaﬂex® bags); avoid freezing. Do not add additives to the injection. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Fluconazole Tablets: 50 mg, 100 mg, 150 mg, & 200 mg; Diﬂucan® (Pﬁzer); generic; (Rx) Fluconazole Powder for Oral Suspension: 10 mg/m L & 40 mg/m L (when reconstituted) in 35 m L; Diﬂucan® (Roerig); (Rx) Fluconazole Injection: 2 mg/m L in 100 m L or 200 m L bottles or Viaﬂex Plus (available with sodium chloride or dextrose diluents); Diﬂucan® (Pﬁzer); generic; (Rx)	pppbs.pdf
FLUCYTOSINE 393 FLUCYTOSINE (ﬂoo-sye-toe-seen) Ancobon® ANTIFUNGAL Prescriber Highlights TT Antifungal used in combination (to reduce resistance development) TT Contraindicated in patients hypersensitive to it TT Extreme Caution: Renal impairment, preexisting bone marrow depression, hematologic diseases, or receiving other bone marrow suppressant drugs TT Caution: Hepatic disease TT Adverse Effects: Most common: GI disturbances; Poten-tially: dose dependent bone marrow depression, cutane-ous eruption & rash primarily seen on the scrotum & nasal planum (in dogs), oral ulceration, increased hepatic enzymes, CNS effects in cats TT Dogs may not tolerate therapy for more than 10-14 days TT Teratogenic in rats Uses/Indications Flucytosine is principally active against strains of Cryptococcus and Candida. When used alone, resistance can develop quite rapidly to ﬂucytosine, particularly with Cryptococcus. Because it penetrates relatively well into the CNS, it has been used in combination for the treatment of CNS cryptococcosis. Some cases of subcutaneous and systemic chromoblastosis may also respond to ﬂucytosine. The drug can have synergistic efﬁcacy when used with amphotericin B. Clinically, it is used primarily with amphotericin B in the treatment of cryptococcosis. Pharmacology/Actions Flucytosine penetrates fungal cells where it is deaminated by cyto-sine deaminase to ﬂuorouracil. Fluorouracil acts as an antimetabo-lite by competing with uracil, thereby interfering with pyrimidine metabolism and eventually RNA and protein synthesis. It is thought that ﬂucytosine is converted to ﬂuorodeoxyuredylic acid that inhib-its thymidylate synthesis and ultimately DNA synthesis. In human cells, cytosine deaminase is apparently not present or only has minimal activity. Rats apparently metabolize some of the drug to ﬂuorouracil, which may explain the teratogenic effects seen in this species. It is unclear how much cytosine deaminase activity dog and cat cells possess. Pharmacokinetics Flucytosine is well absorbed after oral administration. The rate, but not extent, of absorption will be decreased if given with food. Flucytosine is distributed widely throughout the body. CSF concentrations may be 60-100% of those found in the serum. In healthy humans, the volume of distribution is about 0. 7 L/kg. Only about 2-4% of the drug is bound to plasma proteins. It is unknown if ﬂucytosine is distributed into milk. Absorbed ﬂucytosine is excreted basically unchanged in the urine via glomerular ﬁltration. In humans, the half-life is about 3-6 hours in patients with normal renal function, but may be sig-niﬁcantly prolonged in patients with renal dysfunction. Contraindications/Precautions/Warnings Flucytosine is contraindicated in patients hypersensitive to it. Flucytosine should be used with extreme caution in patients with renal impairment. Some clinicians recommend monitoring serum ﬂucytosine levels in these patients and adjusting dosage (or dosing interval) to maintain serum levels at less than 100 micro-grams/m L. One clinician (Macy, 1987) recommends dividing the ﬂucytosine dose by the serum creatinine level if azotemia develops. Use ﬂucytosine with extreme caution in patients with preexist-ing bone marrow depression, hematologic diseases, or receiving other bone marrow suppressant drugs. Flucytosine should also be used cautiously (with enhanced monitoring) in patients with he-patic disease. Adverse Effects Most common adverse effects seen with ﬂucytosine are GI distur-bances (nausea, vomiting, diarrhea). Other potential adverse effects include a dose dependent bone marrow depression (anemia, leuko-penia, thrombocytopenia), cutaneous eruption and rash primarily seen on the scrotum and nasal planum (occurring in dogs), oral ulceration and increased levels of hepatic enzymes. Dogs receiving ﬂucytosine often develop a severe drug reaction within 10-14 days of treatment. Reports of aberrant behavior and seizures in a cat without con-current CNS infection have been noted after ﬂucytosine use. There are anecdotal reports of toxic epidermal necrolysis occurring in cats treated with ﬂucytosine. Reproductive/Nursing Safety Flucytosine has caused teratogenic effects in rats. It should be used in pregnant animals only when the beneﬁts of therapy 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 reproduction studies and no adequate studies in humans. ) It is not known whether this drug is excreted in milk. Because there are potential serious adverse reactions in nursing offspring, consider using milk replacer. Overdosage/Acute Toxicity No speciﬁcs regarding ﬂucytosine overdosage were located. It is suggested that a substantial overdose be handled with gut empty-ing, charcoal and cathartic administration unless contraindicated. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ﬂucytosine and may be of signiﬁcance in veterinary patients: T ! AMPHOTERICIN B : When used with amphotericin B, synergism against Cryptococcus and Candida has been demonstrated in vitro. However, if amphotericin B induces renal dysfunction, tox-icity of ﬂucytosine may be enhanced if it accumulates. Should clinically signiﬁcant renal toxicity develop, ﬂucytosine dosage may need to be adjusted. Laboratory Considerations T ! When determining serum creatinine using the Ektachem® ana-lyzer, false elevations in levels may be noted if patients are also taking ﬂucytosine.	pppbs.pdf
394 FLUDROCORTISONE ACETATE Doses T ! DOGS: For cryptococcosis: a) 25-50 mg/kg four times daily PO for a minimum of 6 weeks; with amphotericin B (0. 5 mg/kg IV 3 times weekly for a minimum of 4-5 weeks until a cumulative dose of 4 mg/kg attained—see amphotericin B monograph for more information) (Noxon 1989) b) Flucytosine 150-175 mg/kg PO divided three to four times daily with amphotericin B 0. 15-0. 4 mg/kg IV 3 times a week. When a total dose of amphotericin B reaches 4-6 mg/ kg start maintenance dosage of amphotericin B at 0. 15-0. 25 mg/kg IV once a month with ﬂucytosine at dosage above or with ketoconazole at 10 mg/kg PO once daily or divided twice daily (Greene, O'Neal, and Barsanti 1984) c) 50-75 mg/kg PO q8h; treatment requires 1-12 months. Must be given with a polyene or azole antifungal agent. (Ma-lik, Krockenberger et al. 2006) For candidiasis/candiduria: a) T o treat aggressively: After correcting identiﬁable predispos-ing factors, alkalinize urine to p H of >7. 5 with oral sodium bicarbonate. Then give ﬂucytosine at 67 mg/kg PO q8h. Re-duce dose if patient has renal failure. (Polzin and Osborne 1985) b) For candidiasis: 25-50 mg/kg PO q6h or 50-65 mg/kg PO q8h for 42 days. Must be given with a polyene or azole anti-fungal agent. (Greene and Watson 1998) T ! CATS: For cryptococcosis: a) As an alternate to ketoconazole therapy: Flucytosine 200 mg/ kg/day PO divided q6h with amphotericin B (0. 25 mg/kg in 30 m L D5W given IV over 15 minutes q48h—See ampho-tericin B monograph for more information). Continue ther-apy for 3-4 weeks after clinical signs have resolved and no organisms can be recovered. (Legendre 1989) b) 25-50 mg/kg four times daily PO for a minimum of 4-6 weeks; with amphotericin B (0. 25 mg/kg IV 3 times weekly for a minimum of 3-4 weeks—see amphotericin B mono-graph for more information) (Noxon 1989) c) Flucytosine at 30 mg/kg PO q6h or 50 mg/kg PO q8h or 75 mg/kg PO q12h). Cats 3. 5 kg or greater should receive 250 mg (total) q6-8h. Must be given with a polyene (amphot-ericin B) or azole antifungal agent. Treatment requires 1-9 months. (Malik, Krockenberger et al. 2006) For candidiasis/candiduria: a) For candidiasis: 25-50 mg/kg PO q6h or 50-65 mg/kg PO q8h for 42 days. Must be given with a polyene or azole anti-fungal agent (Greene and Watson 1998) T ! BIRDS: For susceptible fungal infections: a) In Psittacines: 250 mg/kg twice daily as a gavage. May be used for extended periods of time for aspergillosis. May cause bone marrow toxicity; periodic hematologic assessment is recom mended. In raptors: 18-30 mg/kg q6h as a gavage In Psittacines and Mynahs: 100-250 mg/lb in feed for ﬂock treatment of severe aspergillosis or Candida (especially re-spiratory Candida). Apply to favorite food mix or mixed with mash. (Clubb 1986) b) Ratites: 80-100 mg/kg PO twice daily (Jenson 1998) Monitoring T ! Renal function (at least twice weekly if also receiving amphot-ericin B) T ! CBC with platelets T ! Hepatic enzymes at least monthly Client Information T ! Clients should report any clinical signs associated with hemato-logic toxicity (abnormal bleeding, bruising, etc. ). T ! Prolonged treatment times, as well as costs of medication and as-sociated monitoring, require substantial client commitment. Chemistry/Synonyms A ﬂuorinated pyrimidine antifungal agent, ﬂucytosine occurs as a white to off-white, crystalline powder that is odorless or has a slight odor with p K as of 2. 9 and 10. 71. It is sparingly soluble in water and slightly soluble in alcohol. Flucytosine may also be known as: 5-FC, 5-ﬂuorocytosine, ﬂu-cytosinum, Ro-2-9915, Alcobon®, and Ancotil®. Storage/Stability Store ﬂucytosine capsules in tight, light-resistant containers at temperatures less than 40°C, and preferably at room temperature (15-30°C). The commercially available capsules are assigned an expiration date of 5 years from the date of manufacture. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Flucytosine Capsules: 250 mg, & 500 mg; Ancobon® (ICN); (Rx) FLUDROCORTISONE ACETATE (ﬂue-droe-kor-ti-sone) Florinef® MINERALOCORTICOID Prescriber Highlights TT Oral mineralocorticoid used to treat adrenal insufﬁciency in small animals; may be useful to treat hyperkalemia as well TT Contraindications: Known hypersensitivity TT Adverse Effects: Dosage related; PU/PD, hypertension, edema, & hypokalemia possible TT May be excreted in signiﬁcant quantities in milk TT Patients may require supplemental glucocorticoids TT Expense may be an issue, especially in larger dogs Uses/Indications Fludrocortisone is used in small animal medicine for the treatment of adrenocortical insufﬁciency (Addison's disease). It can also be used as adjunctive therapy in hyperkalemia. Additionally, in humans, ﬂudrocortisone has been used in salt-losing, congenital adrenogenital syndrome and in patients with se-vere postural hypotension. Pharmacology/Actions Fludrocortisone acetate is a potent corticosteroid that possesses both glucocorticoid and mineralocorticoid activity. It is approximately 10-15 times as potent a glucocorticoid agent as hydrocortisone,	pppbs.pdf
FLUDROCORTISONE ACETATE 395 but is a much more potent mineralocorticoid (125 times that of hydrocortisone). It is only used clinically for its mineralocorticoid effects. The site of action of mineralocorticoids is at the renal distal tubule where they increase the absorption of sodium. Mineralocorticoids also enhance potassium and hydrogen ion excretion. Pharmacokinetics In humans, ﬂudrocortisone is well absorbed from the GI with peak levels occurring in approximately 1. 7 hours; plasma half-life is about 3. 5 hours, but biologic activity persists for 18-36 hours. Contraindications/Precautions/Warnings Fludrocortisone is contraindicated in patients known to be hy-persensitive to it. Some dogs or cats may require additional supplementation with a glucocorticoid agent on an ongoing basis. All animals with hypoa-drenocorticism should receive additional glucocorticoids (2-10 times basal) during periods of stress or acute illness. Adverse Effects Adverse effects of ﬂudrocortisone are generally a result of chronic, excessive dosage (see Overdosage below) or if withdrawal is too rapid. Polyuria/polydipsia may be a problem for some dogs. Since ﬂudrocortisone also possesses glucocorticoid activity, it theoretical-ly could cause the adverse effects associated with those compounds. (See the section on the glucocorticoids for more information. ) 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. ) Fludrocortisone may be excreted in clinically signiﬁcant quanti-ties in milk. Puppies or kittens of mothers receiving ﬂudrocortisone should receive milk replacer after colostrum is consumed. Overdosage/Acute Toxicity Overdosage may cause hypertension, edema, and hypokalemia. Electrolytes should be aggressively monitored and potassium may need to be supplemented. Patients should have the drug discontin-ued until clinical signs associated with overdosage have resolved; then restart the drug at a lower dosage. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ﬂudrocortisone and may be of signiﬁcance in veterinary patients: !TAMPHOTERICIN B : Patients may develop hypokalemia if ﬂudrocor-tisone is administered concomitantly with amphotericin B !TASPIRIN : Fludrocortisone may reduce salicylate levels !TDIURETICS, POTASSIUM-DEPLETING (e. g., thiazides, furosemide ): Pa-tients may develop hypokalemia if ﬂudrocortisone is adminis-tered concomitantly with diuretics; diuretics can cause a loss of sodium, and may counteract the effects of ﬂudrocortisone !TINSULIN : Potentially, ﬂudrocortisone could increase the insulin re-quirements of diabetic patients Doses !TDOGS: For hypoadrenocorticism: a) Maintenance therapy: Initial dosage of 0. 015-0. 02 mg/kg/ day (1. 5-2 tablets per 10 kg of body weight), either as a single dose or divided twice a day. Monitor serum sodium and potassium values in 1-2 weeks and adjust dosage by 0. 05-0. 1 mg per day. Reevaluate unstable dogs and cats ev-ery 1-2 months and once stable, once or twice a year. Mild hyponatremia may be corrected by adding salt to the diet. (Reusch 2000) b) For maintenance: Initially, 0. 01-0. 02 mg/kg/day PO and adjusted by 0. 05-0. 1 mg (total dose) increments based on serial electrolyte determinations. Electrolytes are initially checked weekly until stabilized in normal range. In many dogs, dose requirements increase incrementally over the ﬁrst 6-24 months. Most dogs will ultimately require 0. 02-0. 03 mg/kg/day. (Kintzer 2004) c) For chronic or subacute therapy: Begin at 0. 1 mg (total dose) PO daily for small dogs to 0. 5 mg PO daily for large dogs; ad-just dose based on serial electrolytes. Also give glucocorticoid supplementation (prednisone or prednisolone 0. 2-0. 4 mg/ kg/day) and IV ﬂuid therapy if required (see reference for more information). (Feldman, Schrader, and Twedt 1988) d) When DOCA or DOCP are unavailable, may administer ini-tially at 0. 1 mg/5 kg body weight PO once daily; reassessment of serum electrolytes will serve as a guide to further dosage adjustments. (Schaer 2006) For adjunctive therapy of hyperkalemia: a) 0. 1-1 mg per day PO; may induce iatrogenic hyperadreno-corticism (Wheeler 1986) !TCATS: For maintenance therapy of hypoadrenocorticism: a) Once stabilized, 0. 1 mg per day PO. Monitor serum electro-lytes every 1-2 weeks initially and adjust dosage as neces-sary. For additional glucocorticoid supplementation, give either oral prednisolone or prednisone at 1. 25 mg per day or monthly injections of methylprednisolone acetate 10 mg IM monthly. (Greco and Peterson 1989), (Peterson and Ran-dolph 1989) b) Maintenance therapy: 0. 05-0. 1 mg/cat PO twice daily (Re-usch 2000) !TFERRETS: For hypoadrenocorticism: a) For those animals that still exhibit Addisonian signs even with prednisone therapy: 0. 05-0. 1 mg/kg PO q24h or di-vided q12h. (Johnson 2006b) Monitoring !TSerum electrolytes, BUN, creatinine; initially every 1-2 weeks, then every 3-4 months once stabilized !TWeight, PE for edema Client Information !TClients should be familiar with the signs associated with both hypoad renocorticism (e. g., weakness, depression, anorexia, vom-iting, diarrhea, etc. ) and ﬂudrocortisone overdosage (e. g., edema) and report these to the veterinarian immediately. Chemistry/Synonyms A synthetic glucocorticoid with signiﬁcant mineralocorticoid ac-tivity, ﬂudrocortisone acetate occurs as hygroscopic, ﬁne, white to pale yellow powder or crystals. It is odorless or practically odorless and has a melting point of approximately 225°C. Fludrocortisone is insoluble in water and slightly soluble in alcohol. Fludrocortisone acetate may also be known as: ﬂuohydrisone acetate, ﬂuohydrocortisone acetate, 9alpha-ﬂuorohydrocortisone acetate, ﬂudrocortisoni acetas, 9alpha-ﬂuorohydrocortisone 21-acetate, Astonin®, Astonin H®, Florinef®, Florinefe®, and Lonikan®.	pppbs.pdf
396 FLUMAZENIL Storage/Stability Fludrocortisone acetate tablets should be stored at room tem-perature (15-30°C) in well-closed containers; avoid excessive heat. The drug is relatively stable in light and air. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Fludrocortisone Acetate Tablets: 0. 1 mg; Florinef® Acetate (Monarch); generic; (Rx) FLUMAZENIL (ﬂoo-maz-eh-nill) Romazicon® BENZODIAZEPINE ANTAGONIST Prescriber Highlights TT Benzodiazepine antagonist to reverse either OD's or therapeutic effects TT Contraindications: Known hypersensitivity, when benzo-diazepines are treating life-threatening conditions (e. g., status epilepticus, increased CSF pressure), during tri-cyclic antidepressant OD treatment TT Use extreme caution in mixed overdoses TT Adverse Effects: Potentially injection site reactions, vom-iting, cutaneous vasodilatation, vertigo, ataxia, & blurred vision; seizures have been reported in humans TT Potentially teratogenic at high dosages Uses/Indications Flumazenil may be useful for the reversal of benzodiazepine effects after either therapeutic use or overdoses. Flumazenil may be of beneﬁt in the treatment of encephalopathy in patients with severe hepatic failure. Pharmacology/Actions Flumazenil is a competitive blocker of benzodiazepines at benzodi-azepine receptors in the CNS. It antagonizes the sedative and am-nestic qualities of benzodiazepines. Pharmacokinetics Flumazenil is administered by rapid IV injection. Therapeutic ef-fect may occur within 1-2 minutes of administration. It is rapidly distributed and metabolized in the liver. In humans, the average half-life is about one hour. Contraindications/Precautions/Warnings Flumazenil is contraindicated in patients hypersensitive to it or other benzodiazepines or in patients with where benzodiazepines are being used to treat a potentially life-threatening condition (e. g., status epilepticus, increased CSF pressure). It should not be used in patients with a serious tricyclic antidepressant overdose. Flumazenil should not be used, or used with extreme caution, in patients with mixed overdoses where benzodiazepine reversal may lead to sei-zures or other complications. Flumazenil does not alter benzodiazepine pharmacokinetics. Effects of long-acting benzodiazepines may recur after ﬂumazenil's effects subside. Adverse Effects In some human patients, ﬂumazenil use has been associated with seizures. These patients usually have a long history of benzodiaz-epine use or are showing signs of serious tricyclic antidepressant toxicity. Adverse effects reported in humans include injection site reactions, vomiting, cutaneous vasodilatation, vertigo, ataxia and blurred vision. Deaths have been associated with its use in humans having serious underlying diseases. Overdosage/Acute Toxicity Large IV overdoses have rarely caused symptoms in otherwise healthy humans. Seizures, if precipitated, have been treated with barbiturates, benzodiazepines and phenytoin, usually with prompt responses. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ﬂumazenil and may be of signiﬁcance in veterinary patients: T ! CYCLIC (tri-, tetra-) ANTIDEPRESSANTS (e. g., clomipramine, amitrip-tyline, etc. ): Increased risk for seizures; use contraindicated T ! NEUROMUSCULAR BLOCKING AGENTS : Not recommended to use ﬂu-mazenil until neuromuscular blockade has been fully reversed Doses T ! DOGS & CAT S: As an antagonist for benzodiazepines: a) Dogs: 0. 01 mg/kg IV (Bunch 2003) b) Dogs/Cats: 0. 01 mg/kg IV; may need to be repeated as half-life is only about an hour. May also be administered intratra-cheally in an emergency. (Wismer 2004) For adjunctive therapy to improve neurologic function in dogs with severe hepatic encephalopathy: a) 0. 02 mg/kg IV (one time) (Bunch 2003) b) 0. 02 mg/kg IV; if animal responds, safe to use repeatedly (Mi-chel 2003) Monitoring T ! Efﬁcacy T ! Monitor for seizures in susceptible patients Client Information T ! Flumazenil should only be used in a controlled environment by clinically experienced professionals. Chemistry/Synonyms A benzodiazepine antagonist, ﬂumazenil is a 1,4-imidazobenzodi-azepine derivative. Flumazenil may also be known as: ﬂumazenilum, ﬂumazepil, Ro-15-1788, Ro-15-1788/000, Anexate®, Fadaﬂumaz®, Flumage®, Flumanovag®, Flumazen®, Fluxifarm®, Lanexat® and Romazicon®. Storage/Stability/Compatibility Flumazenil is physically compatible with lactated Ringer's, D 5W, or normal saline solutions. Once drawn into a syringe or mixed with the above solutions, discard after 24 hours. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Flumazenil Injection: 0. 1 mg/m L in 5 m L and 10 m L vials; Romazi-con® (Hoffman-La Roche); generic; (Rx)	pppbs.pdf
FLUMETHASONE 397 FLUMETHASONE (ﬂoo-meth-a-sone) Flucort® GLUCOCORTICOID Prescriber Highlights TT Injectable & oral glucocorticoid (oral may not be avail-able commercially in USA) TT Long-acting; 15-30X more potent than hydrocortisone; no appreciable mineralocorticoid activity TT Therapy goal is to use as much as is required & as little as possible for as short an amount of time as possible TT Primary adverse effects are “Cushingoid” in nature with sustained use TT Many potential drug & lab interactions Uses/Indications Flumethasone injection (Flucort®) is labeled in horses as indicated for: 1) Musculoskeletal conditions due to inﬂammation, where per-manent structural changes do not exist, such as bursitis, carpitis, osselets and myositis. Following therapy an appropriate period of rest should be instituted to allow a more normal return to function of the affected part. 2) In allergic states such as hives, urticaria and insect bites. Flumethasone injection (Flucort®) is labeled in dogs as indi-cated for: 1) Musculoskeletal conditions due to inﬂammation of muscles or joints and accessory structures, where permanent struc-tural changes do not exist, such as arthritis, osteoarthritis, the disc syndrome and myositis. In septic arthritis appropriate antibacterial therapy should be concurrently administered. 2) In certain acute and chronic dermatoses of varying etiology to help control the pru-ritus, irritation and inﬂammation associated with these conditions. The drug has proven useful in otitis externa in conjunction with topical medication for similar reasons. 3) In allergic states such as hives, urticaria and insect bites. 4) Shock and shock-like states, by intravenous administration. Flumethasone injection (Flucort®) is labeled in cats as indicated for certain acute and chronic dermatoses of varying etiology to help control the pruritus, irritation and inﬂammation associated with these conditions. Glucocorticoids have been used in an attempt to treat practically every malady that afﬂicts man or animal, but there are three broad uses and dosage ranges for use of these agents. 1) Replacement of glucocorticoid activity in patients with adrenal insufﬁciency, 2) as an antiinﬂammatory agent, and 3) as an immunosuppressive. Among some of the uses for glucocorticoids include treatment of: endocrine conditions (e. g., adrenal insufﬁciency), rheumatic dis-eases (e. g., rheumatoid arthritis), collagen diseases (e. g., systemic lupus), allergic states, respiratory diseases (e. g., asthma), dermato-logic diseases (e. g., pemphigus, allergic dermatoses), hematologic disorders (e. g., thrombocytopenias, autoimmune hemolytic ane-mias), neoplasias, nervous system disorders (increased CSF pres-sure), GI diseases (e. g., ulcerative colitis exacerbations), and renal diseases (e. g., nephrotic syndrome). Some glucocorticoids are used topically in the eye and skin for various conditions or are injected intra-articularly or intra-lesionally. The above listing is certainly not complete. Pharmacology/Actions Glucocorticoids have effects on virtually every cell type and system in mammals. An overview of the effects of these agents follows: Cardiovascular System : Glucocorticoids can reduce capillary per-meability and enhance vasoconstriction. A relatively clinically in-signiﬁcant positive inotropic effect can occur after glucocorticoid administration. Increased blood pressure can result from both the drugs' vasoconstrictive properties and increased blood volume that may be produced. Cells : Glucocorticoids inhibit ﬁbroblast proliferation, macrophage response to migration inhibiting factor, sensitization of lympho-cytes and the cellular response to mediators of inﬂammation. Glucocorticoids stabilize lysosomal membranes. CNS/Autonomic Nervous System : Glucocorticoids can lower seizure threshold, alter mood and behavior, diminish the response to pyro-gens, stimulate appetite and maintain alpha rhythm. Glucocorticoids are necessary for normal adrenergic receptor sensitivity. Endocrine System : When animals are not stressed, glucocorticoids will suppress the release of ACTH from the anterior pituitary, thereby reducing or preventing the release of endogenous corticos-teroids. Stress factors (e. g., renal disease, liver disease, diabetes) may sometimes nullify the suppressing aspects of exogenously admin-istered steroids. Release of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), prolactin, and luteinizing hormone (LH) may all be reduced when glucocorticoids are ad-ministered at pharmacological doses. Conversion of thyroxine (T 4) to triiodothyronine (T 3) may be reduced by glucocorticoids; and plasma levels of parathyroid hormone increased. Glucocorticoids may inhibit osteoblast function. Vasopressin (ADH) activity is re-duced at the renal tubules and diuresis may occur. Glucocorticoids inhibit insulin binding to insulin-receptors and the post-receptor effects of insulin. Hematopoietic System : Glucocorticoids can increase the numbers of circulating platelets, neutrophils and red blood cells, but platelet aggregation is inhibited. Decreased amounts of lymphocytes (pe-ripheral), monocytes and eosinophils are seen as glucocorticoids can sequester these cells into the lungs and spleen and prompt de-creased release from the bone marrow. Removal of old red blood cells becomes diminished. Glucocorticoids can cause involution of lymphoid tissue. GI Tract and Hepatic System : Glucocorticoids increase the secretion of gastric acid, pepsin, and trypsin. They alter the structure of mu-cin and decrease mucosal cell proliferation. Iron salts and calcium absorption are decreased while fat absorption is increased. Hepatic changes can include increased fat and glycogen deposits within he-patocytes,increased serum levels of alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT). Signiﬁcant increases can be seen in serum alkaline phosphatase levels. Glucocorticoids can cause minor increases in BSP (bromosulfophthalein) retention time. Immune System (also see Cells and Hematopoietic System): Glucocorticoids can decrease circulating levels of T-lymphocytes; inhibit lymphokines; inhibit neutrophil, macrophage, and mono-cyte migration; reduce production of interferon; inhibit phagocyto-sis and chemotaxis; antigen processing; and diminish intracellular killing. Speciﬁc acquired immunity is affected less than nonspeciﬁc immune responses. Glucocorticoids can also antagonize the com-plement cascade and mask the clinical signs of infection. Mast cells are decreased in number and histamine synthesis is suppressed. Many of these effects only occur at high or very high doses and there are species differences in response.	pppbs.pdf
398 FLUMETHASONE Metabolic effects : Glucocorticoids stimulate gluconeogenesis. Lipogenesis is enhanced in certain areas of the body (e. g., abdomen) and adipose tissue can be redistributed away from the extremities to the trunk. Fatty acids are mobilized from tissues and their oxi-dation is increased. Plasma levels of triglycerides, cholesterol, and glycerol are increased. Protein is mobilized from most areas of the body (not the liver). Musculoskeletal : Glucocorticoids may cause muscular weakness (also caused if there is a lack of glucocorticoids), atrophy, and os-teoporosis. Bone growth can be inhibited via growth hormone and somatomedin inhibition, increased calcium excretion and inhibi-tion of vitamin D activation. Resorption of bone can be enhanced. Fibrocartilage growth is also inhibited. Ophthalmic : Prolonged corticosteroid use (both systemic or topically to the eye) can cause increased intraocular pressure and glaucoma, cataracts, and exophthalmos. Renal, Fluid, & Electrolytes : Glucocorticoids can increase potassium and calcium excretion, sodium and chloride reabsorption, and ex-tracellular ﬂuid volume. Hypokalemia and/or hypocalcemia rarely occur. Diuresis may develop following glucocorticoid administra-tion. Skin: Thinning of dermal tissue and skin atrophy can be seen with glucocorticoid therapy. Hair follicles can become distended and alopecia may occur. Pharmacokinetics No information was located for this agent. Contraindications/Precautions/Warnings Flumethasone is contraindicated during the last trimester of preg-nancy. Systemic use of glucocorticoids is generally considered con-traindicated in systemic fungal infections (unless used for replace-ment therapy in Addison's), when administered IM in patients with idiopathic thrombocytopenia, and in patients hypersensitive to a particular compound. Use of sustained-release, injectable gluco-corticoids is contraindicated for chronic corticosteroid therapy of systemic diseases. Animals that have received glucocorticoids systemically, other than with “burst” therapy, should be tapered off the drugs. Patients who have received the drugs chronically should be tapered off slowly as endogenous ACTH and corticosteroid function may re-turn slowly. Should the animal undergo a “stressor” (e. g., surgery, trauma, illness, etc. ) during the tapering process or until normal adrenal and pituitary function resume, additional glucocorticoids should be administered. Adverse Effects Adverse effects are generally associated with long-term administra-tion of these drugs, especially if given at high dosages or not on an alternate day regimen. Effects generally manifest as clinical signs of hyperadrenocorticism. When administered to young, grow-ing animals, glucocorticoids can retard growth. Many of the po-tential effects, adverse and otherwise, are outlined above in the Pharmacology section. In dogs, polydipsia (PD), polyphagia (PP), and polyuria (PU) may all be seen with short-term “burst” therapy as well as with alternate-day maintenance therapy on days when giving the drug. Adverse effects in dogs can include: dull, dry haircoat, weight gain, panting, vomiting, diarrhea, elevated liver enzymes, pancreatitis, GI ulceration, lipidemias, activation or worsening of diabetes mellitus, muscle wasting and behavioral changes (depression, lethargy, vi-ciousness). Discontinuation of the drug may be necessary; chang-ing to an alternate steroid may also alleviate the problem. With the exception of PU/PD/PP, adverse effects associated with antiinﬂam-matory therapy are relatively uncommon. Adverse effects associated with immunosuppressive doses are more common and potentially more severe. Cats generally require higher dosages than dogs for clinical effect, but tend to develop fewer adverse effects. Occasionally, polydipsia, polyuria, polyphagia with weight gain, diarrhea, or depression can be seen. Long-term, high dose therapy can lead to “Cushingoid” ef-fects, however. Reproductive/Nursing Safety Corticosteroid therapy may induce parturition in large animal spe-cies during the latter stages of pregnancy. In a 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 Glucocorticoids when given short-term are unlikely to cause harm-ful effects, even in massive dosages. One incidence of a dog develop-ing acute CNS effects after accidental ingestion of glucocorticoids has been reported. Should clinical signs occur, use supportive treat-ment if required. Chronic usage of glucocorticoids can lead to serious adverse ef-fects. Refer to Adverse Effects above for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ﬂumethasone and may be of signiﬁcance in veterinary patients: !TAMPHOTERICIN B : Administered concomitantly with glucocorti-coids may cause hypokalemia !TANTICHOLINESTERASE AGENTS (e. g., pyridostigmine, neostigmine, etc. ): In patients with myasthenia gravis, concomitant glucocor-ticoid and anticholinesterase agent administration may lead to profound muscle weakness. If possible, discontinue anticholin-esterase medication at least 24 hours prior to corticosteroid ad-ministration. !TASPIRIN : Glucocorticoids may reduce salicylate blood levels !TBARBITURATES : May increase the metabolism of glucocorticoids and decrease ﬂumethasone blood levels !TCYCLOPHOSPHAMIDE : Glucocorticoids may inhibit the hepatic metabolism of cyclophosphamide; dosage adjustments may be required !TCYCLOSPORINE : Concomitant administration of glucocorticoids and cyclosporine may increase the blood levels of each by mutu-ally inhibiting the hepatic metabolism of each other; the clinical signiﬁcance of this interaction is not clear !TDIAZEPAM : Flumethasone may decrease diazepam levels !TDIURETICS, POTASSIUM-DEPLETING (e. g., spironolactone, triamterene ): Administered concomitantly with glucocorticoids may cause hy-pokalemia !TEPHEDRINE : May reduce ﬂumethasone blood levels !TINSULIN : Insulin requirements may increase in patients receiving glucocorticoids !TKETOCONAZOLE AND OTHER AZOLE ANTIFUNGALS : May decrease the metabolism of glucocorticoids and increase ﬂumethasone blood levels; ketoconazole may induce adrenal insufﬁciency when glu-cocorticoids are withdrawn by inhibiting adrenal corticosteroid synthesis	pppbs.pdf
FLUMETHASONE 399 T!TMACROLIDE ANTIBIOTICS (erythromycin, clarithromycin ): May de-crease the metabolism of glucocorticoids and increase ﬂumetha-sone blood levels !TMITOTANE : May alter the metabolism of steroids; higher than usu-al doses of steroids may be necessary to treat mitotane-induced adrenal insufﬁciency !TNSAIDS : Administration of ulcerogenic drugs with glucocorticoids may increase the risk of gastrointestinal ulceration !TPHENYTOIN : May increase the metabolism of glucocorticoids and decrease ﬂumethasone blood levels !TRIFAMPIN : May increase the metabolism of glucocorticoids and decrease ﬂumethasone blood levels !TVACCINES : Patients receiving corticosteroids at immunosuppres-sive dosages should generally not receive live attenuated-virus vaccines as virus replication may be augmented; a diminished immune response may occur after vaccine, toxoid, or bacterin administration in patients receiving glucocorticoids Laboratory Considerations !TGlucocorticoids may increase serum cholesterol !TGlucocorticoids may increase urine glucose levels !TGlucocorticoids may decrease serum potassium !TGlucocorticoids can suppress the release of thyroid stimulating hormone (TSH) and reduce T3 & T4 values. Thyroid gland atro-phy has been reported after chronic glucocorticoid administra-tion. Uptake of I131 by the thyroid may be decreased by glucocor-ticoids. !TReactions to skin tests may be suppressed by glucocorticoids !TFalse-negative results of the nitroblue tetrazolium test for systemic bacterial infections may be induced by glucocorticoids !TGlucocorticoids may cause neutrophilia within 4-8 hours after dosing and return to baseline within 24-48 hours after drug dis-continuation !TGlucocorticoids can cause lymphopenia which can persist for weeks after drug discontinuation in dogs Doses !TDOGS: For labeled indications (musculoskeletal conditions due to in-ﬂammation..., certain acute and chronic dermatoses... when given orally, and also for allergic states or shock when given intravenously). Treat and adjust dosage on an individual basis: a) Orally: 0. 0625-0. 25 mg daily in divided doses. Dosage is de-pendent on size of animal, stage and severity of disease. Note : Tablets no longer marketed in the USA Parenterally: 0. 0625-0. 25 mg IV, IM, SC daily; may repeat; Intra-articularly: 0. 166-1 mg; Intra-lesionally: 0. 125-1 mg (Package insert; Flucort®—Fort Dodge) b) 0. 06-0. 25 mg IV, IM, SC, or PO once daily (Kirk 1989) !TCATS: For labeled indications (certain acute and chronic derma-toses..,): Treat and adjust dosage on an individual basis: a) Orally: 0. 03125-0. 125 mg daily in divided doses; Note : Tab-lets no longer marketed in the USA Parenterally: 0. 03125-0. 125 mg IV, IM, or SC. If necessary, may repeat. (Package insert; Flucort®—Fort Dodge) b) 0. 03-0. 125 mg IV, IM, SC, or PO once daily (Kirk 1989) !THORSES: (Note : ARCI UCGFS Class 4 Drug) For labeled indications (musculoskeletal conditions due to in-ﬂammation, where permanent changes do not exist; and also for allergic states such as hives, urticaria and insect bites): a) 1. 25-2. 5 mg daily by IV, IM or intra-articular injection. If necessary, the dose may be repeated. (Package insert; Flucort®—Fort Dodge) b) 1-2. 5 mg/450 kg IV or IM (Robinson 1987) Monitoring Monitoring of glucocorticoid therapy is dependent on its reason for use, dosage, agent used (amount of mineralocorticoid activity), dosage schedule (daily versus alternate day therapy), duration of therapy, and the animal's age and condition. The following list may not be appropriate or complete for all animals; use clinical assess-ment and judgment should adverse effects be noted: !TWeight, appetite, signs of edema !TSerum and/or urine electrolytes !Total plasma proteins, albumin !TBlood glucose !TGrowth and development in young animals !TACTH stimulation test if necessary Client Information !TClients should carefully follow the dosage instructions and should not discontinue the drug abruptly without consulting with vet-erinarian beforehand. !TClients should be briefed on the potential adverse effects that can be seen with these drugs and instructed to contact the veterinar-ian should these effects become severe or progress. Chemistry/Synonyms Flumethasone occurs as an odorless, white to creamy white, crystal-line powder. Its chemical name is 6alpha, 9alpha-diﬂuoro-16alpha methylprednisolone. Flumethasone may also be known as: ﬂumetasone, glumetasoni pivalas, NSC-107680, Cerson®, Flucort®, Locacorten®, Locacortene®, Locorten®, Locortene®, and Lorinden®. Storage/Stability Flumethasone injection should be stored at room temperature; avoid freezing. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Flumethasone Injection: 0. 5 mg/m L in 100 m L vials; Flucort® Solu-tion (Fort Dodge); (Rx). Approved for use in dogs, cats, and horses. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None	pppbs.pdf
400 FLUNIXIN MEGLUMINE FLUNIXIN MEGLUMINE (ﬂoo-nix-in) Banamine® NON-STEROIDAL A NTIINFLA MMATORY AGENT Prescriber Highlights TT Veterinary-only non-steroidal antiinﬂammatory agent used in a variety of species TT Contraindications: History of hypersensitivity TT Caution in patients with preexisting GI ulcers, renal, hepatic, or hematologic diseases; in horses with colic, ﬂunixin may mask the behavioral & cardiopulmo-nary signs associated with endotoxemia or intestinal devitalization TT Use in small animals largely supplanted by approved agents or those with better adverse effect proﬁle in tar-get species TT If ﬁrst dose is ineffective for pain control, subsequent doses unlikely to be of beneﬁt TT Adverse Effects in HORSES & CATTLE: Rare anaphylaxis (especially after rapid IV administration); IM injections (extra-label in food animals) may cause pain/swelling Uses/Indications In the United States, ﬂunixin meglumine is approved for use in horses, cattle and swine; however, it is approved for use in dogs in other countries. The approved indications for its use in the horse are for the alleviation of inﬂammation and pain associated with musculoskeletal disorders and alleviation of visceral pain associ-ated with colic. In cattle it is approved for the control of pyrexia associated with bovine respiratory disease and endotoxemia, and control of inﬂammation in endotoxemia. In swine, ﬂunixin is ap-proved for use to control pyrexia associated with swine respiratory disease. Flunixin has been suggested for many other indications in vari-ous species, including: Horses: foal diarrheas, shock, colitis, respi-ratory disease, post-race treatment, and pre-and post ophthalmic and general surgery; Dogs: disk problems, arthritis, heat stroke, di-arrhea, shock, ophthalmic inﬂammatory conditions, pre-and post ophthalmic and general surgery, and treatment of parvovirus infec-tion; Cattle: acute respiratory disease, acute coliform mastitis with endotoxic shock, pain (downer cow), and calf diarrheas; Swine: agalactia/hypogalactia, lameness, and piglet diarrhea. It should be noted that the evidence supporting some of these indications is equivocal and ﬂunixin may not be appropriate for every case. Pharmacology/Actions Flunixin is a very potent inhibitor of cyclooxygenase and, like other NSAIDs, it exhibits analgesic, antiinﬂammatory, and antipyretic ac-tivity. Flunixin does not appreciably alter GI motility in horses and may improve hemodynamics in animals with septic shock. Pharmacokinetics In the horse, ﬂunixin is rapidly absorbed following oral administra-tion with an average bioavailability of 80% and peak serum levels in 30 minutes. Oral bioavailability is good when the injection is mixed with molasses and given orally. The onset of action is generally within 2 hours; peak response occurs between 12-16 hours and the duration of action lasts up to 30 hours. Flunixin is highly bound to plasma proteins (>99% cattle, 92% dogs, 87% horses). Volume of distributions ranges from approximately 0. 15 L/kg in horses to 0. 78 L/kg in cattle. Elimination is primarily via hepatic routes by biliary excretion. Serum half-lives have been determined in horses ≈ 1. 6-4. 2 hours, dogs ≈ 3. 7 hours; cattle ≈ 3. 1-8. 1 hours. Flunixin is detectable in equine urine for at least 48 hours after a dose. Contraindications/Precautions/Warnings The only contraindication the manufacturer lists for ﬂunixin's use in horses is for patients with a history of hypersensitivity reactions to it. It is suggested, however, that ﬂunixin be used cautiously in animals with preexisting GI ulcers, renal, hepatic, or hematologic diseases. When using to treat colic, ﬂunixin may mask the behav-ioral and cardiopulmonary signs associated with endotoxemia or intestinal devitalization and must be used with caution. In cattle, the drug is contraindicated in animals that have shown prior hypersensitivity reactions. The IM route is extra-label in cattle and should only be used when the IV route is not feasible for use. Longer withdrawal times would be required after IM use. Flunixin should not be used in an attempt to ambulate cattle to be shipped for slaughter. Adverse Effects When used for pain, if the animal does not respond to an initial dose, it is unlikely additional doses will be effective and may result in increased chance for toxicity. In horses following IM injection, reports of localized swelling, induration, stiffness, and sweating have been reported. Do not inject intra-arterially as it may cause CNS stimulation (hysteria), ataxia, hyperventilation, and muscle weakness. Clinical signs are transient and generally do not require any treatment. Flunixin appears to be a relatively safe agent for use in the horse, but the potential exists for GI intolerance, hypopro-teinemia, and hematologic abnormalities to occur. Flunixin is not to be used in horses intended for food. Horses have developed oral and gastric ulcers, anorexia, and depression when given high doses for prolonged periods (>2 weeks). In horses and cattle, rare anaphylactic-like reactions have been reported, primarily after rapid IV administration. IM injections may rarely be associated with clostridial myonecrosis. Hematochezia and hematuria have been reported in cattle treat-ed for longer than the 3-day recommendation. In dogs, GI distress is the most likely adverse reaction. Clinical signs may include, vomiting, diarrhea, and ulceration with very high doses or chronic use. There have been anecdotal reports of ﬂunixin causing renal shutdown in dogs when used at higher dos-ages pre-operatively. In birds, ﬂunixin has been shown to cause dose-related, signiﬁ-cant renal ischemia and nephrotoxicity. Reproductive/Nursing Safety Although reports of teratogenicity, effects on breeding perfor-mance, or gestation length have not been noted, ﬂunixin should be used cautiously in pregnant animals. Flunixin is not recommended for use in breeding bulls (lack of reproductive safety data). Flunixin is usually considered to be contraindicated in cats, but some clinicians may use it short-term (see doses). In a system eval-uating 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 uncov-ered risks, and these drugs should be used cautiously as a last resort when the beneﬁt of therapy clearly outweighs the risks. )	pppbs.pdf