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ATROPINE SUl FATE 85 For treatment of cholinergic toxicity (organophosphates): a) 0. 5 mg/kg (average dose); give G th of the dose IV and the remainder SC or IM; may re peat q3-4h for 1-2 days (Bailey 1986) HORSES:T! (Note : ARCI UCGFS Class 3 Drug) For treatment of bradyarrhythmias due to increased parasym-pathetic tone:a) 0. 01-0. 02 mg/kg IV (Mogg 1999) b) 0. 045 mg/kg parenterally (Hilwig 1987) As a bronchodilator: a) 5 mg IV for a 400-500 kg animal (Beech 1987) b) 5-7 mg/kg IV for a 450 kg horse can serve as a rescue medi-cation in cases with severe airway obstruction, but it has an abbreviated duration of action (0. 5-2 hours) and adverse effects (ileus, CNS toxicity, tachycardia, increased mucus se-cretion, and impaired mucociliary clearance) limit its use to a single rescue dose. (Rush 2006b) For organophosphate poisoning: a) Approximately 1 mg/kg given to effect, IV (use mydriasis and absence of salivation as therapy endpoints), may repeat every 1. 5-2 hours as required subcutaneously (Oehme 1987) b) 0. 22 mg/kg, G th of the dose administered IV and the remain-der SC or IM (Package In sert; Atropine Injectable, L. A. — Fort Dodge) SWINE:T! The equine dose (above) may be used to initially treat organo-phosphate toxicity in swine. As an adjunctive preanesthetic agent: a) 0. 04 mg/kg IM (Thurmon and Benson 1986) SHEEP, g OATS:T! As a preanesthetic: a) Because of a lack of extended efficacy and potential adverse reactions, atropine is not used routinely as a preoperative agent in ruminants. If it is desired for use, a dose of 0. 15-0. 3 mg/kg IM has been suggested. (Thurmon and Benson 1986) For treating organophosphate toxicity: a) Use the dose for cattle (above). b IRDS:T! For organophosphate poisoning: a) 0. 1-0. 2 mg/kg IM or SC as needed (Clubb 1986) b) 0. 2 mg/kg IM every 3-4 hours as needed; G th the initial dose is administered. Use with pralidoxime (not in raptors) at 10-20 mg/kg IM q8-12h as needed. Do not use prali-doxime in carbamate poisonings. T o assist in diagnosing organophosphate poisoning (with history, clinical signs, etc. ) in birds presenting with bradycar-dia: May administer atropine at 0. 02 mg/kg IV. If bradycar-dia does not reverse, may consider organophosphate toxicity. (La Bond 2006) As a preanesthetic: a) 0. 04-0. 1 mg/kg IM or SC once (Clubb 1986) REPTIl ES:T! For organophosphate toxicity in most species: a) 0. 1-0. 2 mg/kg SC or IM as needed. (Gauvin 1993) For ptyalism in tortoises: a) 0. 05 mg/kg (50 cg/kg) SC or IM once daily (Gauvin 1993)monitoring Dependent on dose and indication: Heart rate and rhythm T! Thirst/appetite; urination/defecation capability T! Mouth/secretions dryness T! Client Information Parenteral atropine administration is best performed by profes-T! sional staff and where adequate cardiac monitoring is available. If animal is receiving atropine systemically, allow animal free ac-T! cess to water and encourage drinking if dry mouth is a problem. Chemistry/Synonyms The prototype tertiary amine antimuscarinic agent, atropine sul-fate is derived from the naturally occurring atropine. It is a racemic mixture of d-hyoscyamine and l-hyoscyamine. The l-form of the drug is active, while the d-form has practically no antimuscarinic activity. Atropine sul fate occurs as colorless and odorless crystals, or white, crystalline powder. One gram of atropine sul fate is soluble in approximately 0. 5 m L of water, 5 m L of alcohol, or 2. 5 m L of glycerin. Aqueous so lutions are practically neutral or only slightly acidic. Commercially available injections may have the p H adjusted to 3. 0-6. 5. Atropine may also be known as dl-hyoscyamine. Atropine sulfate may also be known as: atrop. sulph., atropine sulphate, or atropini sulfas; many trade names are available. Storage/Stability/Compatibility Atropine sulfate tablets or soluble tablets should be stored in well-closed containers at room temperature (15-30°C). Atropine sulfate for injection should be stored at room temperature; avoid freezing. Atropine sulfate for injection is reportedly compatible with the following agents: benzquinamide HCl, butorphanol tartrate, chlorpromazine HCl, cimetidine HCl (not with pentobarbital), dimenhy drinate, diphenhydramine HCl, dobutamine HCl, dro-peridol, fentanyl citrate, glycopyrrolate, hydro morphone HCl, hy-droxyzine HCl (also with meperidine), meperidine HCl, morphine sulfate, nal buphine HCl, pentazocine lactate, pentobarbital sodium (OK for 5 minutes, not 24 hours), per phenazine, prochlorperazine edisylate, promazine HCl, promethazine HCl (also with meperi-dine), and scopolamine HBr. Atropine sulfate is reported physically incompatible with norepi-nephrine bitar trate, metaraminol bitartrate, methohexital sodium, and sodium bicarbonate. Compatibility is depen dent upon factors such as p H, concentration, temperature, and diluent used; consult specialized references for more specific information. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Atropine Sulfate for Injection: 0. 54 mg/m L (1/120 grain); Atroject ® (Vetus), Atropine SA® (Butler), generic, (various); (Rx) Atropine Sulfate for Injection: 15 mg/m L (organophosphate treat-ment) 100 m L vial; At ropine L. A. ® (Butler), (RXV); generic (vari-ous) (Rx) Atropine is labeled for use in dogs, cats, horses, cattle, sheep, and swine in the USA. No withdrawal times are mandated when used in food animals in the USA, but FARAD recommends a 28 day meat and 6 day milk withdrawal time. (Haskell, Payne et al. 2005). In the UK, slaughter withdrawal for cattle, sheep, and pigs is 14 days when used as an antimuscarinic and 28 days when used as an antidote; milk withdrawal is 3 days when used as an antimuscarinic and 6 days when used as an antidote. For guidance with determining use associated withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix)

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86 AURANOFIN The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Atropine Sulfate for Injection: 0. 05 mg/m L in 5 m L syringes; Atropine Sulfate (Hospira); (Rx) 0. 1 mg/m L in 5 and 10 m L syringes; Atropine Sulfate (Hospira); (Rx) 0. 3 mg/m L in 1 m L and 30 m L vials; generic; (Rx)0. 4 mg/m L in 1 m L amps and 1, 20, and 30 m L vials; generic; (Rx)0. 5mg/m L in 1 and 30 m L vials & 5 m L syringes; generic; (Rx)0. 8 mg/m L in 0. 5 and 1 m L amps and 0. 5 m L syringes; generic; (Rx) 1 mg/m L in 1 m L amps and vials and 10 m L syringes; generic; (Rx)0. 5 mg, 1 mg & 2 mg pre-filled, auto-injectors; Atro Pen ® (Meridian Medical T echnologies); (Rx)Atropine Sulfate Tablets: 0. 4 mg; Sal-Tropine® (Hope); (Rx) See also the monograph for atropine sulfate for ophthalmic use in the appendix. Atropine sulfate ophthalmic drops have been used buccally to decrease excessive oral secretions in human patients. Aur Anofin (au-rane-oh-fin) Ridaura® Oral g Old immun Osuppressive Prescriber Highlights Orally administered gold; used for pemphigus & idiopath-T T ic polyarthritis in dogs or cats Can be quite toxic & expensive, intensive ongoing moni-T T toring required; dosages must be compounded from 3 mg capsules Probably less toxic, but also less efficacy than injectable T T gold Considered contraindicated in SLE (exacerbates) T T Known teratogen & maternotoxic T T Renal, hepatic & GI toxicity possible; dose dependent T T immune-mediated thrombocytopenia, hemolytic anemia or leukopenias have been seen Uses/Indications Auranofin has been used to treat idiopathic polyarthritis and pem-phigus foliaceous in dogs and cats. Several clinicians report that while auranofin may be less toxic, it also less efficacious than inject-able gold (aurothioglucose). Pharmacology/Actions Auranofin is an orally available gold salt. Gold has antiinflammato-ry, an tirheumatic, immunomodulating, and antimicrobial (in vitro) effects. The exact mechanisms for these actions are not well under-stood. Gold is taken up by macrophages where it inhibits phagocy-tosis and may inhibit lysosomal enzyme activity. Gold also inhib-its the release of histamine, and the produc tion of prostaglandins. While gold does have antimicrobial effects in vitro, it is not clinically useful for this purpose. Auranofin suppresses helper T-cells, without affecting suppressor T-cell popula tions. Pharmacokinetics Unlike other available gold salts, auranofin is absorbed when given by mouth (20-25% of the gold) primarily in the small and large intestines. In contrast to the other gold salts, auranofin is only mod-erately bound to plasma proteins (the others are highly bound). Auranofin crosses the placenta and is distributed into maternal milk. Tissues with the highest levels of gold are kidneys, spleen, lungs, adrenals and liver. Accumulation of gold does not appear to occur, unlike the parenteral gold salts. About 15% of an administered dose (60% of the absorbed dose) is excreted by the kidneys, the remain-der in the feces. Contraindications/Precautions/Warnings Auranofin should only be administered to animals where other less expensive and toxic therapies are ineffective and the veterinarian and owner are aware of the potential pitfalls of auranofin therapy and are willing to accept the associated risks and expenses. Gold salts are contraindicated in SLE as they may exacerbate the signs associ-ated with this disease. Adverse Effects A dose dependent immune-mediated thrombocytopenia, hemolytic anemia or leukopenias have been noted in dogs. Discontinuation of the drug and administration of steroids has been recommended. Auranofin has a higher incidence of dose dependent GI distur bances (particularly diarrhea) in dogs than with the injectable products. Discontinuation of the drug or a lowered dose will generally resolve the problem. Renal toxicity manifested by proteinuria is possible as is hepatotoxicity (increased liver enzymes). These effects are less likely than either the GI or hematologic effects. Dermatosis and cor-neal ulcers have also been associated with auranofin therapy. Reproductive/Nursing Safety Auranofin has been demonstrated to be teratogenic and mater-notoxic in laboratory animals; it should not be used during preg-nancy unless the owner accepts the potential risks of use. In humans, the FDA 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. ) Following auranofin administration, gold is excreted in the milk of rodents. Trace amounts appear in the serum and red blood cells of nursing offspring. As this may cause adverse effects in nursing off-spring, switching to milk replacer is recommended if auranofin is to be continued in the dam. Because gold is slowly excreted, persistence in milk will occur even after the drug is discontinued. Overdosage/Acute Toxicity Very limited data is available. The minimum lethal oral dose in rats is 30 mg/kg. It is recommended that gut-emptying protocols be employed after an acute overdose when applicable. Chelating agents (e. g., penicillamine, dimercaprol) for severe toxicities have been used, but are controversial. One human patient who took an overdose over 10 days developed vari ous neurologic sequelae, but eventually (after 3 months) recovered completely after discontinua-tion of the drug and chelation therapy.

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Az APERONE 87 Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving auranofin and may be of significance in veterinary patients: Cy TOTOx IC Ag ENTST! (including high dose corticosteroids ): Aura-nofin's safety when used with these agents has not been estab-lished; use with caution PENICIll Am INET! or ANTIm Al ARIAl DRUg S : Use with gold salts is not recommended due to the in creased potential for hematologic or renal toxicity laboratory Considerations In humans, response to T! tuberculin skin tests may be enhanced; vet erinary significance is unclear Doses DOg S:T! a) For immune-mediated arthropathies and dermatopathies: 0. 05-0. 2 mg/kg (up to 9 mg/day total dose) PO q12h (Vaden and Cohn 1994), (Kohn 2003) b) For treatment of pemphigus complex (with corticosteroids): 0. 12-0. 2 mg/kg twice daily (White 2000) CATS:T! a) As a rescue drug for feline pemphigus and for idiopathic der-matoses and plasma cell pododermatitis/stomatitis: 0. 2-0. 3 mg/kg twice daily; must be reformulated for accurate dosing. (Morris 2004) monitoring The following should be performed prior to therapy, then once monthly for 2-3 months, then every other month: Hepatic and renal function tests (including urinalysis); T! CBC, with platelet counts; T! Note : eosinophilia may denote im-pending reactions Client Information Clients must understand that several months may be required T! before a positive response may be seen. Commitment to the twice daily dosing schedule, the costs asso-T! ciated with therapy, and the potential adverse effects should be discussed before initiating therapy. Chemistry/Synonyms An orally administered gold compound, auranofin occurs as a white, odorless, crys talline powder. It is very slightly soluble in wa-ter and soluble in alcohol. Auranofin contains 29% gold. Auranofin may also be known as: SKF-39162, SKF-D-39162, Crisinor®, Crisofin®, Goldar®, Ridaura® or Ridauran®. Storage/Stability Store capsules in tight, light resistant containers at room tempera-ture. After manufacture, expiration dates of 4 years are assigned to the capsules. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Auranofin Capsules: 3 mg; Ridaura® (SK-Beecham); (Rx) Aurothioglucose — See Gold Salts, Injectable Az Aperone (a-zap-peer-ohne) Stresnil® butyr Ophen One tranquilizer Prescriber Highlights A butyrophenone tranquilizer for swine; also used in T T wildlife Do not give IV, allow pigs to be undisturbed for 20 min-T T utes after injecting No analgesic activity T T May cause transient piling, salivation & shivering T T Uses/Indications Azaperone is officially indicated for the “control of aggressiveness when mixing or regrouping weanling or feeder pigs weighing up to 36. 4 kg” (Package Insert, Stresnil® —P/M; Mallinckrodt). It is also used clinically as a general tranquilizer for swine, to al low piglets to be accepted by aggressive sows, and as a preoperative agent prior to general anesthesia or cesarean section with local anesthesia. Azaperone has been used as a neuroleptic in horses, but some horses develop adverse reactions (sweating, muscle tremors, panic reaction, CNS excitement) and IV administration has resulted in significant arterial hypotension. Because of these effects, most clini-cians avoid the use of this drug in equines. Pharmacology/Actions The butyrophenones as a class cause tranquilization and sedation (sedation may be less than with the phenothiazines), anti-emetic ac-tivity, reduced motor activity, and inhibition of CNS catecholamines (dopamine, norepinephrine). Azaperone appears to have minimal effects on respiration and may inhibit some of the respiratory de-pressant actions of general anesthetics. A slight reduction of arte-rial blood pressure has been measured in pigs after IM injections of azaperone, apparently due to slight alpha-adrenergic blockade. Azaperone has been demonstrated to prevent the development of halothane-induced malignant hyperthermia in susceptible pigs. Prelimi nary studies have suggested that the effects of butyrophe-nones may be antagonized by 4-aminopyri dine. Pharmacokinetics Minimal information was located regarding actual pharmacokinetic parameters, but the drug is considered to have a fairly rapid onset of action following IM injections in pigs (5-10 minutes) with a peak effect at approximately 30 minutes post injection. It has a duration of action of 2-3 hours in young pigs and 3-4 hours in older swine. The drug is metabolized in the liver with 13% of it excreted in the feces. At 16 hours post-dose, practically all of the drug is eliminated from the body; however in the UK a 10-day slaughter withdrawal has been assigned. Contraindications/Precautions/Warnings When used as directed, the manufacturer reports no contraindica-tions (other than for slaughter withdrawal) for the drug. It should not be given IV as a significant excitatory phase may be seen in pigs. Avoid use in very cold conditions as cardiovascular collapse may occur secondary to peripheral vasodilation. Do not exceed dosing recommendation in boars as the drug may cause the penis to be extruded.

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

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Az ATHIOPRINE 89 Pharmacokinetics Azathioprine is absorbed from the GI tract and is rapidly metabo-lized to mer captopurine; it is then further metabolized to several other compounds. These metabolites are ex creted by the kidneys. Only minimal amounts of either azathioprine or mercaptopurine are excreted unchanged. Cats have low activity of thiopurine methyltransferase (TPMT), one of the routes used to metabolize azathioprine. Approximately 11% of humans have low thiopurine methyltransferase activity, and these individuals have a greater incidence of bone marrow sup-pression, but also greater azathioprine efficacy. Dogs have variable TMPT activity levels similar to that seen in humans, which may explain why some canine patients respond better and/or develop more myelotoxicity than others. However, one study (Rodriguez, Mackin et al. 2004) in dogs did not show significant correlation between TMPT activity in red blood cells and drug toxicity. Contraindications/Precautions/Warnings Azathioprine is contraindicated in patients hypersensitive to it. The drug should be used cautiously in patients with hepatic dysfunction. Use of azathioprine in cats is controversial; they seem to be more susceptible to azathioprine's bone marrow suppressive effects. Adverse Effects The principal adverse effect associated with azathioprine is bone mar row suppression. Cats are more prone to develop these effects and the drug is generally not recom mended for use in this species. Leukopenia is the most prevalent consequence, but anemias and throm bocytopenia may also be seen. GI upset, poor hair growth, acute pancreatitis and hepatotoxicity have been associated with azathioprine therapy in dogs. Because azathioprine depresses the immune system, animals may be susceptible to infections or neoplastic illnesses with long-term use. In recovering dogs with immune-mediated hemolytic anemia, taper the withdrawal of the drug slowly over several months and monitor for early signs of relapse. Rapid withdrawal can lead to a rebound hyperimmune response. Reproductive/Nursing Safety Azathioprine is mutagenic and teratogenic in lab animals. In hu-mans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be accept-able despite its potential risks. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the benefit of therapy clearly outweighs the risks. ) Azathioprine is distributed into milk; it is recommended to use milk replacer while the dam is receiving azathioprine. Overdosage/Acute Toxicity No specific information was located regarding acute overdose of azathioprine. It is suggested to use standard protocols to empty the GI tract if ingestion was recent and to treat supportively. Contact an animal poison control center for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving azathioprine and may be of significance in veterinary patients: ACE INHIb ITORST! (benazepril, enalapril, etc. ): Increased potential for hematologic toxicity All OPURINOl T! : The hepatic metabolism of azathioprine may be decreased by concomitant ad ministration of allopurinol; in humans, it is recommended to reduce the azathioprine dose to G-N usual if both drugs are to be used together Am INOSAl ICyl ATEST! (sulfasalazine, mesalamine, olsalazine ): Increased risk for azathioprine toxicity NON­DEPOl ARIz INg m USCl E REl Ax ANTS T! (e. g., pancuronium, tubocura­ rine): The neuromuscular blocking activity of these drugs may be inhibited or reversed by azathioprine CORTICOSTEROIDST! : Although azathioprine is often used with corti-costeroids, there is greater potential risk for toxicity development DRUg S AFFECTINg my El OPOIESIS T! (e. g., trimethoprim/sulfa, cyclophos­ phamide, etc. ): Increased potential for hematologic toxicity WARFARINT! : Potential for reduced anticoagulant effect Doses DOg S:T! As an immunosuppressive:a) For inflammatory bowel disease: Initially 2 mg/kg PO once daily for 2 weeks, then tapered to 2 mg/kg PO every other day for 2-4 weeks, then 1 mg/kg PO every other day. May take 2-6 weeks before beneficial effects are seen. (Moore 2004) b) For immune-mediated anemia, colitis, immune-mediated skin disease, and acquired myasthenia gravis: 2 mg/kg PO once daily (q24h); long-term therapy 0. 5-1 mg/kg PO every other day, with prednisolone administered on the alternate days (Papich 2001) c) For adjunctive therapy in myasthenia gravis in non-respon-sive patients: Initially, 1 mg/kg PO once daily. CBC is evalu-ated every 1-2 weeks. If neutrophil and platelet counts are normal after 2 weeks, dose is increased to 2 mg/kg PO once daily. CBC is repeated every week for the first month and then monthly thereafter. Recommend to discontinue aza-thioprine if WBC falls below 4,000 cells/mc L or neutrophil count is less than 1,000 cells/mc L. Serum ACHR antibody concentrations reevaluated q4-6 weeks. Azathioprine dose is tapered to every other day when clinical remission occurs and serum ACHR antibody concentra tions are normalized. (Coates 2000) d) For lymphoplasmacytic enteritis if clinical response to pred-nisolone is poor or the adverse effects (of prednisolone) pre-dominate: azathioprine 2 mg/kg PO once daily for 5 days, then on alternate days to prednisolone (Simpson 2003a) e) For severe cases (autoagglutination, hemolytic crisis with rapid decline of hematocrit, intravascular hemolysis, Cocker Spaniels) of immune-mediated hemolytic anemia: 2. 2 mg/kg PO once daily (q24h) in addition to prednisone (initially at 2. 2 mg/kg PO q12h until hematocrit reaches 25-30%; then dose is gradually tapered by approximately 25% q2-3 weeks until a dose of 0. 5 mg/kg PO q48h is reached). (Macintire 2006d) f) For adjunctive therapy in immune-mediated hemolytic ane-mia: 2 mg/kg PO once daily or on alternate days; continue until remission; then attempt to re duce prednisone to al-ternate day therapy. Azathioprine may be given on the days pred nisone is not. If remission persists for 4 weeks, azathio-prine may be discontinued. For dogs sensitive to the side ef-fects of glucocorticoids, azathioprine may be used on alter-nate days. (Miller 2000) g) For severe and refractory inflammatory bowel disease: 2. 2 mg/kg PO once daily; a lag time of 3-5 weeks is expected before clinical improvement is noted (Jergens and Willard 2000)

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

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Az ITHROmy CIN 91 Azithromycin (ay-zith-roe-my-sin) Zithromax® macr Olide antibi O tic Prescriber Highlights Oral & parenteral human macrolide antibiotic; poten-T T tially useful for a wide range of infections in veterinary patients Very long tissue half-lives in dogs & cats T T Contraindications: Hypersensitivity to macrolides T T Caution: Hepatic disease T T Adverse Effects: Potentially GI distress, but less so than T T with erythromycin Relatively expensive, but prices are dropping secondary T T to the availability of generic products Uses/Indications Azithromycin with its relative broad spectrum and favorable phar-macokinetic profile may be useful for a variety of infections in veterinary species. Little data is published at this time, however. Azithromycin has been shown to be ineffective in the treatment of Mycoplasma haemofelis in cats. Azithromycin may be potentially useful for treating Rhodococcus infections in foals. Pharmacology/Actions Like other macrolide antibiotics, azithromycin inhibits protein synthesis by pene trating the cell wall and binding to the 50S ribo-somal subunits in susceptible bacteria. It is consid ered a bacterio-static antibiotic. Azithromycin has a relatively broad spectrum. It has in vitro activity (does not necessarily indicate clinical efficacy) against gram-positive organisms such as Streptococcus pneumoniae, Staph aureus; gram-negative organisms such as Haemophilus influenzae; Bordetella spp. ; and Mycoplasma pneu moniae, Borrelia burgdorferi and Toxoplasma spp. Pharmacokinetics The pharmacokinetics of azithromycin have been described in cats and dogs. In dogs, the drug has excellent bioavailability after oral administration (97%). Tissue concentrations apparently do not mirror those in the serum after multiple doses and tissue half-lives in the dogs may be up to 90 hours. Greater than 50% of an oral dose is excreted unchanged in the bile. In cats, oral bioavailability is 58%. Tissue half-lives are less than in dogs, and range from 13 hours in adipose tissue to 72 hours in cardiac muscle. As with dogs, cats ex-crete the majority of a given dose in the bile. In foals, azithromycin is variably absorbed after oral administra-tion with a mean systemic bioavailability ranging from 40-60%. It has a very high volume of distribution (11. 6-18. 6 L/kg). Elimination half-life is approximately 20-26 hours. The drug con-centrates in bronchoalveolar cells and pulmonary epithelial fluid. Elimination half-life in PMN's is about 2 days. In adult horses, oral bioavailability is low (1-7%). When compared to erythromycin, azithromycin has better ab-sorption characteristics, longer tissue half-lives, and higher concen-trations in tissues and white blood cells. Goats have an elimination half-life of 32. 5 hours (IV), 45 hours (IM), an apparent volume of distribution (steady-state) of 34. 5 L/kg and a clearance of 0. 85 L/kg/hr. Rabbits have an elimination half-life of 24. 1 hours (IV), and 25. 1 hours (IM). IM injection has a high bioavailability, but causes some degree of muscle damage at the injection site. Sheep have an elimination half-life average of 48 hours (IV), 61 hours (IM), an apparent volume of distribution (steady-state) of 34. 5 L/kg and a clearance of 0. 52 L/kg/hr. Contraindications/Precautions/Warnings Azithromycin is contraindicated in animals hypersensitive to any of the macrolides. It should be used with caution in patients with impaired hepatic function. Adverse Effects Azithromycin can cause vomiting in dogs if high doses are given. When compared to erythromycin, azithromycin has less GI adverse effects. Other adverse effects, particularly those associated with the liver, may become apparent in dogs and cats as more experience is attained. Local IV site reactions have occurred in patients receiving IV azithromycin. Reproductive/Nursing Safety Safety during pregnancy has not been fully established; use only when clearly necessary. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Overdosage/Acute Toxicity Acute oral overdoses are unlikely to cause significant morbidity other than vomiting, diarrhea and GI cramping. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving azithromycin and may be of significance in veterinary patients: ANTACIDST! (oral; magnesium­ and aluminum­containing ): May reduce the rate of absorption of azithromycin; suggest separating dos-ages by 2 hours CISAPRIDET! : No data on azithromycin, but other macrolides con-traindicated with cisapride; use with caution Cy Cl OSPORINET! : Azithromycin may potentially increase cy-closporine blood levels; monitor carefully DIg Ox INT! : No data on azithromycin, but other macrolides can in-crease digoxin levels; monitor carefully PIm Oz IDET! : Azithromycin use is contraindicated in patients taking pimozide (unlikely to be used in vet med—used for T ourette's disorder in humans). Acute deaths have occurred. Doses DOg S:T! For susceptible infections:a) 5-10 mg/kg PO once daily for 3-5 days (Trepanier 1999), (Sykes 2003) b) 5 mg/kg PO once daily for 2 days, then every 3-5 days for a total of 5 doses (Aucoin 2002b) c) For “Derm” infections: 5-10 mg/kg PO once daily for 5-7 days. For animals that are diffi cult to pill, a dose given every 5 days (after the initial 5-7 day course of therapy) may be ef-fective if continued treatment is necessary. (Merchant 2000)

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

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Az TREONAm 93 clinical experience or research findings have been published with regard to target species. Aztreonam has also been used to treat pet fish (koi) infected with Aeromonas salmonocida. Pharmacology/Actions Aztreonam is a bactericidal antibiotic that binds to penicillin-bind-ing protein-3 thereby inhibiting bacterial cell wall synthesis result-ing in cell lyses and death of susceptible bacteria. Aztreonam is rela-tively stable to the effects of bacterial beta-lactamases and unlike many other beta-lactam antibiotics, it does not induce the activity of beta-lactamases. Aztreonam has activity against many species and most strains of the following gram-negative bacteria: Aeromonas, Citrobacter, Enterobacter, E. coli, Klebsiella, Pasturella, Proteus, Pseudomonas and Serratia. It is not clinically efficacious against gram-positive or an-aerobic bacteria. Aztreonam can be synergistic against Pseudomonas aeruginosa and other gram-negative bacilli when used with aminoglycosides. Pharmacokinetics There is limited information published on the pharmacokinetic pa-rameters of aztreonam in dogs and none was located for cats. In dogs, after a 20mg/kg dose was administered IM, peak plasma levels of approximately 40 mcg/m L occurred in about 20 minutes. Serum protein binding is about 20-30%, compared to 65% in humans. High tissue levels are found in the kidney (approx. 2. 5X that of plasma). Liver concentrations approximate those found in plasma and lower levels are found in the lung and spleen. The drug is primarily (80%) excreted unchanged in the dog. Elimination half-lives are approximately 0. 7 hours after IV administration and 0. 9 hours after IM administration. These values are approximately twice as short as those reported in humans (ages 1 yr to adult) with normal renal function. Contraindications/Precaution/Warnings Aztreonam should not be used in patients with documented severe hypersensitivity to the compound. Patients with serious renal dys-function may need dosage adjustment. Use cautiously in patients with serious liver dysfunction. Adverse Effects Adverse effect profiles for aztreonam specific to target species were not located. Aztreonam's adverse effects in humans are similar to those of other beta-lactam antibiotics: hypersensitivity, gastrointes-tinal effects including GI bacterial overgrowth/Pseudomembranous colitis, pain and/or swelling after IM injection, and phlebitis after IV administration. Transient increases in liver enzymes, serum cre-atinine, and coagulation indices have been noted. Reproductive/Nursing Safety Aztreonam crosses that placenta and can be detected in fetal circu-lation. However, no evidence of teratogenicity or fetal toxicity have been reported after doses of up to 5 times normal were given to pregnant rats and rabbits. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Aztreonam has been detected in human breast milk at levels approximately 1% of those found in serum. As the drug is not absorbed orally, it is likely safe to use in nursing animals though antibiotic-associated diarrhea is possible. Overdosage/Acute Toxicity There is little reason for concern in patients with adequate renal function. The IV LD 50 for mice is 3. 3 g/kg. Hemodialysis or perito-neal dialysis may be used to clear aztreonam from the circulation. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving aztreonam and may be of significance in veterinary patients: PROb ENECIDT! : Can reduce the renal tubular secretion of aztreonam, thereby maintaining higher systemic levels for a longer period of time; this potential “beneficial” interaction requires further investigation before dosing recommendations can be made for veterinary patients For in vitro interactions, see the Storage-Stability-Compatibility section. laboratory Considerations Aztreonam may cause false-positive T! urine glucose determina tions when using cupric sulfate solution (Benedict's Solution, Clinit-est®). T ests utilizing glucose ox idase (Tes-Tape®, Clinistix®) are not affected by aztreonam. Doses DOg S:T! NOTE : Dosages for this medication are not well established for use in veterinary patients. For dogs, an anecdotal dosing suggestion is to use the human pediatric dose of 30 mg/kg IM or IV q6-8h. When compared to humans, aztreonam has a shorter half-life, but is about half as bound to plasma proteins; the human pedi-atric dose may be a reasonable choice until more data becomes available. FISH:T! For treating a) Aeromonas salmonicida in koi: 100 mg/kg IM or ICe (intracoelemic) every 48 hours for 7 treatments. (Lewbart 2005) monitoring Because monobactams usually have minimal toxicity associated T! with their use, monitoring for efficacy is usually all that is re-quired unless toxic signs develop Serum levels and therapeutic drug monitoring are not routinely T! performed with this agent Client Information Veterinary professionals only should administer this medication T! Because of the dosing intervals required, this drug is best admin-T! istered to inpatients only Chemistry/Synonyms Aztreonam is a synthetic monobactam antimicrobial. It occurs as a white, odorless crystalline powder. Aztreonam may also be know as: Aztreonamum, Azthreonam, Atstreonaami, SQ-26776, Monobac®, Azactam®, Aztreotic®, Azenam®, Primbactam®, Trezam®, or Urobactam®. Storage/Stability/Compatibility Commercially available powder for reconstitution should be stored at room temperature (15°-30°C). For IM use, add at least 3 m L of diluent (sterile water for injec-tion, bacteriostatic sterile water for injection, NS, or bacteriostatic sodium chloride injection. ) Solutions are stable for 48 hours at room temperature, 7 days if refrigerated. For direct IV use, add 6-10 m L of sterile water for injection to each 15 or 30 m L vial. If the medication is to be given as an infu-sion, add at least 3 m L of sterile water for injection for each gram of

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

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b ARb ITURATE PHARm ACOl Ogy 95 Doses DOg S:T! T o treat urinary retention by decreasing urethral resistance: a) 1-2 mg/kg PO q8h (Lane 2000), (Coates 1999), (Labato 2005), (Lulich 2004) b) 5-10 mg (total dose) PO q8h (Senior 1999) monitoring Efficacy T! Adverse effects T! Client Information Do not stop therapy abruptly without veterinarian approval T! Chemistry/Synonyms A skeletal muscle relaxant that acts at the spinal cord level, baclofen occurs as white to off-white crystals. It is slightly soluble in water and has p Ka values of 5. 4 and 9. 5. Baclofen may also be known as: aminomethyl chlorohydrocin-namic acid, Ba-34647, baclofenum, Baclo®, Baclohexal®, Baclon®, Baclopar®, Baclosal®, Baclospas®, Balgifen®, Clinispas®, Clofen®, Kemstro®, Lebic ®, Lioresal®, Liotec ®, Miorel®, Neurospas®, Nu-Baclo®, Pacifen®, or Vioridon®. Storage/Stability/Compatibility Do not store tablets above 30°C (86°F). Intrathecal product should be stored at room temperature; do not freeze or heat sterilize. An oral liquid compounding recipe has been described (Olin 2000): T o prepare a 5 mg/m L liquid (35 day expiration date). Grind fifteen 20 mg tablets in a glass mortar to fine powder. Wet the pow-der with 10 m L of glycerin and form a fine paste. Slowly add 15 m L of simple syrup to the paste and transfer to a glass amber bottle. Rinse the mortar and pestle with another 15 m L of simple syrup and transfer to the bottle. Repeat until final volume is 60 m L. Shake well before each use and store in the refrigerator. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Baclofen Tablets: 10 mg, & 20 mg; Lioresal® (Novartis); gener-ic; (Rx); 10 mg & 20 mg orally disintegrating tablets: Kemstro® (Schwarz); (Rx) Baclofen for Intrathecal: 0. 05 mg/m L, 10 mg per 20 m L (500 mcg/ m L) & 10 mg per 5 m L (2000 mcg/m L); Lioresal® Intrathecal (Medtronic); (Rx) BAL in Oil — see Dimercaprolb Arbitur A te ph Arm Acology (bar-bich-yoo-rate; bar-bi-toor-ate) Also see the monographs for Methohexital, Phenobarbital, Pentobarbital, and Thiopental. While barbiturates are generally considered CNS depressants, they can invoke all levels of CNS mood alteration from paradoxical ex-citement to deep coma and death. While the exact mecha nisms for the CNS effects caused by barbiturates are unknown, they have been shown to inhibit the release of acetylcholine, norepinephrine, and glutamate. The barbiturates also have effects on GABA and pento-barbital has been shown to be GABA-mimetic. At high anesthetic doses, barbiturates have been demonstrated to inhibit the uptake of calcium at nerve endings. The degree of depression produced is dependent on the dosage, route of administration, pharmacokinetics of the drug, and species treated. Additionally, effects may be altered by patient age, physi-cal condition, or concurrent use of other drugs. The barbiturates depress the sensory cortex, lessen motor activity, and produce seda-tion at low dosages. In humans, it has been shown that barbiturates reduce the rapid-eye movement (REM) stage of sleep. Barbiturates have no true intrinsic analgesic activity. In most species, barbiturates cause a dose-dependent respira-tory depression, but, in some species, they can cause slight respira-tory stimulation. At sedative/hypnotic doses, respiratory depression is similar to that during normal physiologic sleep. As doses increase, the medullary respiratory center is progressively depressed with re-sultant decreases in rate, depth, and volume. Respiratory arrest may occur at doses four times lower than those will cause cardiac arrest. These drugs must be used very cautiously in cats; they are particu-larly sensitive to the respiratory depressant effects of barbiturates. Besides the cardiac arresting effects of the barbiturates at eutha-natizing dosages, the barbiturates have other cardiovascular effects. In the dog, pentobarbital has been demonstrated to cause tachycar-dia, decreased myocardial contractility and stroke volume, and de-creased mean arterial pressure and total peripheral resistance. The barbiturates cause reduced tone and motility of the intes-tinal musculature, probably secondary to its central depressant ac-tion. The thiobarbiturates (thiamylal, thiopental) may, after initial depres sion, cause an increase in both tone and motility of the in-testinal musculature; however, these effects do not appear to have much clinical significance. Administration of barbiturates reduc-es the sensi tivity of the motor end-plate to acetylcholine thereby slightly relaxing skeletal muscle. Because the musculature is not completely relaxed, other skeletal muscle relaxants may be neces-sary for surgical procedures. There is no direct effect on the kidney by the barbiturates, but severe renal impairment may occur secondary to hypotensive effects in overdose situations. Liver function is not directly affected when used acutely, but hepatic microsomal enzyme induction is well documented with extended barbitu rate (especially phenobarbital) administration. Although barbiturates reduce oxygen consumption of all tissues, no change in metabolic rate is measurable when given at sedative dosages. Basal metabolic rates may be reduced with re-sultant decreases in body temperature when barbiturates are given at anesthetic doses.

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

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b ETAm ETHASONE 97 ANTIDIAb ETIC Ag ENTS T! (insulin, oral agents ): Possible increased risk for hypoglycemia; enhanced monitoring recommended DIURETICST! (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 for heart failure DIURETICS, POTASSIUm­SPARINg T! (e. g., spironolactone, triamterene ): Increased hyperkalemic effects, enhanced monitoring of serum potassium l ITHIUm T! : Increased serum lithium levels possible; increased moni-toring required POTASSIUm SUPPl Em ENTST! : Increased risk for hyperkalemia laboratory Considerations When using T! iodohippurate sodium I123/I134 or Technetium Tc99 pen­ tentate renal imaging in patients with renal artery stenosis, ACE inhibitors may cause a re versible decrease in localization and ex-cretion of these agents in the affected kidney which may lead to confusion in test interpretation. Doses DOg S:T! For adjunctive treatment of heart failure:a) 0. 25-0. 5 mg/kg PO once daily (Miller and Tilley 1995); (Trepanier 1999), (Kittleson 2007) b) 0. 25-0. 5 mg/kg PO once to twice daily (Ware 1997) For adjunctive treatment of hypertension:a) 0. 25 mg/kg PO q12h (Brown and Henik 2000) b) 0. 25-0. 5 mg/kg q12-24h; Co-administration with a calcium channel antagonist may lower blood pressure when mono-therapy is not sufficient. In diabetic dogs, an ACE inhibitor may block adverse effects of calcium channel antagonists. (Brown 2003) c) For hypertension associated with protein-losing renal dis-ease: 0. 5 mg/kg PO once daily (q24h) Response may be vari-able in dogs with hypertension secondary to other diseases; ACE inhibitors are usually well tolerated and can be tried in non-emergency hypertension. (Stepian 2006a) CATS:T! For adjunctive treatment of heart failure:a) 0. 25-0. 5 mg/kg PO once daily (Trepanier 1999), (Kittleson 2007) b) For CHF or hypertension: 0. 25-0. 5 mg/kg PO once to twice daily (Atkins 2003b) For adjunctive treatment of hypertension:a) 0. 5-1 mg/kg PO once daily (Sparkes 2003b) b) 0. 25-1 mg/kg PO once to twice daily. Because of their an-tiproteinuric effects, ACE inhibitors are the drugs of first choice to treat hypertension in animals with proteinuria. (Langston 2003) c) 0. 25-0. 5 mg/kg PO once daily (q24h) (Stepian 2006a) d) For proteinuria, hypertension associated with chronic kidney disease: 0. 25-0. 5 mg/kg PO once to twice daily (q12-24h); rarely higher (Polzin 2006) monitoring Clinical signs of CHFT! Serum electrolytes, creatinine, BUN, urine protein T! Blood pressure (if treating hypertension or clinical signs associ-T! ated with hypotension arise)Client Information Do not abruptly stop or reduce therapy without veterinarian's T! approval. Con tact veterinarian if vomiting or diarrhea persist or is severe or if animal's condition deteriorates. Chemistry/Synonyms Benazepril HCl, an angiotensin converting enzyme inhibitor, oc-curs as white to off-white crystalline powder. It is soluble in water and ethanol. Benazepril does not contain a sulfhydryl group in its structure. Benazepril may also be known as: CGS-14824A (benazepril or benazepril hydrochloride), Benace®, Boncordin®, Briem®, Cibace®, Cibacen®, Cibacen®, Cibacene®, Fortekor®, Labopal®, Lotensin®, Lotrel ®, Tensanil®, or Zinadril®. Storage/Stability/Compatibility Benazepril tablets (and combination products) should be stored at temperatures less than 86°F (30°C) and protected from moisture. They should be dispensed in tight containers. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None in the USA In the UK (and elsewhere): Benazepril Tablets: 2. 5, 5, & 20 mg; Fortekor® (Novartis—UK); (POM-V) Labeled for use in cats for chronic renal insufficiency and for heart failure in dogs. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Benazepril HCl Tablets: 5 mg, 10 mg, 20 mg, & 40 mg; Lotensin® (Novartis); generic; (Rx) Also available in fixed dose combination products containing am-lodipine (Lotrel ®) or hy drochlorothiazide (Lotensin HCT®) bet Ameth Asone bet Ameth Asone Acet Ate bet Ameth Asone sodium phosph A te (bet-ta-meth-a-sone) Celestone® gluc Oc Ortic Oid Note : For more information on the pharmacology of glucocorticoids re-fer to the monograph: Glucocorticoids, General information. For topical or otic use, see the T opical Dermatology & Otic sections in the appendix. Prescriber Highlights Injectable (long-acting) & topical glucocorticoid T T Long acting; 25T T -40X more potent than hydrocortisone; no mineralocorticoid activity Goal is to use as much as is required & as little as pos-T T sible for as short an amount of time as possible Primary adverse effects are “Cushingoid” in nature with T T sustained use Many potential drug & lab interactions when used T T systemically

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98 b ETAm ETHASONE Contraindications/Precautions/Warnings For the product Betasone® (Schering), the manu facturer states that the drug is “contraindicated in animals with acute or chronic bacte-rial infections unless therapeutic doses of an effective antimicrobial agent are used. ” Systemic use of glucocorti coids is generally consid-ered contraindicated in systemic fungal infections (unless used for replacement therapy in Addison's), when administered IM in pa-tients with idiopathic thrombocy topenia and in patients hypersen-sitive to a particular compound. Use of sustained-release injectable glucocorticoids 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 return slow-ly. Should the animal undergo a “stressor” (e. g., surgery, trauma, ill-ness, etc. ) during the tapering process or until normal adrenal and pituitary function resume, additional glucocorticoids should be ad-ministered. Corticosteroid therapy may induce parturition in large animal species during the latter stages of pregnancy. Adverse Effects Adverse effects are generally associated with long-term administra-tion of these drugs, especially if given at high dosages or not on an alternate day regimen. Effects generally manifest as clinical signs of hyperadrenocorticism. When administered to young, growing ani-mals, glucocorticoids can retard growth. Many of the potential ef-fects, adverse and otherwise, are outlined in the Phar macology sec-tion of the Glucocorticoids, General information monograph. In dogs, polydipsia (PD), polyphagia (PP) and polyuria (PU), may all be seen with short-term “burst” therapy as well as with alter-nate-day maintenance therapy on days when given the drug. Adverse effects in dogs associated with long-term use can include: dull, dry haircoat, weight gain, panting, vomiting, diarrhea, ele vated liver enzymes, pancreatitis, GI ulceration, lipidemias, activation or wors-ening of diabetes mellitus, muscle wasting and behavioral changes (depression, lethargy, viciousness). Discontinuation of the drug may be necessary; changing to an alternate steroid may also alleviate the problem. With the exception of PU/PD/PP, adverse effects as-sociated with antiinflammatory therapy are relatively uncommon. Adverse effects associated with immunosuppressive doses are more common and po tentially more severe. Cats generally require higher dosages than dogs for clinical effect but tend to develop fewer ad verse effects. Occasionally, polydipsia, polyuria, polyphagia with weight gain, diarrhea, or depres sion can be seen. Long-term, high dose therapy can lead to “Cushingoid” ef-fects. Reproductive/Nursing Safety In addition to the contraindications, precautions and adverse effects outlined above, betamethasone has been demonstrated to cause de-creased sperm output and semen volume and increased percent ages of abnormal sperm in dogs. Use with caution in nursing dams. Corticosteroids appear in milk and could suppress growth, interfere with endogenous corticoster-oid production or cause other unwanted effects in the nursing off-spring. However, in humans, several studies suggest that amounts excreted in breast milk are negligible when prednisone or predni-solone doses in the mother are less than or equal to 20 mg/day or methylprednisolone doses are less than or equal to 8 mg/day. Larger doses for short periods may not harm the infant. Overdosage/Acute Toxicity Glucocorticoids when given short-term are unlikely to cause harm-ful effects, even in massive dosages. One incidence of a dog develop-ing acute CNS effects after accidental ingestion of glucocorticoids has been reported. Should clinical signs occur, use supportive treat-ment if required. 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 betamethasone systemi-cally and may be of significance in veterinary patients: Am PHOTERICIN b T! : When administered concomitantly with gluco-corticoids may cause hypokalemia ANTICHOl INESTERASE Ag ENTS T! (e. g., pyridostigmine, neostigmine, etc. ): In patients with myasthenia gravis, concomitant glucocorticoid and anticholinesterase agent administration may lead to profound muscle weakness; if possi ble, discontinue anticholinesterase med-ication at least 24 hours prior to corticosteroid administration ASPIRIN T! and OTHER SAl ICyl ATES : Glucocorticoids may reduce sali-cylate blood levels b ARb ITURATEST! : May increase the metabolism of glucocorticoids Cy Cl OPHOSPHAm IDET! : Glucocorticoids may inhibit the hepatic me-tabolism of cyclophos phamide; dosage adjustments may be re-quired Cy Cl OSPORINET! : Concomitant administration of glucocorticoids and cyclosporine may increase the blood levels of each by mu-tually inhibiting hepatic metabolism; clinical significance is not clear DIg Ox INT! : When glucocorticoids are used concurrently with digi-talis glycosides, an increased chance of digitalis toxicity may occur should hypokalemia develop; diligent monitoring of potassium and digitalis glycoside levels is recommended. DIURETICS,T! POTASSIUm­DEPl ETINg (e. g., furosemide, thiazides ): When administered concomitantly with glucocorticoids may cause hy-pokalemia ESTROg ENST! : May decrease corticosteroid clearance INSUl INT! Requirements may increase in patients receiving gluco-corticoids ISONIAz IDT! : May have serum levels decreased by corticosteroids KETOCONAz Ol ET! : Corticosteroid clearance may be reduced and the AUC increased m ITOTANET! : May alter the metabolism of steroids; higher than usual doses of steroids may be neces sary to treat mitotane-induced ad-renal insufficiency RIFAm PINT! : May increase the metabolism of glucocorticoids THEOPHyll INEST! : Alterations of pharmacologic effects of either drug can occur Ul CEROg ENIC DRUg S T! (e. g., NSAIDs ): Use with gluco corticoids may increase the risk of gastrointestinal ulceration VACCINEST! : Patients receiving corticosteroids at immunosuppres-sive dosages should generally not receive live at tenuated-virus vaccines as virus replication may be augmented; diminished im-mune response may occur after vaccine, toxoid, or bacterin ad-ministration in patients receiving glucocorticoids laboratory Considerations Glucocorticoids may increase T! serum cholesterol and urine glu cose levels Glucocorticoids may decrease T! serum potassium

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b ETHANECHOl CHl ORIDE 99 Glucocorticoids can suppress the release of thyroid stimulating T! hormone (TSH) and reduce T3 & T4 values; thyroid gland atrophy has been reported after chronic glucocorticoid administration Uptake of T! I131 by the thyroid may be decreased by glucocorticoids Reactions to T! skin tests may be suppressed by glucocorticoids False-negative results of the T! nitroblue tetrazolium test for systemic bacterial infections may be induced by glucocorticoids Betamethasone does not cross-react with the cortisol assay T! Doses DOg S:T! For the control of pruritus: a) Betasone® Aqueous Suspension: 0. 25-0. 5 m L per 20 pounds body weight IM. Dose de pendent on severity of condition. May repeat when necessary. Relief averages 3 weeks in dura-tion. Do not exceed more than 4 injections. (Package Insert; Betasone®—Schering) Note : Product no longer marketed in the USA. HORSES:T! Source of product an issue. Alternative is triamcinolone (see that monograph for additional information). ( Note : ARCI UCGFS Class 4 Drug)As a relatively short-acting corticosteroid for intraarticular administration: a) 6-15 mg per joint IA. Frequency of re-injection is limited to the minimum number needed to achieve soundness. (Fris-bee 2003) monitoring Monitoring of glucocorticoid therapy is dependent on its reason for use, dosage, agent used (amount of mineralocorticoid activity), dosage schedule (daily versus alternate day therapy), duration of therapy, and the animal's age and condition. The following list may not be appropriate or complete for all animals; use clinical assess-ment and judgment should adverse ef fects be noted: Weight, appetite, signs of edema T! Serum and/or urine electrolytes T! T otal plasma proteins, albumin T! Blood glucose T! Growth and development in young animals T! ACTH stimulation test if necessary T! Client Information Clients should carefully follow the dosage instructions and should T! not discon tinue the drug abruptly without consulting veterinar-ian beforehand Clients should be briefed on the potential adverse effects that can T! be seen with these drugs and instructed to contact the veterinar-ian should these effects become severe or progress Chemistry/Synonyms A synthetic glucocorticoid, betamethason is available as the base and as the dipropi onate, acetate and sodium phosphate salts. The base is used for oral dosage forms. The sodium phos phate and ac-etate salts are used in injectable preparations. The dipropionate salt is used in topical formulations and in combination with the sodium phosphate salt in a veterinary-approved injectable preparation. Betamethasone occurs as an odorless, white to practically white, crystalline powder. It is insoluble in water and practically insoluble in alcohol. The dipropionate salt occurs as a white or creamy-white, odorless powder. It is practically insoluble in water and sparingly soluble in alcohol. The sodium phosphate salt occurs as an odorless, white to practically white, hygroscopic powder. It is freely soluble in water and slightly soluble in alcohol. Betamethasone may also be known as flubenisolone or Celestone®. Storage/Stability/Compatibility Betamethasone tablets should be stored in well-closed containers at 2-30°C. The oral solution should be stored in well-closed contain-ers, protected from light and kept at temperatures less than 40°C. The sodium phosphate injection should be protected from light and stored at room temperature (15-30°C); protect from freezing. The combination veterinary injectable product (Betasone®) should be stored between 2-30°C and protected from light and freezing. When betamethasone sodium phosphate was mixed with hepa-rin sodium, hydrocortisone sodium succinate, potassium chloride, vitamin B-complex with C, dextrose 5% in water (D 5W), D 5 in Ringer's, D 5 in lactated Ringer's, Ringer's lactate injection or nor-mal saline, no physical incompat ibility was noted immediately or after 4 hours. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: The following product is apparently no longer marketed in the USA. Betamethasone Diproprionate Injection equivalent to 5 mg/m L of betamethasone and betametha sone sodium phosphate equivalent to 2 mg/m L betamethasone in 5 m L vials; Betasone® (Schering-Plough); (Rx). Approved for use in dogs. Betamethasone valerate is also found in Gentocin® Otic, Gentocin® Topical Spray and Topa gen® Ointment, (Schering-Plough). There are several other otic and topical products containing betametha-sone and gentamicin on the veterinary market. See the appendix for more information on these products. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Betamethasone Tablets: 0. 6 mg; Celestone® (Schering); (Rx) Betamethasone Solution: 0. 6 mg/5 m L in 118 m L; Celestone® (Schering); (Rx)Betamethasone Injection: betamethasone (as sodium phosphate) 3 mg/m L and betamethasone acetate 3 mg/m L injection in 5 m L vi-als; Celestone Soluspan® (Schering); (Rx) beth Anechol chloride (beh-than-e-kole) Urecholine® ch Olinergic Prescriber Highlights Cholinergic agent used primarily to increase bladder con-T T tractility; symptomatic treatment of dysautonomia Principle contraindications are GI or urinary tract obstruc-T T tions or if bladder wall integrity is in ques tion Adverse Effects: “SLUD” (salivation, lacrimation, urination, T T defecation)Cholinergic crisis possible if injecting IV or SC, have atro-T T pine at the ready

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

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b ISACODyl 101 a) 0. 025-0. 075 mg/kg subcutaneously q8h. Dosage is variable and should be adjusted for each patient. (Jose-Cunilleras and Hinchcliff 1999) If bladder is capable of weak contractions: a) 0. 025-0. 075 mg/kg SC 2-3 times; or 0. 25-0. 75 mg/kg PO 2-4 times a day. Note : Oral dose is 10X that of SC dose (Schott II and Carr 2003) CATTl E:T! For adjunctive medical therapy (with fluids, mineral oil, and NSAIDs if needed) of cecal dilation/dislocation (CDD): a) Only if animal is “normal” or only slightly disturbed, defeca-tion is present, and rectal exam does not reveal torsion or retroflexion. If these criteria are not met, or no improvement within 24 hours of medical therapy, surgical therapy is rec-ommended. Bethanechol at 0. 07 mg/kg SC three times daily for 2 days. Withhold feed for 24 hours and then gradually give increasing amounts of hay if defecation is present and CDD is resolved. (Meylan 2004) monitoring Clinical efficacy T! Urination frequency, amount voided, bladder palpation T! Adverse effects (see above section)T! Client Information Give medication to animal with an empty stomach unless other-T! wise instructed by veteri narian Contact veterinarian if salivation or GI (vomiting, diarrhea, or T! anorexia) effects are pro nounced or persist Chemistry/Synonyms A synthetic cholinergic ester, bethanechol occurs as a slightly hygro-scopic, white or colorless crystalline powder with a slight, amine-like or “fishy” odor. It exhibits polymorphism, with one form melting at 211° and the other form at 219°. One gram of the drug is soluble in approxi mately 1 m L of water or 10 m L of alcohol. Bethanechol Chloride may also be known as: carbamylmethyl-choline chloride, Duvoid®, Miotonachol®, Muscaran®, Myo Hermes®, Myocholine®, Myotonine®, Ucholine®, Urecholine®, Urocarb®, or Urotonine®. Storage/Stability Bethanechol tablets should be stored at room temperature in tight containers. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Bethanechol Chloride Tablets: 5 mg, 10 mg, 25 mg, & 50 mg; Ure-choline® (Odyssey); generic; (Rx) An injectable product was formerly commercially available; a com-pounding pharmacy may be able to prepare a bethanechol inject-able form. Bicarbonate — see Sodium Bicarbonatebis Acodyl (bis-a-koe-dill) Dulcolax® Oral/rectal l a Xative Prescriber Highlights Stimulant laxative used in dogs & cats T T Contraindicated in GI obstruction T T GI cramping/diarrhea possible T T Don't give with milk products or antacids T T Uses/Indications Bisacodyl oral and rectal products are used as stimulant cathartics in dogs and cats. Pharmacology/Actions A stimulant laxative, bisacodyl's exact mechanism is unknown. It is thought to produce catharsis by increasing peristalsis by direct stimulation on the intramural nerve plexuses of intestinal smooth muscle. It has been shown to increase fluid and ion accumulation in the large intestine thereby enhancing catharsis. Pharmacokinetics Bisacodyl is minimally absorbed after either oral or rectal adminis-tration. Onset of action after oral administration is generally 6-10 hours and 15 minutes to an hour after rectal ad ministration. Contraindications/Precautions/Warnings Stimulant cathartics are contraindicated in the following conditions: intestinal obstruction (not constipation), undiagnosed rectal bleed-ing, or when the patient is susceptible to intestinal perforation. Bisacodyl should only be used short-term as chronic use can damage myenteric neurons. Adverse Effects Bisacodyl has relatively few side effects when used occasionally; cramping, nausea, or diarrhea may be noted after use. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Bisacodyl may be distributed into milk but at quantities unlikely to cause any problems in nursing offspring. Overdosage/Acute Toxicity Overdoses may result in severe cramping, diarrhea, vomiting and po tentially, fluid and electrolyte imbalances. Animals should be monitored and given replacement par enteral fluids and electrolytes as necessary. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bisacodyl and may be of significance in veterinary patients: ANTACIDS/m Il KT! : Do not give milk or antacids within an hour of bisacodyl tablets as it may cause premature disintegration of the enteric coating.

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

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b ISm UTH SUb SAl ICyl ATE 103 Overdosage/Acute Toxicity Bismuth subsalicylate liquid/suspension contains approximately 8. 7 mg/m L salicylate. Two tablespoonsful (30 m L) is approximately equivalent to one 325 mg aspirin tablet. See the As pirin monograph for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bismuth subsalicylate and may be of significance in veterinary patients: TETRACy Cl INET! : Bismuth containing products can decrease the absorption of orally administered tetracycline products. If both agents are to be used, separate drugs by at least 2 hours and ad-minister tetracycline first. ASPIRINT! : Because bismuth subsalicylate contains salicylate, con-comitant administration with aspirin may increase salicylate se-rum levels; monitor appropriately. laboratory Considerations At high doses, salicylates may cause false-positive results for T! uri­ nary glucose if using the cupric sulfate method (Clinitest®, Bene-dict's solution) and false-negative results if using the glucose oxi-dase method (Clinistix® or Tes-Tape®). Urinary ketones T! measured by the ferric chloride method (Ger-hardt) may be affected if salicylates are in the urine (reddish-color produced). 5­HIAAT! determinations by the fluorometric method may be inter-fered by salicylates in the urine. Falsely elevated T! Vm A (vanillylmandelic acid) may be seen with most methods used if salicylates are in the urine. Falsely lowered Vm A levels may be seen if using the Pisano method. Urinary excretion of T! xylose may be decreased if salicylates are given concurrently. Falsely elevated T! serum uric acid values may be measured if using colorimetric methods. Doses Note : Doses of liquids below are for the 17. 5 mg/m L (1. 75%) liquids (veterinary suspensions; original Pepto-Bismol® liquid, etc. ) unless otherwise specified. DOg S:T! For acute diarrhea: a) 1 m L per 5 kg of body weight PO 3 times a day; should prob-ably not exceed 5 days of therapy (Hall and Simpson 2000) b) Pepto-Bismol®: 0. 25 m L/kg PO q4-6h, up to 2 m L/kg q 6-8h (Cote 2000) For eliminating Helicobacter gastritis infections: a) Using triple therapy: Metronidazole 15. 4 mg/kg q8h, amoxi-cillin 11 mg/kg q8h and bismuth subsalicylate (original Pep-to-Bismol®) 0. 22 m L/kg PO q4- 6h. Give each for 3 weeks (Hall 2000) As a gastroprotectant/coating agent in the adjunctive treatment of uremic gastritis: a) 2 m L/kg PO q6-8h (Bartges 2006d) CATS:T! For diarrhea: a) Pepto-Bismol® : 0. 25 m L/kg PO q4-6h; cats are sensitive to salicylates and probably should not receive frequent or high dosages (Cote 2000) b) Using “Pepto-Bismol® Regular” or equivalent strength (17. 5 mg/m L) liquid: 0. 5-1 m L/kg PO q12h for 3 days. (Scherk 2005b)c) For diarrhea in kittens and young cats: 1-2 m L Pepto-Bis-mol® 3-4 times a day. Refrigera tion may increase palatability. (Tams 1999) For eliminating Helicobacter gastritis infections: a) Using triple therapy: Metronidazole 15. 4 mg/kg q8h, amoxi-cillin 11 mg/kg q8h and bismuth subsalicylate (original Pep-to-Bismol®) 0. 22 m L/kg PO q4- 6h. Give each for 3 weeks (Hall 2000) FERRETS:T! For eliminating Helicobacter gastritis infections: a) Using triple therapy: Metronidazole 22 mg/kg, amoxicillin 22 mg/kg and bismuth subsal icylate (original Pepto-Bismol®) 17. 6 mg/kg PO. Give each 3 times daily for 3-4 weeks. (Hall 2000) b) Using triple therapy: Metronidazole 20 mg/kg PO q12h, amoxicillin 20 mg/kg PO q12h and bismuth subsal icylate 17. 5 mg/kg PO q8h; continue for 21 days. Used with famoti-dine (0. 5 mg/kg PO once daily) and sucralfate (25 mg/kg PO q8h) (Johnson 2006c) CATTl E:T! For diarrhea:a) For calves: 60 m L two to four times a day for two days (Label Directions; Corrective Mixture® —Beecham). b) 2-3 ounces PO 2-4 times a day (Braun 1986) HORSES:T! For diarrhea:a) For foals: 3-4 ounces per 45 kg (100 lb. ) body weight PO q6-8h (Madigan 2002a) b) For foals or adults: 1 ounce per 8 kg of body weight PO 3-4 times daily (Clark and Becht 1987) c) For foals: 3-4 oz. PO q6-8h (Martens and Scrutchfield 1982) d) For foals: 60 m L two to four times a day for two days (Label Directions; Corrective Mixture® —Beecham). SWINE:T! For diarrhea in baby pigs: a) 2-5 m L PO two to four times a day for 2 days (Label Direc-tions; Corrective Mixture® —Beecham) monitoring Clinical efficacy T! Fluid and electrolyte status in severe diarrhea T! Client Information Shake product well before using. T! Re frigeration of the suspension may improve palatability. Do not T! mix with milk before administering. If diarrhea persists, contact veterinarian. T! May change stool color to a gray-black or greenish-black; contact T! veterinarian if stool becomes “tarry” black. Chemistry/Synonyms Bismuth subsalicylate occurs as white or nearly white, tasteless, odorless powder and contains about 58% bismuth. It is insoluble in water, glycerin and alcohol. Bismuth subsalicylate may also be known as: BSS, basic bis-muth salicylate, bismuth oxysalicylate, bismuth salicylate, bismuthi subsalicylas, Bismu-kote®, Bismukote®, Bismupaste®, Bismatrol®, Bismed®, Bismusal®, Bismylate®, Bisval®, Equi-Phar®, Gastrocote®, Jatrox®, Kalbeten®, Kaopectate®, Katulcin-R®, Pala BIS®, Peptic Relief®, Pink Biscoat®, Pink Bismuth Rose®, or Ulcolind Wismut®; many other human trade names are available.

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104 bl EOmy CIN SUl FATE Storage/Stability/Compatibility Bismuth subsalicylate should be stored protected from light. Unless otherwise labeled store at room temperature; do not freeze. It is in­ compatible with mineral acids and iron salts. When exposed to alkali bicarbonates, bismuth subsal icylate decomposes with effervescence. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Bismuth Subsalicylate Paste: 5% (50 mg/m L) in 15 m L tubes; Bismukote Paste for Small Dogs® (Vedco), (OTC). Labeled for use in small dogs. 10% (100 mg/m L) in 15 m L, 30 m L tubes; Bismukote Paste for Me-dium and Large Dogs® (Vedco), Bismu paste D® (Butler); (OTC). Depending on product, labeled for use in small, medium and large dogs. 20% (200 mg/m L) in 60 m L tubes; Bismupaste E® (Butler), Equi-Phar® (Vedco); (OTC). Labeled for use in horses. Bismuth Subsalicylate Oral Suspension: Bismuth subsalicylate Oral Suspension 1. 75% (17. 5 mg/m L; 262 mg/15 m L). Bismu-kote® Suspension (Vedco), Bismusal® (Bimeda), Bismusal® Suspension (Agri Pharm), Bismusol® (First Priority), Cor-rective Suspension® (Phoenix), Gastrocote ® (Butler); generic; (OTC). Available in gallons. Labeled for use in cattle, horses, calves, foals, dogs and cats. Each m L contains about 8. 7 mg salicylate. Bismuth Subsalicylate Tablets: Bismuth Subsalicylate tablets (each tablet contains 262 mg of bis-muth subsalicylate). Labeled for use in dogs. Pala BIS® (Pharm X); (OTC). One tablet contains about 102 mg salicylate. HUm AN­l Ab El ED PRODUCTS: Bismuth Subsalicylate (BSS) Liquid/Suspension: 87 mg/5 m L; 130 mg/15 m L; 262 mg/15 m L; 524 mg/15 m L; 525 mg/15 m L; in 120 m L, 236 m L, 237 m L, 240 m L, 355 m L, 360 m L, or 480 m L; Kao-pectate®, Kaopectate® Children's & Extra Strength (Pharmacia); Pink Bismuth (various); Kao-Tin® (Major); Peptic Relief® & K-Pek® (Rugby); Pepto-Bismol® & Maximum Strength (Procter & Gamble); Kapectolin® (United Research Laboratories); Maalox® Total Stom-ach Relief Liquid (Novartis); (OTC). Note : Regular strength (262 mg/ m L) contains 8. 7 mg salicylate per m L; Extra-Strength (525 mg/m L) contains 15. 7 mg of salicylate per m L. Bismuth Subsalicylate Tablets and Caplets: 262 mg (regular & chew-able); Kaopectate® (Pfizer Consumer Health); Bismatrol® (Major); Peptic Relief® (Rugby); Pepto-Bismol® (Major); (OTC). One tablet contains about 102 mg salicylate. bleomycin sulf Ate (blee-oh-mye-sin) Blenoxane® antine Oplastic Prescriber Highlights Antibiotic antineoplastic agent infrequently used for a va-T T riety of neoplasms in dogs & cats; intralesional adminis-tration may have promise Two main toxicities: acute (fever, anorexia, vomiting, & al-T T lergic reactions) & delayed (dermatologic effects, stomati-tis, pneumonitis & pul monary fibrosis) Do not exceed total dosage recommendations T T Intensive adverse effect monitoring required when used T T systemically Uses/Indications Bleomycin has occasionally been used as adjunctive treatment of lymphomas, squamous cell carcinomas, teratomas, and nonfunc-tional thyroid tumors in both dogs and cats. Recent work has dem-onstrated that bleomycin may be promising for intralesional treat-ment for a variety of localized tumors with or without concomitant electropermeabilization. Pharmacology/Actions Bleomycin is an antibiotic that has activity against a variety of gram-negative and gram-positive bacteria as well as some fungi. While its cytotoxicity prevents it from being clinically useful as an antimicro-bial, it can be useful against a variety of tumors in small animals. Bleomycin has both a DNA binding site and a site that binds to the ferrous form of iron. By accepting an electron from ferrous ion to an oxygen atom in the DNA strand, DNA is cleaved. Resistance to bleomycin therapy is via reduced cellular uptake of the drug, reduced ability to damage DNA and increased rates of DNA repair by the cell and, probably most importantly, via the en-zyme bleomycin hydrolase. Pharmacokinetics Bleomycin is not appreciably absorbed from the gut and must be adminis tered parenterally. It is mainly distributed to the lungs, kid-neys, skin, lymphatics and peritoneum. In patients with normal re-nal function, terminal half-life is about 2 hours. In humans, 60-70% of a dose is excreted as active drug in the urine. Contraindications/Precautions/Warnings Because bleomycin is a toxic drug with a low therapeutic index, it should be used only by those having the facilities to actively monitor pa tients and handle potential complications. Bleomycin is contrain-dicated in patients with prior hypersensitivity reactions from the drug, preexisting pulmonary disease, or adverse pulmonary effects from prior therapy. The drug should be used very cautiously in pa-tients with significant renal impairment and dosage reduction may be necessary. Bleomycin can be teratogenic; it should only be used in pregnant animals when the owners accept the associated risks. Adverse Effects T oxicity falls into two broad categories: acute and delayed. Acute toxicities include fever, anorexia, vomiting, and allergic reactions (including anaphylaxis). Delayed toxic effects include dermatologic effects (e. g., alopecia, rashes, etc. ), stomatitis, pneumonitis and pul-monary fibrosis. These latter two effects have been associated with

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bl EOmy CIN SUl FATE 105 drug-induced fatalities. Initial signs associated with pulmonary toxicity include pulmonary interstitial edema with alveolar hya-line membrane formation and hyperplasia of type II alveolar mac-rophages. Pulmonary toxicity is potentially reversible if treatment is stopped soon enough. Unlike many other antineoplastics, bleomy-cin does not usually cause bone marrow toxicity but thrombocy-topenia, leukopenia and slight decreases in hemoglobin levels are possible. Renal toxicity and hepatotoxicity are potentially possible. T o reduce the likelihood of pulmonary toxicity developing, a to-tal maximum dosage of 125-200 mg/m2 should not be exceeded. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the po-tential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) It not known if bleomycin enters milk; it is not recommended to nurse while receiving the medication. Overdosage/Acute Toxicity No specific information was located. Because of the toxicity of the drug, it is important to determine dosages carefully. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bleomycin and may be of significance in veterinary patients: ANESTHETICS, g ENERAl T! : Use of general anesthetics in patients treated previously with bleomycin should be exercised with cau-tion. Bleomycin sensitizes lung tissue to oxygen (even to concen-trations of inspired oxygen considered to be safe) and rapid dete-rioration of pulmonary function with post-operative pulmonary fibrosis can occur. PRIOR OR CONCOm ITANT CHEm OTHERAPy T! WITH OTHER Ag ENTS OR RA­ DIATION THER APy : Can lead to increased hematologic, mucosal and pulmonary toxicities with bleomycin therapy. Doses For more information, refer to the protocols found in the appendix or other dosages/protocols found in numerous references, includ-ing: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). Note : T o reduce the likelihood of pulmonary toxicity developing, a total maximum dosage of 125-200 mg/m2 should not be exceeded. Sm All ANIm Al S:T! For squamous cell carcinomas, lymphomas and other carcinomas: a) 10 U/m2 IV or SC once daily for 3-4 doses, then 10 U/m2 every 7 days. Maximum ac cumulative dose: 200 U/m2 (Ja-cobs, Lumsden et al. 1992) b) 0. 3-0. 5 mg/kg IM, SC or IV (over 10 minutes) once weekly (Kitchell and Dhaliwal 2000)monitoring Efficacy T! Pulmonary T oxicity: Obtain chest films, (baseline and on a regu-T! lar basis—in humans they are recommended q1-2 weeks); lung auscultation (dyspnea and fine rales may be early signs of toxici-ty); other initial signs associated with pulmonary toxicity include pulmonary interstitial edema with alveolar hyaline membrane formation and hyperplasia of type II alveolar macrophages Blood chemistry (encompassing renal and hepatic function T! markers) and hematologic profiles (CBC) may be useful to mon-itor potential renal, hepatic and hematologic toxicities T otal dose accumulation T! Client Information Clients must be informed of the potential toxicities associated T! with therapy and urged to report any change in pulmonary func-tion (e. g., shortness of breath, wheezing) immedi ately Chemistry/Synonyms An antibiotic antineoplastic agent, bleomycin sulfate is obtained from Streptomyces verticullis. It occurs as a cream colored, amor-phous powder that is very soluble in water and spar ingly soluble in alcohol. After reconstitution, the p H of the solution ranges from 4. 5-6. Bleomycin is assayed microbiologically. One unit of bleomycin is equivalent to one mg of the reference Bleomycin A 2 standard. Bleomycin sulfate may also be known as: bleomycin sulphate, bleomycini sulfas, Bileco®, Blanoxan®, Blenamax®, Blenoxane®, Bleo®, Bleo-S®, Bleo-cell®, Bleocin®, Bleolem®, Blio®, Blocamicina®, Bonar®, Oil Bleo®, or Tecnomicina®. Storage/Stability/Compatibility Powder for injection should be kept refrigerated. After reconsti-tuting with sterile saline, water, or dextrose, the resulting solution is stable for 24 hours. Bleomycin is less stable in dextrose solutions than in saline. After reconstituting with normal saline, bleomycin is reportedly stable for at least two weeks at room temperature and for 4 weeks when refrigerated; however, since there are no preserva-tives in the resulting solution, the product is recommended for use within 24 hours. Bleomycin sulfate is reported to be compatible with the following drugs: amikacin sulfate, cis platin, cyclophosphamide, dexametha-sone sodium phosphate, diphenhydramine HCl, doxorubicin, hep-arin sodium, metoclopramide HCl, vinblastine sulfate, and vincris-tine sulfate. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Bleomycin Sulfate Powder for Injection: 15 and 30 units per vial; Blenoxane® (Bristol-Myers On cology); generic; (Rx)

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

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b ROm IDES 107 monitoring Androgenic side effects T! Fluid and electrolyte status, if indicated T! Liver function tests if indicated T! Red blood cell count, indices, if indicated T! Weight, appetite T! Client Information Because of the potential for abuse by humans, anabolic steroids T! are controlled drugs. Boldenone should be kept in a se cure area and out of the reach of children. Contact veterinarian of patient develops yellowing of whites of T! the eyes, or develops a decreased appetite or lethargy. Chemistry/Synonyms An injectable anabolic steroid derived from testosterone, boldenone undecylenate has a chemical name of 17 beta-hydroxyandrosta-1, 4-dien-3-one. The commercially available product is in a sesame oil vehicle. Boldenone undecylenate may also be known as: Ba-29038, bold-enone undecenoate, Equipoise®, or Vebonol®. Storage/Stability/Compatibility Boldenone injection should be stored at room temperature; avoid freezing. Because it is in an oil vehicle, it should not be physically mixed with any other medica tions. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Boldenone Undecylenate for Injection: 25 mg/m L in 10 m L vials; 50 mg/m L in 10 m L and 50 m L vials; Equipoise® (Fort Dodge); (Rx, C-III). Approved for use in horses not to be used for food. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: None bromides pot Assium bromide sodium bromide (broe-mide) antic Onvulsant Prescriber Highlights Primary or adjunctive therapy for seizure disorders in T T dogs; 2nd or 3rd line agent for cats Very long half-life, must give loading dose to see steady-T T state therapeutic levels within a month Most prevalent adverse effect in dogs is sedation, espe-T T cially when used with phenobarbital Cats may develop adverse respiratory effects T T Therapeutic levels in dogs approximately 1-2 mg/m L T T Toxic effects include profound sedation to stupor, ataxia, T T tremors, hind limb paresis, or other CNS manifestations If using sodium bromide (vs. potassium bromide), dosage T T adjustments must be made Uses/Indications Bromides are used both as primary therapy and as adjunctive ther-apy to control seizures in dogs that are not adequately controlled by phenobarbital (or primidone) alone (when steady state trough phe-nobarbital levels are >30 mcg/m L for at least one month). While historically bromides were only recommended for use alone in pa-tients suffering from phenobarbital (or primidone) hepatotoxicity, they are more frequently used as a drug of first choice. Although not frequently used, bromides are also considered suitable by some for use in cats with chronic seizure disorders, but cats may be more susceptible to the drug's adverse effects. Pharmacology/Actions Bromide's anti-seizure activity is thought to be the result of its generalized depres sant effects on neuronal excitability and activity. Bromide ions compete with chloride transport across cell mem-branes resulting in membrane hyperpolarization, thereby raising seizure threshold and limiting the spread of epileptic discharges. Pharmacokinetics Bromides are well absorbed after oral administration, primarily in the small in testine. Bromides are also well absorbed after solutions are administered rectally in dogs (bioavailability of 60-100%). Bromide is distributed in the extracellular fluid and mimics the vol-ume of distribution of chloride (0. 2-0. 4 L/Kg). It is not bound to plasma proteins and readily enters the CSF (in dogs: 87% of serum concentration; in humans: 37%). Bromides enter maternal milk (see Reproductive Safety below). Bromides are principally excreted by the kidneys. The half-life in dogs has been reported to be from 16-25 days; cats, 10 days; and humans, 12 days. Contraindications/Precautions/Warnings Older animals and those with additional diseases, may be prone to intolerance (see Adverse Effects below) at blood levels that are easily tolerable by younger, healthier dogs. Patients with renal dysfunc-tion may need dosage adjustments. Adverse Effects A transient sedation (lasting up to 3 weeks) is commonly seen in dogs receiving bromides. Serum concentrations of bromide above 15 m Mol/L (150 mg/d L) are considered “toxic” by some, but many dogs apparently tolerate levels of up to 30 m Mol/L. T oxicity gener-ally presents as profound sedation to stupor, ataxia, tremors, hind limb pare sis, or other CNS manifestations. Pancreatitis has been reported in dogs receiving combination ther apy of bromides with either primidone or phenobarbital; however, since this effect has been reported with both primidone and phenobarbital, its direct re-lationship with bromide is unknown. Additional poten tial adverse effects reported include: polyphagia, polydipsia, polyuria, anorexia, vomiting, and con stipation. Pruritic dermatitis and paradoxical hy-peractivity are rarely reported. If administering an oral loading dose of potassium bromide, acute GI upset may occur if given too rapidly. Potentially, large loading doses could affect serum potassium levels in patients re-ceiving potassium bromide. If the patient cannot tolerate the gastrointestinal effects (vomit-ing) of potassium bromide and divided doses with food do not al-leviate the problem, switching to sodium bromide may be tried. Lower respiratory effects (cough, dyspnea) have been associated with bromide therapy in cats. Peribronchial infiltrates may be seen on radiographs and dyspnea may be serious or fatal. Signs appear to be reversible in most cats once bromides are discontinued. Other adverse effects in cats include polydipsia, sedation, and weight gain.

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

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b ROm OCRIPTINE m ESyl ATE 109 Client Information Clients must be committed to administering doses of anticon-T! vulsant medica tions on a regular basis. Lack of good compliance with dosing regimens is a major cause of thera peutic failures with anti-seizure medications. If a dose is missed, give it when remem-bered; a dose may be doubled the next day, but should preferably be separated by several hours to reduce the chance for gastroin-testinal upset. Clients should also understand and accept that this treatment in-T! volves using a non-approved “drug. ” Dose measurements of bromide solutions should be done with a T! needle-less syringe or other accurate measuring device. The dose may either be sprin kled on the dog's food (assuming he/she con-sumes it entirely) or squirted in the side of the mouth. T oxic effects (T! e. g., profound sedation, ataxia, stupor, GI effects) should be explained to the owner and if they occur, they should be reported to the veterinarian. Dogs that cannot tolerate the gastrointestinal effects (vomiting) T! of potassium chloride with single daily doses may better tolerate doses divided through the day given with food. Clients should not alter diet without first consulting with veterinarian and to avoid giving dogs salty treats (e. g., pig ears). Chemistry Potassium bromide occurs as white, odorless, cubical crystals or crystalline powder. One gram will dissolve in 1. 5 m L of water. Potassium bromide contains 67. 2% bromide. Each gram contains 8. 4 m Eq (m Mol) of potassium and bromide. Sodium bromide occurs as white, odorless, cubic crystals or granular powder. One gram will dis solve in 1. 2 m L of water. Sodium bromide contains 77. 7% bromide. Because of the different molecular weights of sodium and po-tassium, with respect to actual bromide content, sodium bromide solutions of 250 mg/m L contain about 20% more bromide than potassium bromide 250 mg/m L solution. This is generally not clini-cally significant unless changing from one salt to another for a given patient. Storage/Stability/Compatibility Store in tight containers. Solutions may be stored for up to one year in clear or brown, glass or plastic containers at room temperature. Refrigerating the solution may help reduce the change for micro-bial growth, but may cause crystals or precipitants to form. Should precipitation occur, warming the solution should resolubolize the bromide. Bromides can precipitate out alkaloids in solution. Mixing with strong oxidizing agents can liberate bromine. Metal salts can pre-cipitate solutions containing bromides. Sodium bromide is hygro-scopic; potassium bromide is not. Dosage Forms/Regulatory Status Neither potassium or sodium bromide are available in approved dosage forms in North America. Reagent grade or USP grade may be obtained from various chemical supply houses to compound an acceptable oral product. If purchasing a reagent grade, specify American Chemical Society (ACS) grade. At a concentration of 250 mg/m L, 25 grams of potassium bromide are weighed and add a sufficient amount of distilled water to a final volume of 100 m L; potassium bromide dissolves easily in water, sodium bromide may take longer to dissolve. Flavoring agents are not usually necessary for patient acceptance. bromocriptine mesyl A te (broe-moe-krip-teen) Parlodel® d Opamine ag Onist/pr Olactin inhibit Or Prescriber Highlights Dopamine agonist & prolactin inhibitor occasionally used T T in dogs for pregnancy termi nation or pseudopregnancy; in horses for pituitary adenomas; in cats for acromegaly Many adverse effects possible; GI, CNS depression & T T hypotension are most likely; much more likely to cause emesis in dogs than cabergoline Interferes with lactation T T Uses/Indications Bromocriptine may potentially be of benefit in treating acromega-ly/pituitary ade nomas or pseudopregnancy in a variety of species. However, because of adverse effects, its potential value for treating hyperadrenocorticism in dogs is low. It has been used in dogs for pregnancy termi nation and pseudopregnancy. Pharmacology/Actions Bromocriptine exhibits multiple pharmacologic actions. It inhibits prolactin release from the anterior pituitary thereby reducing se-rum prolactin. The mechanism for this action is by a direct effect on the pituitary and/or stimulating postsynaptic dopamine recep-tors in the hypothalamus to cause release of prolactin-inhibitory factor. Bromocriptine also activates dopaminergic receptors in the neostriatum of the brain. Pharmacokinetics In humans, only about 28% of a bromocriptine dose is absorbed from the gut and, due to a high first-pass effect, only about 6% reaches the systemic circulation. Distribution char acteristics are not well described but in humans, it is highly bound (90-96%) to serum albu min. Bromocriptine is metabolized by the liver to inac-tive and non-toxic metabolites. It has a bipha sic half-life; the alpha phase is about 4 hours and the terminal phase is about 15 hours, but one source says 45-50 hours. Contraindications/Precautions/Warnings Bromocriptine is generally contraindicated in patients with hyper-tension. It should be used with caution in patients with hepatic dis-ease as metabolism of the drug may be reduced. Adverse Effects Bromocriptine may cause a plethora of adverse effects that are usually dose related and minimized with dosage reduction. Some more likely possibilities include: gastrointestinal effects (nausea, vomiting), nervous system effects (sedation, fatigue, etc. ), and hy-potension (particularly with the first dose, but it may persist). At dosages used in dogs, more likely to cause emesis than cabergoline. Reproductive/Nursing Safety Usage during pregnancy is contraindicated in humans, al though documented teratogenicity has not been established. Because bromocriptine interferes with lactation, it should not be used in animals that are nursing.

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110 b UDESONIDE Overdosage/Acute Toxicity Overdosage may cause vomiting, severe nausea, and profound hy-potension. Standardized gut removal techniques should be employed when applicable and cardiovas cular support instituted as needed. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving bromocriptine and may be of significance in veterinary patients: Al COHOl T! : Use with alcohol may cause a disulfiram-type reaction b UTy ROPHENONEST! (e. g., haloperidol, azaperone ), Am ITRIPTyl INE, PHENOTHIAz INES, and RESERPINE : May increase prolactin con-centrations and bromocriptine doses may need to be increased Cy Cl OSPORINET! : May elevate cyclosporine levels ERy THROmy CIN, Cl ARITHROmy CINT! : May increase bromocriptine levels ESTROg ENST! or PROg ESTINS : May inter fere with the effects of bromocriptine ERg OT Al KAl OIDST! : Use of bromocriptine and ergot al kaloids is not recommended; some human patients receiving both have devel-oped severe hyperten sion and myocardial infarction Hy POTENSIVE m EDICATIONS T! : May cause additive hypotension if used with bromocriptine m AO INHIb ITORST! (including amitraz, and maybe selegiline ): Avoid use of bromocriptine with these compounds OCTREOTIDET! : May increase bromocriptine levels Sym PATHOm Im ETICST! (e. g., phenylpropanolamine ): Enhanced bro-mocriptine effects have been reported in humans (rare), includ-ing ventricular tachycardia and cardiac dysfunction Doses DOg S:T! For treatment of pseudocyesis (pseudopregnancy):a) 10-100 mcg/kg PO daily in divided doses until lactation ceases. Vomiting, depression and anorexia are common side effects, usually more problematic than the lactation. (David-son and Feldman 2005) b) 10-100 mcg/kg PO twice daily for 10-14 days. Vomiting is very common; reducing dose and administering after meals may help. (Johnson 2003a) c) 30 mcg/kg PO once daily for 16 days (Root Kustritz 2003) For pregnancy termination after mismating:a) From day 35-45 after LH surge 50-100 mcg/kg PO or IM twice daily for 4-7 days. Not uniformly effective and may cause vomiting at this dosage (a peripheral acting antiemetic 30 minutes before dose may be helpful) (Verstegen 2000) b) As an abortifacient 25 days after LH surge: Cloprostenol at 1 mcg/kg SC q48 hours (every other day) plus bromocriptine at 30 mcg/kg PO q24h (every day) (Johnson 2003a) CATS:T! For adjunctive treatment of acromegaly:a) Initial dose of 0. 2 mg (total dose); may reduce insulin require-ments (Jones 2004a) HORSES: T! (Note : ARCI UCGFS Class 2 Drug) For treatment of pituitary adenoma:a) 0. 03-0. 09 mg/kg (30-90 mcg/kg) twice daily PO or SC, but its use is limited (T oribio 2004b) b) 5 mg IM q12h. T o prepare an injectable formulation for IM use from oral dosage forms: Bromocriptine mesylate 70 mg is added to 7 m L of a solution of 80% normal saline and 20% absolute alcohol (v/v). Final concentration is 1% (10 mg/m L) (Beck 1992)monitoring Monitoring is dependent upon the reason for use to evaluate ef-T! ficacy. However, blood pressures should be evaluated if patients have clinical signs associated with hypoten sion. Client Information Have client administer drug with food to reduce GI adverse ef-T! fects. Chemistry/Synonyms A dopamine agonist and prolactin inhibitor, bromocriptine mesy-late is a semisynthetic ergot alkaloid derivative. It occurs as a yel-lowish-white powder and is slightly soluble in water and sparingly soluble in alcohol. Bromocriptine mesylate may also be known as: bromocryptine, brom-ergocryptine, 2-bromergocryptine, bromocriptine methane-sulphonate, bromocriptini mesilas, 2-bromo-alpha-ergocryptine mesylate, 2-bromoergocryptine monomethanesulfonate, or CB-154 (bromocriptine); many trade names are available. Storage/Stability Tablets and capsules should be protected from light and stored in tight containers at temperatures less than 25°C. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Bromocriptine Mesylate Capsules: 5 mg (as base); Parlodel® (San-doz); Bromocriptine Mesylate (Mylan); (Rx) Bromocriptine Mesylate Tablets: 2. 5 mg (as base); Parlodel® Snap Tabs (Sandoz); Bromocriptine Mesylate (Mylan) (Rx) budesonide (bue-des-oh-nide) Entocort EC® gluc Oc Ortic Oid Prescriber Highlights Orally administered glucocorticoid with limited systemic T T glucocorticoid effects; may be useful in treating IBD in small animals that are either refractory to, or intolerant of, systemic steroids Limited veterinary experience T T Drug interactions (CYP3A inhibitors, antacids) T T Expense may be an issue; may need to be compounded T T to smaller dosage strengths Uses/Indications While there are inhalational forms of the medication for treating asthma or allergic rhinitis, most veterinary interest involves its po-tential oral use to treat inflammatory intestinal diseases in small ani-mals that are either refractory to, or intolerant of, systemic steroids. In humans, oral budesonide is indicated for Crohn's disease. Pharmacology/Actions Budesonide is a potent glucocorticoid (15X more potent than pred-nisolone) with high topical activity. It has weak mineralocorticoid activity. By delaying dissolution until reaching the duodenum and

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b UDESONIDE 111 subsequent controlled release of the drug, the drug can exert its topical antiinflammatory activity in the intestines. While the drug is absorbed from the gut into the portal circulation, it has a high first-pass metabolism effect through the liver that reduces sys-temic blood levels and resultant glucocorticoid effects of the drug. However, significant suppression of the HPA-axis does occur in pa-tients taking the drug. Pharmacokinetics Budesonide's pharmacokinetics have been reported in dogs. The drug has a bioavailability of 10- 20%. When dosed at 10 mcg/kg, half-life is about 2 hours and clearance 2. 2 l/hr/kg. At 100 mcg/kg, half-life is slightly prolonged to 2-3 hours. Upon oral administration of the commercially available product in humans, budesonide is nearly completely absorbed from the gut, but time to achieve peak concentrations are widely variable (30-600 minutes). The presence of food in the gut may delay absorption, but does not impact the amount of drug absorbed. Because of a high first-pass effect, only about 10% of a dose is systemically bio-available in healthy adults. In patients with Crohn's disease, oral bioavailability may be twice that initially, but with further dosing, reduces to amounts similar to healthy subjects. Budesonide's mean volume of distribution in humans ranges from 2. 2-3. 9 L/kg. The drug is completely metabolized and these metabolites are excreted in the feces and urine. Budesonide's terminal half-life is about 4 hours. Contraindications/Precautions/Warnings Budesonide is contraindicated in patients hypersensitive to it. Because budesonide can cause systemic corticosteroid effects, it should be used with caution in any patient where glucocorticoid therapy may be problematic including those with GI ulcers, active infections, diabetes mellitus, or cataracts. Adverse Effects There are limited reports of the clinical use of budesonide in small animals and the determination of the drug's adverse effect profile is ongoing. Steroid hepatopathy is possible. In humans, oral budes-onide is generally well tolerated and glucocorticoid adverse effects occur infrequently when the drug is used for courses of therapy of no more than 8 weeks duration. Patients with moderate to severe hepatic dysfunction may be more likely to develop signs associated with hypercorticism. Because budesonide does suppress the HPA-axis, animals un-dergoing stressful procedures such as surgery, should be considered for exogenous steroid administration. Reproductive/Nursing Safety In humans, the FDA categorizes budesonide as a category C drug for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). Like other corticosteroids, budesonide has been demon-strated to be embryocidal and teratogenic in rats and rabbits. Specific data on budesonide levels in maternal milk are not avail-able and the manufacturer warns against use by nursing women; however, because of the drugs high first pass effect, the amounts are unlikely to be of clinical significance to nursing animal offspring. Overdosage/Acute Toxicity Acute, oral overdoses are unlikely to be of much concern although doses of 200 mg/kg were lethal in mice. Gut evacuation should be considered for massive overdoses. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving budesonide and may be of significance in veterinary patients: ERy THROmy CIN, CIm ETIDINE, KETOCONAz Ol E, ITRACONAz Ol E, Fl UCON­T! Az Ol E, DIl TIAz Em, g RAPEFRUIT JUICE POWDER, etc: Because the he-patic enzyme CYP3A extensively metabolizes budesonide, drugs that inhibit this isoenzyme can significantly increase the amount of drug that enters the systemic circulation. Ketoconazole given with budesonide may increase the area under the curve (AUC) of budesonide by eight fold. ORAl ANTACIDST! : Because the dissolution of the drug's coating is p H dependent, oral antacids should not be given at the same time as the drug. Other drugs that potentially would increase gastric p H (e. g., omeprazole, ranitidine, etc. ) apparently do not signifi-cantly impact the oral pharmacokinetics of the drug. laboratory Considerations While no specific laboratory interactions were located, budes-T! onide could potentially alter laboratory test results similarly to other corticosteroids. Doses DOg ST! For treatment of IBD:a) 1 mg PO once daily for small dogs and 2 mg PO once daily for large dogs (Mackin 2002) b) 3 mg/m2 (0. 5-3 mg per dog depending on body weight) PO once daily or every other day (Gaschen 2006) CATS:T! For treatment of IBD:a) 1 mg PO once daily (Mackin 2002) monitoring Efficacy T! Adverse effects T! Client Information Do not open the capsule unless your veterinarian instructs you to T! do so; do not crush or allow animal to chew capsules This drug must be given as prescribed to be effective, do not stop T! therapy without contacting your veterinarian If animal exhibits increased thirst or appetite or their coat chang-T! es, contact your veterinarian Chemistry/Synonyms Budesonide, a non-halogenated glucocorticoid, occurs as a white to off-white, odorless, tasteless powder. It is practically insoluble in water, freely soluble in chloroform and sparingly soluble in alcohol. The commercially available capsules contain a granulized micron-ized form of the drug that is coated to protect from dissolution in gastric juice, but will dissolve at p H >5. 5. In humans, this p H usu-ally corresponds with the drug reaching the duodenum. Budesonide may also be known as S 1320, Entocord®, Entocort EC®, Pulmicort®, and Rhinocort®. Storage/Stability Budesonide oral capsules should be stored in tight containers at room temperature. Exposures to temperatures as low as 15°C (59°F) and as high as 30°C (86°F) are permitted. If reformulating into smaller capsules, do not alter (damage) the micronized enter-ic-coated sugar spheres inside of the capsules.

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

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b UPRENORPHINE HCl 113 Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving buprenorphine and may be of significance in veterinary patients: ANESTHETICS, l OCAl T! (mepivacaine, bupivacaine ): May be potenti-ated by concomitant use of buprenor phine ANTICONVUl SANTST! (phenobarbital, phenytoin ): May decrease plasma buprenorphine levels b ENz ODIAz EPINEST! : Case reports of humans developing respira-tory/cardiovascular/CNS depression; use with caution CNS DEPRESSANTST! (e. g., anesthetic agents, antihistamines, phenoth­ iazines, barbiturates, tranquilizers, alcohol, etc. ): May cause increased CNS or respiratory depression when used with buprenorphine ERy THROmy CINT! : Can increase plasma buprenorphine levels FENTANyl T! (and other pure opiate agonists ): Buprenorphine may potentially antagonize some analgesic effects ( Note : This is con-troversial), but may also reverse some of the sedative and respira-tory depressant effects of pure agonists HAl OTHANET! : Potentially can increase buprenorphine effects KETOCONAz Ol E, ITRACONAz Ol E, Fl UCONAz Ol ET! : Can increase plasma buprenorphine levels m ONAm INE Ox IDASE T! (m AO) IN HIb ITORS (e. g., selegiline, amitraz ): Pos-sible additive effects or increased CNS depression NAl Ox ONET! : May reduce analgesia associated with high dose buprenorphine PANCURONIUm T! : If used with buprenorphine may cause increased conjunctival changes RIFAm PINT! : Potentially decrease plasma buprenorphine concentrations Doses DOg S:T! For analgesia: a) 0. 005-0. 02 mg/kg IM, IV or SC q6-12h (Hendrix and Han-sen 2000) b) 0. 01-0. 015 mg/kg IM, IV (may also be given orally) (Mathews 1999) c) 0. 005-0. 03 mg/kg IV, IM, SC, epidural (Boothe 1999) d) 0. 006-0. 02 mg/kg IV, IM, SQ; duration of effect 6-12 hours and is a relatively effective analgesic, but may be difficult to reverse with naloxone if untoward effects are seen. (Perkows-ki 2006b) CATS:T! For analgesia: a) 0. 005-0. 01 mg/kg IM, IV or SC q6-12h (Hendrix and Han-sen 2000) b) 0. 01-0. 03 mg/kg PO transmucosally (squirted directly into the mouth) q8h (Lichtenberger 2006e) c) 0. 01-0. 03 mg/kg IM, IV, SC q6-8h; 0. 01-0. 03 mg/kg PO q6-12h (Hansen 2003a) d) 0. 01-0. 03 mg/kg IM, IV, Buccal. Effects may last up to 6 hours. Buccal use is well accepted by cats. (Robertson and Lascelles 2003) FERRETS:T! a) 0. 01-0. 05 mg/kg SC or IM 2-3 times daily (Williams 2000) HORSES : T! (Note : ARCI UCGFS Class 2 Drug) For neuroleptanalgesia: a) 0. 004 mg/kg IV (given with acepromazine 0. 02 mg/kg) (Thurmon and Benson 1987)b) 0. 006 mg/kg IV (given with xylazine 0. 07 mg/kg) (Thurmon and Benson 1987) RAbb ITS/RODENTS/Sm All m Amm Al S:T! As an analgesic (for control of acute or chronic visceral pain): a) Rabbits: 0. 02-0. 05 mg/kg SC or IM q6-12h; 0. 5 mg/kg per rectum q12h Rodents: 0. 1-3 mg/kg IM or SC q6-12h (Huerkamp 1995) b) Rabbits: 0. 01-0. 05 mg/kg SC, IM or IV q6-12h; 0. 5 mg/kg rectally q12h (Ivey and Morrisey 2000) c) Guinea pigs: 0. 05 mg/kg SC or IV q8-12h Mice: 0. 05-0. 1 mg/kg SC q12h. Rats: 0. 01- 0. 05 mg/kg SC or IV q8-12h or 0. 1-0. 25 mg/kg PO q8-12h. (Adamcak and Otten 2000) monitoring Analgesic efficacy T! Respiratory status T! Cardiac status T! Client Information This agent should be used parenterally in an inpatient setting or T! with direct professional supervision Buccal/SL dosing may be performed at home, but pre-measur-T! ing dosages in syringes (if using the injection orally) should be considered Chemistry/Synonyms A thebaine derivative, buprenorphine is a synthetic partial opiate agonist. It occurs as a white, crystalline powder with a solubility of 17 mg/m L in water and 42 mg/m L in alcohol. The com mercially available injectable product (Buprenex®—Norwich Eaton) has a p H of 3. 5-5 and is a ster ile solution of the drug dissolved in D 5W. T erms of potency are expressed in terms of buprenor phine. The commercial product contains 0. 324 mg/m L of buprenorphine HCl, which is equivalent to 0. 3 mg/m L of buprenorphine. Buprenorphine HCl may also be known as: buprenorphini hydro-chloridum, CL-112302, NIH-8805, UM-952; Anorfin®, Buprenex®, Buprine®, Finibron®, Magnogen®, Nopan®, Norphin®, Pentorel®, Prefin®, Suboxone®, Subutex®, Temgesic®, or Temgesic-n X®. Storage/Stability/Compatibility Buprenorphine should be stored at room temperature (15-30° C). T emperatures above 40° C or below freezing should be avoided. Buprenorphine products should be stored away from bright light. Autoclaving may considerably decrease drug potency. The drug is stable between a p H of 3. 5-5. Buprenorphine is reported to be compatible with the following IV solutions and drugs: acepro mazine, atropine, diphenhydramine, D5W, D 5W and normal saline, droperidol, glycopyrrolate, hy-droxyzine, lactated Ringer's, normal saline, scopolamine, and xyla-zine. Buprenorphine is reportedly incompatible with diazepam and lorazepam. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Buprenorphine HCl for Injection: 0. 324 mg/m L (equivalent to 0. 3 mg/m L buprenorphine); 1 m L amps & Carpuject; Buprenex® (Reckitt Benkhiser); Buprenorphine Hydrochloride (Abbott); (Rx, C-III)

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114 b USPIRONE HCl Buprenorphine HCl Sublingual Tablets: 2 mg (as base), & 8 mg (as base); Subutex® (Reckitt Benkhiser); (Rx, C-III) Buprenorphine HCl Combinations: Sublingual Tablets: 2 mg bu-prenorphine base/0. 5 mg naloxone; 8 mg buprenorphine base/2 mg naloxone; Suboxone® (Reckitt Benkhiser); (C-III) buspirone hcl (byoo-spye-rone) Bu Spar® an Xi Olytic Prescriber Highlights Non-benzodiazepine anxiolytic agent used in dogs & cats T T May take a week or more to be effective; not appropriate T T for acute treatment of situational anxieties Use with caution in patients with severe hepatic or renal T T disease Adverse Effects relatively uncommon; cats may exhibit T T behavior changes Uses/Indications Buspirone may be effective in treating certain behavior disorders in dogs and cats, principally those that are fear/phobia related and especially those associated with social interactions. Buspirone may also be useful for urine spraying or treatment of motion sickness in cats. Pharmacology/Actions Buspirone is an anxioselective agent. Unlike the benzodiazepines, buspirone does not possess any anticonvulsant or muscle relaxant activity and little sedative or psychomotor im pairment activity. Buspirone does not share the same mechanisms as the benzodiaz-epines (does not have significant affinity for benzodiazepine recep-tors and does not affect GABA binding). It appears to act as a partial agonist at serotonin (5-HT1A) receptors and as an agonist/antago-nist of dopamine (D2) receptors in the CNS. In neurons, buspirone slows the neuronal flow depletion of serotonin stores. Pharmacokinetics In humans, buspirone is rapidly and completely absorbed but a high first pass effect limits systemic bioavailability to approximately 5%. Binding to plasma proteins is very high (95%). In rats, high-est tissue concentrations are found in the lungs, kidneys, and fat. Lower levels are found in the brain, heart, skeletal muscle, plasma and liver. Both buspirone and its metabolites are distributed into maternal milk. The elimination half-life (in humans) is about 2- 4 hours. Buspirone is hepatically metabolized to several metabolites (including one that is active: 1-PP). These metabolites are excreted primarily in the urine. Contraindications/Precautions/Warnings Buspirone should be used with caution with either significant renal or hepatic disease. Because buspirone may reduce disinhibition, it should be used with caution in aggressive animals. While buspirone has far less sedating properties than many other anxiolytic drugs, it should be used with caution in working dogs. Because buspirone often takes a week or more for effect, it should not be used as the sole therapy for situational anxieties. Adverse Effects Adverse effects are usually minimal in animals with buspirone and it is generally well tolerated. Bradycardia, GI disturbances and ste-reotypic behaviors are possible. Cats may demonstrate increased affection. In multi-cat households, cats that have previously been extremely timid in the face of repeated aggression from other cats may, after receiving buspirone begin turning on their at tacker. The most likely adverse effect profile seen with buspirone in hu-mans in cludes dizziness, headache, nausea/anorexia, and restless-ness; other neurologic effects (including sedation) may be noted. Rarely, tachycardias and other cardiovascular clinical signs may be present. Reproductive/Nursing Safety While the drug has not been proven safe during pregnancy, doses of up to 30 times the labeled dosage in rabbits and rats demonstrated no teratogenic effects. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Buspirone and its metabolites have been detected in the milk of lactating rats; avoid use during nursing if possible. Overdosage/Acute Toxicity Limited information is available. The oral LD 50 in dogs is 586 mg/ kg. Oral overdoses may produce vomiting, dizziness, drowsiness, miosis and gastric distention. Standard overdose protocols should be followed after ingestion has been determined. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving buspirone and may be of significance in veterinary patients: CNS DEPRESSANTST! : Potentially could cause increased CNS depression DIl TIAz Em T! : May cause increased buspirone plasma levels and ad-verse effects ERy THROmy CINT! : May cause increased buspirone plasma levels and adverse effects g RAPEFRUIT JUICE T! (powder ): May cause increased buspirone plasma levels and adverse effects KETOCONAz Ol E, ITRACONAz Ol ET! : May cause increased buspirone plasma levels and adverse effects m ONOAm INE Ox IDASE INHIb ITORST! (e. g., selegiline, amitraz ): Use with buspirone is not recommended because dangerous hypertension may occur RIFAm PINT! : May cause decreased buspirone plasma levels TRAz ODONET! : Use with buspirone may cause increased ALT VERAPAm Il T! : May cause increased buspirone plasma levels Doses DOg S:T! For low-grade anxieties and fears: a) 1 mg/kg PO q8-24h (mild anxiety); 2. 5-10 mg per dog PO q8-24h (mild anxiety); 10-15 mg per dog PO q8-12h (more severe anxiety, thunderstorm phobia) (Overall 2000) b) 1-2 mg/kg PO q12h; 5-15 mg per dog PO q8-12h (Siebert 2003c) c) 5-10 mg (total dose) PO q8-12h (Reisner and Houpt 2000)

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b USUl FAN 115 d) For global anxiety: 0. 5-2 mg/kg PO q8-12h; may take 2-4 weeks until effect. (Horwitz 2006) e) 1 mg/kg PO q8-12h; most useful in social phobias; may also be useful for panic disorders (Virga 2005b) CATS:T! For adjunctive treatment of low-grade anxieties/fears, spraying, overgrooming: a) 0. 5-1 mg/kg PO q8-12h; 2. 5-5 mg per cat PO q8-12h for 6-8 weeks; some cats do well on once daily dosing (Overall 2000) b) 2. 5-5 mg (total dose) PO once a day to 3 times a day (Seksel 2003) c) 2. 5-5 mg per cat PO twice daily (Reisner and Houpt 2000), (Crowell-Davis 1999) d) 0. 5-1 mg/kg PO q12h; 2. 5-7. 5 mg per cat PO q12h (Siebert 2003c) e) 0. 5-1 mg/kg PO q8-12h; most useful in social phobias; may also be useful for panic disorders (Virga 2005b) monitoring Efficacy T! Adverse effect profiles T! Chemistry/Synonyms An arylpiperazine derivative anxiolytic agent, buspirone HCl dif-fers structurally from the benzodiazepines. It occurs as a white, crystalline powder with solubilities at 25°C of 865 mg/m L in water and about 20 mg/m L in alcohol. Buspirone HCl may also be known as MJ-9022; many trade names are available. Storage/Stability/Compatibility Buspirone HCl tablets should be stored in tight, light-resistant con-tainers at room temperature. After manufacture, buspirone tablets have an expiration date of 36 months. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Buspirone HCl Tablets: 5 mg (4. 6 mg as base), 7. 5 mg (6. 85 mg as base), 10 mg (9. 1 mg as base), 15 mg (13. 7 mg as base) and 30 mg (27. 4 mg as base); Bu Spar® (Bristol-Myers Squibb); generic; (Rx) busulf An (byoo-sul-fan) Myleran®, Busulfex® antine Oplastic Prescriber Highlights Antineoplastic used in treating chronic granulocytic leu-T T kemias in small animals Myelosuppression; may be severe T T May increase uric acid levels T TUses/Indications Busulfan may be useful in the adjunctive therapy of chronic granu-locytic leukemias or polycythemia vera in small animals. Not com-monly used in veterinary medicine. Pharmacology/Actions Busulfan is a bifunctional alkylating agent antineoplastic and is cell cycle-phase nonspecific. The exact mechanism of action has not been determined but is thought to be due to its alkylating, cross-linking of strands of DNA and myelosuppressive proper-ties. Busulfan's primary activity is against cells of the granulocytic series. Pharmacokinetics Busulfan is well absorbed after oral administration. Distribution characteristics are not well described but in humans, drug concen-trations in the CSF are nearly equal to those found in plasma. It is unknown whether the drug enters maternal milk. Busulfan is rap-idly, hepatically metabolized to at least 12 different metabolites that are slowly ex creted into the urine. In humans, serum half-life of busulfan averages about 2. 5 hours. Contraindications/Precautions/Warnings Busulfan is contraindicated in patients who have shown resistance to the drug in the past or are hypersensitive to it. Only veterinar-ians with the expe rience and resources to monitor the toxicity of this agent should administer this drug. The risk versus benefits of therapy must be carefully considered in patients with preexisting bone marrow depression or concurrent infections. Additive bone marrow depression may occur in patients undergoing concomitant radiation therapy. Adverse Effects The most commonly associated adverse effect seen with busulfan ther apy is myelosuppression. In humans, anemia, leukopenia, and thrombocytopenia may be observed. Onset of leukopenia is gen-erally 10-15 days after initiation of therapy and leukocyte nadirs occur ring on average around 11-30 days. Severe bone marrow de-pression can result in pancytopenia that may take months to years for recovery. In humans, bronchopulmonary dysplasia with pulmo-nary fi brosis, uric acid nephropathy, and stomatitis have been re-ported. These effects are uncommon and generally associated with chronic, higher dose therapy. Reproductive/Nursing Safety Busulfan's teratogenic potential has not been well documented, but it is mutagenic in mice and may potentially cause a variety of fetal abnormalities. It is generally recommended to avoid the drug dur-ing pregnancy, but because of the seriousness of the diseases treated with busulfan, the potential benefits to the mother must be consid-ered. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) It is unknown if busulfan enters milk; avoid nursing if the dam is receiving the drug. Overdosage/Acute Toxicity There is limited experience with busulfan overdoses. The LD50 in mice is 120 mg/kg. Chronic overdosage is more likely to cause se-rious bone marrow suppression than is an acute overdose; how-ever, any overdose, should be treated seriously with standard gut emptying protocols used when appropriate and supportive therapy initiated when required. There is no known specific antidote for busulfan intoxication.

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

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b UTORPHANOl TARTRATE 117 Besides the analgesic qualities of butorphanol, it possesses sig-nificant antitussive activity. In dogs, butorphanol has been shown to elevate CNS respiratory center threshold to CO 2 but, unlike opi-ate agonists, not depress respiratory center sensitivity. Butorphanol, unlike morphine, apparently does not cause histamine release in dogs. CNS depression may occur in dogs, while CNS excitation has been noted (usually at high doses) in horses and dogs. Although possessing less cardiovascular effects than the classical opiate agonists, butorphanol can cause a decrease in cardiac rate secondary to increased parasympathetic tone and mild decreases in arterial blood pressures. The risk of causing physical dependence seems to be minimal when butorphanol is used in veteri nary patients. Pharmacokinetics Butorphanol is absorbed completely in the gut when administered orally but, because of a high first-pass effect, only about 1/6th of the administered dose reaches the systemic cir culation. The drug has also been shown to be completely absorbed following IM admin-istration. Butorphanol is well distributed, with highest levels (of the par-ent compound and metabolites) found in the liver, kidneys, and intestine. Concentrations in the lungs, endocrine tissues, spleen, heart, fat tissue and blood cells are also higher than those found in plasma. Approximately 80% of the drug is bound to plasma pro-teins (human data). Butorphanol will cross the placenta and neo-natal plasma levels have been roughly equivalent to maternal levels. The drug is also distributed into maternal milk. Butorphanol is metabolized in the liver, primarily by hydroxy-lation. Other methods of metabolism include N-dealkylation and conjugation. The metabolites of butorphanol do not exhibit any analgesic activity. These metabolites and the parent compound are mainly excreted into the urine (only 5% is excreted unchanged), but 11 -14% of a dose is excreted into the bile and eliminated with the feces. Following IV doses in horses, the onset of action is approximate-ly 3 minutes with a peak analgesic effect at 15-30 minutes. The du-ration of action in horses may be up to 4 hours after a single dose. Contraindications/Precautions/Warnings The drug is contraindicated in patients having known hypersensi-tivity to it. All opiates should be used with caution in patients with hypothy roidism, severe renal insufficiency, adrenocortical insuffi-ciency (Addison's), and in geriatric or severely debilitated patients. Like other opiates, butorphanol must be used with extreme caution in patients with head trauma, in creased CSF pressure or other CNS dysfunction (e. g., coma). Dogs with MDR1 mutations (many Collies, Australian shep-herds, etc. ) may develop a more pronounced sedation that persists longer than normal. It may be prudent to reduce initial doses by 25% to determine the reaction of a patient identified or suspected of having this mutation. The manufacturer states that butorphanol “should not be used in dogs with a history of liver dis ease” and, because of its effects on suppressing cough, “it should not be used in conditions of the lower respiratory tract associated with copious mucous production. ” The drug should be used cau tiously in dogs with heartworm disease, as safety for butorphanol has not been established in these cases. Adverse Effects Adverse effects reported in dogs/cats include sedation, excitement, respiratory depression, ataxia, anorexia or diarrhea (rarely). Adverse effects may be less severe than those seen with pure agonists. Adverse effects seen in horses (at usual doses) may include a transient ataxia and sedation, but ex citement has been noted as well (see below). Although reported to have minimal effects on the GI, butorphanol has the potential to decrease intestinal motility and ileus can occur. Horses may exhibit CNS excitement (tossing and jerking of head, increased ambulation, augmented avoidance re-sponse to auditory stim uli) if given high doses (0. 2 mg/kg) IV rap-idly. Very high doses IV (1-2 mg/kg) may lead to the de velopment of nystagmus, salivation, seizures, hyperthermia and decreased GI motility. These effects are considered transitory in nature. Reproductive/Nursing Safety Although no controlled studies have been performed in domestic animals or humans, the drug has exhibited no evidence of terato-genicity or of causing impaired fertility in laboratory animals. The manufacturer, however, does not recommend its use in pregnant bitches, foals, weanlings (equine), and breeding horses. In hu-mans, the FDA categorizes this drug as category C 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 uncovered some risk, but these drugs appear to be safe in dogs and cats; or these drugs are safe if they are not administered when the animal is near term. ) Butorphanol can be distributed into milk, but not in amounts that would cause concern in nursing offspring. Overdosage/Acute Toxicity Acute life-threatening overdoses with butorphanol should be un-likely. The LD 50 in dogs is reportedly 50 mg/kg. However, because butorphanol injection is available in two dosage strengths (0. 5 mg/m L and 10 mg/m L) for veterinary use, the possibility exists that inadvertent over doses may occur in small animals. It has been sug-gested that animals exhibiting clinical signs of over dose (CNS ef-fects, cardiovascular changes, and respiratory depression) be treat-ed immediately with intravenous naloxone. Additional supportive measures (e. g., fluids, O 2, vasopressor agents, and me chanical ven-tilation) may be required. Should seizures occur and persist, diaz-epam may be used for con trol. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving butorphanol and may be of significance in veterinary patients: OTHER CNS DEPRESSANTS T! (e. g., anesthetic agents, antihistamines, phenoth iazines, barbiturates, tranquilizers, alcohol, etc. ): May cause increased CNS or respiratory depression when used with butor-phanol; dosage may need to be decreased ERy THROmy CINT! : Could potentially decrease metabolism of butor-phanol FENTANyl T! (and other pure opiate agonists ): Butorphanol may po-tentially antagonize some analgesic effects ( Note : this is contro-versial), but may also reverse some of the sedative and respiratory depressant effects of pure agonists PANCURONIUm T! If used with butorphanol may cause increased con-junctival changes THEOPHyll INET! : Could potentially decrease metabolism of butorphanol

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118 b UTORPHANOl TARTRATE Doses Note : All doses are expressed in mg/kg of the base activity. If using the human product (Stadol®), 1 mg of tartrate salt = 0. 68 mg base. DOg S:T! As an antitussive: a) 0. 055-0. 11 mg/kg SC q6-12h; treatment should not nor-mally be required for longer than 7 days; or 0. 55 mg/kg PO q6-12h; may increase dose to 1. 1 mg/kg PO q6-12h (The oral doses correspond to one 5 mg tablet per 20 lbs. and 10 lbs. of body weight, respectively); treatment should not nor-mally be required for longer than 7 days (Package Insert; Tor-butrol ®—Fort Dodge) b) 0. 05-1 mg/kg PO q6-12h; goal is to suppress coughing with-out causing excessive seda tion (Johnson 2000) c) 0. 55-1. 1 mg/kg PO as needed (Johnson 2004d) As an analgesic:a) 0. 1-1 mg/kg IM, IV or SC q1-3h (Hendrix and Hansen 2000) b) 0. 2-0. 4 mg/kg SC, IM or IV (use lower dose if given IV); Ef-ficacy is 1-2 hours for mod erate pain and 2-4 hours for mild pain. May give orally at 0. 4 mg/kg to the nearest quarter tablet 3 times a day (Mathews 1999) c) 0. 5-1 mg/kg PO q6-8h (Hardie 2000) d) 0. 1-0. 5 mg/kg IV, IM, SQ; provides only mild to moderate analgesia (good visceral analgesia); duration of sedative ac-tion 2-4 hours, but analgesic action may be 1 hour or less (Perkowski 2006b) e) As a constant rate infusion: 0. 1-0. 4 mg/kg/hr; occasionally used for abdominal pain (Hellyer 2006) As a preanesthetic:a) 0. 05 mg/kg IV or 0. 4 mg/kg SC, IM (Morgan 1988) b) 0. 2-0. 4 mg/kg IM (with acepromazine 0. 02-0. 04 mg/kg IM) (Reidesel) As an anti-emetic prior to cisplatin treatment: a) 0. 4 mg/kg IM H hour prior to cisplatin infusion (Klausner and Bell 1988) CATST! : As an analgesic: a) 0. 1-1 mg/kg IM, IV or SC q1-3h (Hendrix and Hansen 2000) b) 0. 2-0. 4 mg/kg SC, IM or IV (use lower dose if given IV); Ef-ficacy is 1-2 hours for mod erate pain and 2-4 hours for mild pain. May give orally at 0. 4 mg/kg to the nearest quarter tablet 3 times a day (Mathews 1999) c) 0. 5-1 mg/kg PO q6-8h (Hardie 2000) d) 0. 1-0. 5 mg/kg IV, IM, SQ; provides only mild to moderate analgesia (good visceral analgesia); duration of sedative ac-tion 2-4 hours, but analgesic action may be 1 hour or less (Perkowski 2006b) e) As a postoperative CRI (usually in combination with ket-amine) for mild to moderate pain: Loading dose of 0. 1-0. 2 mg/kg IV, then a CRI of 0. 1-0. 2 mg/kg/hr; Ketamine is used at a loading dose of 0. 1 mg/kg IV with a CRI of 0. 4 mg/kg/hr. When used with an opioid CRI may allow reduction in dosage of both. (Lichtenberger 2006d) As a preanesthetic:a) 0. 2-0. 4 mg/kg IM (with glycopyrrolate 0. 01 mg/kg IM and ketamine 4-10 mg/kg IM) (Reidesel)FERRETS:T! a) As a sedative/analgesic: Butorphanol alone 0. 05-0. 1 mg/kg IM, SC. Butor phanol/Xy-lazine: Butorphanol 0. 2 mg/kg + Xylazine 2 mg/kg IM For injectable anesthesia: Butorphanol 0. 1 mg/kg, Ketamine 5 mg/kg, medetomidine 80 mcg/kg. Combine in one syringe and give IM. May need to supplement with isoflurane (0. 5-1. 5%) for abdominal sur-gery. (Finkler 1999) b) X ylazine (2 mg/kg) plus butorphanol (0. 2 mg/kg) IM; T elazol (1. 5 mg/kg) plus xylazine (1. 5 mg/kg) plus butorph-anol (0. 2 mg/kg) IM; may reverse xylazine with yohimbine (0. 05 mg/kg IM) (Williams 2000) As an analgesic:a) 0. 05-0. 5 mg/kg SC or IM q4h (Williams 2000) b) For post-op analgesia: 0. 1-0. 2 mg/kg loading dose, then a constant rate infusion of 0. 1-0. 2 mg/kg/hr (Lichtenberger 2006a) RAbb ITS/RODENTS/Sm All m Amm Al S:T! For chemical restraint in rabbits: a) 0. 1-0. 5 mg/kg IV (Burke 1999); (Ivey and Morrisey 2000) For analgesia:a) For postsurgical analgesia in rabbits: 0. 1-0. 5 mg/kg IV or SC q2-4h; lower dosages may be more effective due to “ceiling effect” (Ivey and Morrisey 2000) b) Rabbits: As an analgesic (post-operative pain): 0. 4 mg/kg SC q4-6h; for surgical procedures (in combo with xylazine/ket-amine): 0. 1 mg/kg once IM or SC (Huerkamp 1995) c) Rabbits for post-op analgesia: 0. 1-0. 2 mg/kg loading dose, then a constant rate infusion of 0. 1-0. 2 mg/kg/hr (Lichten-berger 2006a) b IRDS:T! As an analgesic:a) Psittacines: 2-4 mg/kg IM; frequent re-dosing every 2-4 hours is needed to maintain analgesia. If adverse effects are an issue (e. g., respiratory or cardiovascular de pression), may re-verse with naloxone (0. 05-0. 25 mg/kg IM or slow IV) (Clyde and Paul-Murphy 2000) b) 1-2 mg/kg IM (Lichtenberger 2006a) c) 1-4 mg/kg q4h IM, IV, PO (Bays 2006) d) Parrots: 1-3 mg/kg IM (Carpenter 2006) CATTl E:T! As an analgesic: a) For surgery in adult cattle: 20-30 mg IV (jugular) (may wish to pretreat with 10 mg xylazine) (Powers 1985) b) 0. 02-0. 25 mg/kg IV, SQ; 20-30 mg (total dose) IV for an adult animal. Duration of effect is 4 hours. An appropriate withdrawal period is 72 hours for milk, and 4 days for meat. (Walz 2006b) HORSES:T! (Note : ARCI UCGFS Class 3 Drug) As an analgesic:a) 0. 1 mg/kg IV q3-4h; not to exceed 48 hours (Package Insert; Torbugesic®—Fort Dodge) b) For moderate to marked abdominal pain: 0. 01-0. 02 mg/kg IV alone or in combination with xylazine (0. 02-0. 1 mg/kg IM) (Moore 1999)

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b UTORPHANOl TARTRATE 119 c) For colic pain: 5-10 mg (total dose for a 450-500 kg horse) IV combined with 100-200 mg xylazine (total dose). Com-pared to IV bolus, a constant rate infusion of butorphanol at 23. 7 mcg/kg/hr induces fewer GI side effects while providing analgesia. (Zimmel 2003) d) Foals: 0. 1-0. 2 mg/kg IV or IM (Robertson 2003) e) Two studies have looked at butorphanol CRI in horses for post-op pain. 1) Loading dose of 0. 0178 mg/kg (17. 8 mcg/ kg), then a constant rate infusion of 23. 7 mcg/kg/hr; 2) Con-stant rate infusion of 13 mcg/kg/hr (Mogg 2006) As a preanesthetic, outpatient surgery, or chemical restraint:a) 0. 01-0. 04 mg/kg IV (with xylazine 0. 1-0. 5 mg/kg IV) (Ors-ini 1988) b) For field anesthesia: Sedate with xylazine (1 mg/kg IV; 2 mg/kg IM) given 5- 10 minutes (longer for IM route) before induction of anesthesia with ketamine (2 mg/kg IV). Horse must be adequately sedated (head to the knees) before giving the ketamine (ketamine can cause muscle rigidity and sei-zures). If adequate sedation does not occur, either 1) Redose xylazine: up to half the original dose, 2) Add butorphanol (0. 02-0. 04 mg/kg IV). Butor phanol can be given with the original xylazine if you suspect that the horse will be diffi cult to tranquilize (e. g., high-strung Thoroughbreds) or added before the ketamine. This combination will improve induc-tion, increase analgesia and increase recumbency time by about 5- 10 minutes. 3) Diazepam (0. 03 mg/kg IV). Mix the diazepam with the ketamine. This combination will improve induction when sedation is marginal, improve muscle re-laxation during anesthesia and prolong anesthesia by about 5-10 minutes. 4) Guaifenesin (5% solution administered IV to effect) can also be used to increase sedation and muscle relaxation. (Mathews 1999) As an antitussive: a) 0. 02 mg/kg IM two to three times daily (Orsini 1988) REPTIl ES/Am PHIb IANS:T! As an analgesic:a) 0. 05-1 mg/kg q12h IM, IV, PO, SC (up to 20 mg/kg in tor-toises) (Bays 2006) monitoring Analgesic and/or antitussive efficacy T! Respiratory rate/depth T! Appetite and bowel function T! CNS effects T! Client Information Clients should report any significant changes in behavior, appe-T! tite, bowel or urinary function in their animals Chemistry/Synonyms A synthetic opiate partial agonist, butorphanol tartrate is related structurally to mor phine but exhibits pharmacologic actions simi-lar to other partial agonists such as pentazocine or nal buphine. The compound occurs as a white, crystalline powder that is sparingly soluble in water and insoluble in alcohol. It has a bitter taste and a p Ka of 8. 6. The commercial injection has a p H of 3-5. 5. One mg of the tartrate is equivalent to 0. 68 mg of butorphanol base. Butorphanol tartrate may also be known as: levo-BC-2627 (bu-torphanol), Dolorex®, Equanol®, Stadol®, Torbutrol®, Torbugesic®, and Verstadol®. Storage/Stability/Compatibility The injectable product should be stored out of bright light and at room temperature; avoid freezing. The injectable product is reported to be compatible with the fol-lowing IV fluids and drugs: ace promazine, atropine sulfate, chlo-rpromazine, diphenhydramine HCl, droperidol, fentanyl citrate, hy droxyzine HCl, meperidine, morphine sulfate, pentazocine lac-tate, perphenazine, prochlorperazine, promethazine HCl, scopol-amine HBr, and xylazine. The drug is reportedly incompatible with the following agents: dimenhydrinate, and pentobarbital sodium. Dosage Forms/Regulatory Status Note : Butorphanol is a class IV controlled substance. The veterinary products (Torbutrol®, Torbugesic®) strengths are listed as base activ-ity. The human product (Stadol®) strength is labeled as the tartrate salt. VETERINAR y­l Ab El ED PRODUCTS: T! Butorphanol Tartrate Injection: 0. 5 mg/m L (activity as base) in 10 m L vials; Torbutrol® (Fort-Dodge); (Rx, C-IV). Approved for use in dogs. Butorphanol Tartrate Injection: 2 mg/m L (activity as base) in 10 m L vials. Torbugesic-SA® (Fort Dodge); (Rx, C-IV). Approved for use in cats. Butorphanol Tartrate Injection: 10 mg/m L (activity as base) in 10 m L, 50 m L vials; Torbugesic® (Fort-Dodge), Dolorex® (Intervet), Bu-torject® (Phoenix), Torphaject® (Butler); Equanol® (Vedco) generic; (Rx, C-IV). Approved for use in horses not intended for food. Butorphanol Tartrate Tablets: 1 mg, 5 mg, and 10 mg (activity as base) tablets; bottles of 100; Torbutrol® (Fort-Dodge); (Rx, C-IV). Approved for use in dogs. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS:T! Butorphanol Tartrate Injection: 1 mg/m L (as tartrate salt; equiva-lent to 0. 68 mg base) in 1 m L & 2 m L vials; 2 mg/m L (as tartrate salt) in 1 m L, 2 m L, and 10 m L vials; Stadol® (Bristol-Myers Squibb); generic; (Rx, C-IV) Butorphanol Nasal Spray: 10 mg/m L in 2. 5 m L metered dose); ge-neric; (Rx, C-IV) n-Butylscopolammonium Bromide — See the monograph found in the “N's” before neomycin

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120 CAb ERg Ol INE c Abergoline (ka-ber-go-leen) Dostinex® pr Olactin inhibit Or/d Opamine (d2) ag Onist Prescriber Highlights Ergot derivative that may be useful in inducing/ T T synchronizing estrus in dogs & as an abortifacient in dogs or cats Limited clinical experience & published references T T available Appears to be well tolerated in dogs & cats; vomiting T T has been reported Potentially very expensive, particularly in large dogs, T T but generic tablets now available; must usually be compounded Uses/Indications For dogs, cabergoline may be useful for inducing estrus, treatment of primary or secondary anestrus, pseudopregnancy, and pregnancy termination in the second half of pregnancy. Cabergoline may be useful in treating some cases of pituitary-dependent hyperadreno-corticism (Cushing's). In cats, cabergoline, with or without a prostaglandin, may be use-ful for pregnancy termination, particularly earlier in pregnancy. Preliminary work has been done in psittacines (primarily Cockatiels) for adjunctive treatment of reproductive-related disor-ders, particularly persistent egg laying. In humans, cabergoline is indicated for the treatment of disorders associated with hyperprolactenemia or the treatment of Parkinson's disease. Pharmacology/Actions Cabergoline has a high affinity for dopamine2 (D2) receptors and has a long duration of action. It exerts a direct inhibitory effect on the secretion of prolactin from the pituitary. When compared to bromocriptine it has greater D2 specificity, a longer duration of ac-tion, and less tendency to cause vomiting. Pharmacokinetics The pharmacokinetics of cabergoline have apparently not been re-ported for dogs or cats. In humans, the drug is absorbed after oral dosing but its absolute bioavailability is not known. Food does not appear to significantly alter absorption. The drug is only moderately bound to plasma proteins (≈ 50%). Cabergoline is extensively me-tabolized in the liver via hydrolysis; these metabolites and about 4% of unchanged drug are excreted into the urine. Half-life is estimated to be around 60 hours. Duration of pharmacologic action may per-sist for 48 hours or more. Renal dysfunction does not appear to sig-nificantly alter elimination characteristics of the drug. Contraindications/Precautions/Warnings Cabergoline is contraindicated in dogs and cats that are pregnant unless abortion is desired (see indications). Cabergoline should not be used in patients who are hypersensitive to ergot derivatives. Patients that do not tolerate bromocriptine may or may not tolerate cabergoline. In humans, cabergoline is contraindicated in patients who have uncontrolled hypertension. Patients with significantly impaired liver function should receive the drug with caution, and if required, possibly at a lower dosage. When using to induce estrus, it is recommended to wait at least 4 months after the prior cycle to allow the uterus to recover. Adverse Effects Cabergoline is usually well tolerated by animal patients. Vomiting has been reported, but may be alleviated by administering with food. Dogs receiving cabergoline for more than 14 days may exhibit changes in coat color. Human patients have reported postural hypotension, dizziness, headache, nausea and vomiting while receiving cabergoline. Reproductive/Nursing Safety This drug can cause spontaneous abortion in pregnant dogs or cats. In pregnant humans, cabergoline 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. ) Because cabergoline suppresses prolactin, it should not be used in nursing mothers. Overdosage/Acute Toxicity Overdose information is not available for dogs or cats, and remains very limited for humans. It is postulated that cabergoline overdoses in people could cause hypotension, nasal congestion, syncope or hallucinations. Treatment is basically supportive and primarily fo-cuses on supporting blood pressure. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cabergoline and may be of significance in veterinary patients: Hy POTENSIVE DRUg ST! : Because cabergoline may have hypotensive effects, concomitant use with other hypotensive drugs may cause additive hypotension m ETOCl OPRAm IDET! : Use with cabergoline may reduce the efficacy of both drugs and should be avoided PHENOTHIAz INEST! (e. g., acepromazine, chlorpromazine ): Use of caber-goline with dopamine (D2) antagonists may reduce the efficacy of both drugs and should be avoided laboratory Considerations No particular laboratory interactions or considerations were lo-T! cated for this drug. Doses Because of the dosage differences in animals versus human patients and the strength of the commercially available product, a com-pounding pharmacist must usually reformulate this medication. DOg S:T! For estrus induction:a) 5 mcg/kg PO once daily induces fertile proestrus in 4-25 days. (Davidson 2004c) b) 5 mcg/kg PO once daily until an induced proestrus is pro-nounced for 2 days or until onset of estrus (Concannon 2005) c) 0. 6 mcg/kg PO once daily. Make a 10 mcg per m L solution by dissolving commercial tablets in warm distilled water (One 0. 5 mg tablet (500 mcg) per 50 m L of distilled water. ) Give the appropriate dose for the patient within 15 minutes of prepa-ration and discard the remaining solution. Continue until day 2 after the onset of the first signs of proestrus, or until day 42 without signs of proestrus. 81% (22 of 27) of dogs treated at

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CAl CITONIN SAlm ON 121 this low dose showed proestrus between days 4 and 48. (Cirit, Bacinoglu et al. 2006) For treatment of pseudocyesis (pseudopregnancy): 5 mcg/kg once a day PO for 5a) -10 days. (Gobello, Concan-non et al. 2001) b) 5 mcg/kg once a day or every other day SC (likely needs to be compounded). (Davidson 2004c) For pregnancy termination:a) Administer after day 40: 5 mcg/kg PO for 5 days; approxi-mately 50% effective (Romagnoli 2006a) b) Between days 35-45: Cabergoline 5 mcg/kg PO once daily for 7 days in food and cloprostenol at 1 mcg/kg SC (after a tenfold dilution with physiologic saline) on days 1 and 3 given at least 8 hours after food. If pregnancy not terminated by day 8, cabergoline continued (at same dose) until day 12. (Corrada, Rodriguez et al. 2006) For pituitary-dependent hyperadrenocorticism (Cushing's Dis-ease):a) 0. 1 mg/kg PO every 3 days. Effective in 70% of dogs treated. Dogs with tumor sizes greater than 5 mm did not respond. (Castillo, Lalia et al. 2005) CATS:T! For pregnancy termination:a) At 30 days post-coitus, cabergoline at 5 mcg/kg PO q24h and cloprostenol 5 mcg/kg SC q48h in 7-13 days was used to induce abortion. (Davidson 2004c) b IRDS:T! For persistent egg laying in psittacines combination with remov-al of males, altered light cycle: a) Initially 10-20 mcg/kg PO daily; higher dosages were also used. Further work needed to determine the dose rate, etc. (Chitty, Raftery et al. 2006) monitoring Efficacy T! Adverse effects T! Client Information Give this medication with food; contact veterinarian if vomiting T! persists Chemistry/Synonyms Cabergoline, a synthetic, ergot-derivative, dopamine agonist sim-ilar to bromocriptine, occurs as a white powder that is insoluble in water, and soluble in ethanol or chloroform. The commercially available tablets also contain the inactive ingredients, leucine and lactose. Cabergoline may also be known as FCE-21336, cabergolina, Cabasar®, Actualene®, Sostilar®, Dostinex® or Galastop®. Storage/Stability/Compatibility The commercially available tablets should be stored at controlled room temperature (20°-25°C; 68°-77°F). It has been reported that the drug is unstable or degrades in aqueous suspensions and if com-pounded into a liquid that will not be used immediately, should be compounded into a lipid-based product. Preparing a fresh aque-ous solution for immediate use should be stable (see Dog dose “c” above). The veterinary (Europe) product Galastop® should be stored below 25°C and protected from light. Do not refrigerate. Once opened, it should be used within 28 days. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None in USA. Cabergoline is available in Europe as Galastop® (Ceva) 50 mcg/m L oral liquid (miglyol base). HUm AN­l Ab El ED PRODUCTS: Cabergoline Tablets: 0. 5 mg (500 mcg); Dostinex® (Pfizer); generic; (Rx) c Alcitonin s Almon (kal-si-toe-nin sam-in) Miacalcin®, Calcimar® Oste O clast inhibiting h Orm One Prescriber Highlights Hormone used primarily to control hypercalcemia in small T T animals (esp. dogs) Hypersensitivity possible T T Young animals may be extremely sensitive to effects T T May cause GI effects T T Do not confuse with calcitriol T T Uses/Indications In small animals, calcitonin has been used as adjunctive therapy to control hyper calcemia. Its use has been limited by expense, avail-ability and resistance development to its effects after several days of treatment. Pharmacology/Actions Calcitonin has a multitude of physiologic effects. It principally acts on bone inhibit ing osteoclastic bone resorption. By reducing tubu-lar reabsorption of calcium, phosphate, sodium, magnesium, po-tassium and chloride, it promotes their renal excretion. Calcitonin also increases jeju nal secretion of water, sodium, potassium and chloride (not calcium). Pharmacokinetics Calcitonin is destroyed in the gut after oral administration and therefore must be administered parenterally. In humans, the onset of effect after IV administration of calcitonin salmon is immedi-ate. After IM or SC administration, onset occurs within 15 minutes with maximal effects occurring in about 4 hours. Duration of ac-tion is 8-14 hours after IM or SC injection. The drug is thought to be rapidly metabolized by the kidneys, in the blood and peripheral tissues. Contraindications/Precautions/Warnings Calcitonin is contraindicated in animals hy persensitive to it. Patients with a history of hypersensitivity to other proteins may be at risk. Y oung animals are reportedly up to 100 times more sensitive to calcitonin than are older animals (adults). Adverse Effects There is not a well-documented adverse effect profile for calcitonin in domestic animals. Anorexia and vomiting have been reported to occur in dogs. Overmedicating can lead to hypocalcemia. The fol-lowing ef fects are documented in humans and potentially could be seen in animals: diarrhea, anorexia, vomit ing, swelling and pain at injection site, redness and peripheral paresthesias. Rarely, allergic reactions may occur. Tachyphylaxis (resistance to drug therapy with time) may occur in some dogs treated.

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122 CAl CITRIOl Reproductive/Nursing Safety There is little information on the reproductive safety of calcitonin; however, it does not cross the placenta. Very high doses have de-creased birth weights in laboratory animals, presumably due to the metabolic effects of the drug. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no ad-equate studies in humans. ) Calcitonin has been shown to inhibit lactation. Safe use during nursing has not been established. Overdosage/Acute Toxicity Very limited data is available. Nausea and vomiting have been re-ported after accidental overdose injections. Chronic overdosing can lead to hypocalcemia. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving calcitonin and may be of significance in veterinary patients: VITAm IN D ANAl Og ST! or CAl CIUm products: May interfere with the efficacy of calcitonin Doses DOg S:T! For hypervitaminosis D (toxicity)/hypercalcemia:a) 4-6 IU/kg SC q12h to q8h (Carothers, Chew et al. 1994) b) In animals with severe hypercalcemia (>16 mg/d L) calcitonin may be beneficial when used in combination with furosemide, IV fluids, and prednisone. Initially, give 4 U/kg IV, followed by 4-8 mg/kg SC once or twice daily (dose extrapolated from human informa tion) (Carothers, Chew et al. 1994) c) 4-6 IU/kg SC q2-3 hours until serum calcium levels are nor-malized (Firth 2000) d) For adjunctive therapy if fluid deficit replacement, saline di-uresis, furosemide and prednisone have failed to control cal-cium: 4 Units/kg IV, then 4-8 U/kg SC q12-24h (Nelson and Elliott 2003b) e) 4-6 Units/kg SC q8-12h (Davies 2005) REPTIl ES:T! For hypercalcemia: a) Green iguanas in combination with fluid therapy: 1. 5 IU/kg SC q8h for several weeks if necessary (Gauvin 1993) For secondary nutritional hyperparathyroidism or nutritional secondary hyperparathyroidism (NSHP):a) If reptile is not hypocalcemic: 50 Units/kg IM once weekly for 2-3 doses. (Hernandez-Divers 2005) b) Correct husbandry problems and correct hypocalcemia with calcium and vitamin D. Once calcium level is normal and patient is on oral calcium supplementation (usually about 7 days after starting therapy) give calcitonin at 50 Units/kg IM weekly for 2-3 doses. Supportive care can be tapered off once patient becomes stable. (Johnson 2004a) monitoring Serum Calcium T!Chemistry/Synonyms A polypeptide hormone, calcitonin is a 32-amino acid polypeptide having a molecular weight of about 3600. Calcitonin is available commercially as either calcitonin human or calcitonin salmon, both of which are synthetically prepared. Potency of calcitonin salmon is expressed in inter national units (IU). Calcitonin salmon is approx-imately 50X more potent than calcitonin human on a per weight basis. Calcitonin salmon may also be known as calcitonin-salmon, cal-citoninum salmonis, salmon calcitonin, SCT-1, or Calcimar®; many other trade names are available internationally. Storage/Stability Calcitonin salmon for injection should be stored in the refrigera tor (2-8°C). The nasal solution should be stored in the refrigerator but protected from freezing. Once in use it should be stored at room temperature in an upright position; use within 35 days. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Calcitonin Salmon for Injection: 200 IU/m L in 2 m L vials; Miacal-cin® (Novartis); (Rx) Calcitonin Salmon Intranasal Spray: 200 Units/activation (0. 09 m L/ dose) in 2 m L (Miacalcin®) and 3. 7 m L (Fortical®) glass bottles with pump; Miacalcin® (Novartis); Fortical® (Upsher-Smith); (Rx) c Alcitriol (kal-si-trye-ole) Rocaltrol®, Calcijex® vitamin d anal Og Prescriber Highlights Vitamin D analog may be useful in dogs (& possibly cats) T T for treatment of hypocalcemia, chronic renal disease or idiopathic seborrhea. Contraindications: Hypercalcemia, hyperphosphatemia, T T malabsorption syndromes Adverse Effects: Hypercalcemia, hypercalcuria or hyper-T T phosphatemia greatest concerns May need to have oral dosage forms compounded T T Do not confuse with calcitonin T T Uses/Indications Calcitriol may be potentially beneficial in the adjunctive treatment of chronic re nal disease in dogs and cats but its use is somewhat controversial, particularly the decision on how soon in the course of chronic renal insufficiency it should employed. It may also be of benefit in treating some types of dermatopathies (primary idiopath-ic seborrhea). Pharmacology/Actions Calcitriol is a vitamin D analog. Vitamin D is considered a hormone and, in con junction with parathormone (PTH) and calcitonin, reg-ulates calcium homeostasis in the body. Active analogues (or metab-olites) of vitamin D enhance calcium absorption from the GI tract, promote re absorption of calcium by the renal tubules, and increase the rate of accretion and resorption of min erals in bone. Calcitriol has a rapid onset of action (approximately 1 day) and a short dura-

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CAl CITRIOl 123 tion of ac tion. Unlike other forms of vitamin D, calcitriol does not require renal activation for it to be effec tive. Pharmacokinetics If fat absorption is normal, vitamin D analogs are readily absorbed from the GI tract (small intestine). Bile is required for adequate absorption and patients with steatorrhea, liver or biliary disease will have diminished absorption. Calcitriol has a rapid onset of biologic action and has a short duration of action (<1 day to 2-3 days). Dogs and cats appear to require much smaller doses of calcitriol than do humans. Contraindications/Precautions/Warnings Calcitriol is contraindicated in patients with hypercalcemia, vita-min D toxicity, malabsorption syndrome, or abnormal sensitivity to the effects of vitamin D. It should be used with extreme caution in patients with hyperphosphatemia (many clini cians believe hy-perphosphatemia or a combined calcium/phosphorous product of >70 is a contraindication to the use of vitamin D analogs). Adverse Effects While hypercalcemia is a definite concern, calcitriol adminis tered in low dosages to dogs with chronic renal disease infrequently causes hypercalcemia, unless it is used with a calcium-containing phos-phorus binder, particularly calcium carbonate. Signs of hypercalce-mia include polydipsia, polyuria and anorexia. Hyperphosphatemia may also occur and patients' serum phosphate levels should be nor-malized before therapy is begun. Monitoring of serum calcium lev-els is mandatory while using this drug. Reproductive/Nursing Safety Calcitriol has proven to be teratogenic in laboratory animal when given at doses several times higher than those used therapeutically. In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Safe use during lactation has not been established. Overdosage/Acute Toxicity Overdosage can cause hypercalcemia, hypercalciuria, and hyperphos phatemia. Intake of excessive calcium and phosphate may also cause the same effect. Acute inges tions should be man-aged using established protocols for removal or prevention of the drug being ab sorbed from the GI. Orally administered mineral oil may reduce absorption and enhance fecal elimi nation. Hypercalcemia secondary to chronic dosing of the drug should be treated by first temporarily dis continuing (not dose reduction) calcitriol and exogenous calcium therapy. If the hypercalcemia is severe, furosemide, cal cium-free IV fluids (e. g., normal saline), urine acidification, and corticosteroids may be employed. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving calcitriol and may be of significance in veterinary patients: CAl CIUm­CONTAININg PHOSPHORUS b INDINg Ag ENTS T! (e. g., calcium carbonate ): Use with calcitriol may induce hypercalcemia CORTICOSTEROIDST! : Can nullify the effects of vitamin D analogs DIg Ox INT! or VERAPAm Il : Patients on verapamil or digoxin are sen-sitive to the effects of hypercalcemia; intensified monitor ing is required PHENy TOIN, b ARb ITURATES T! or PRIm IDONE : May induce hepatic en-zyme systems and increase the metabolism of Vitamin D analogs thus decreasing their activity THIAz IDE DIURETICST! : May cause hypercalcemia when given in con-junction with Vitamin D analogs laboratory Considerations SERUm CHOl ESTEROl T! levels may be falsely elevated by vitamin D analogs when using the Zlatkis-Zak reaction for determination Doses DOg S:T! T o suppress secondary hyperparathyroidism in CRF: a) Decision to use calcitriol must be made with caution because hypercalcemia is potentially a serious complication that if prolonged can result in a reduction (reversible or irrevers-ible) of GFR. Hypercalcemia is an uncommon side effect (unless used with a calcium-containing phosphorus binding agent) if calcitriol is dosed at 2. 5-3. 5 ng/kg/day PO. (Polzin, Osborne et al. 2005) b) 2. 5-3. 5 ng/kg PO once daily. Dogs with refractory hyper-parathyroidism may require up to 6 ng/kg/day. (Chew 2003) c) 1) Confirm the diagnosis of chronic renal failure (serum creatinine >2 mg/dl); 2) Reduce hyperphosphatemia to <6 mg/dl; 3) If serum creatinine between 2-3 mg/dl and serum phosphorus <6 mg/dl, start calcitriol at 2. 5-3. 5 ng/kg/day PO (so-called “preventative” dose); if serum creatinine >3 mg/dl and serum phosphorus <6 mg/dl, obtain a baseline PTH level and start calcitriol at 3. 5 ng/kg/day. Monitoring of preventative dose: assess serum calcium on days 7 and 14 after starting calcitriol and then every 6 months. Serum creatinine should be measured every 1-3 months. If hypercalcemia occurs, stop calcitriol for one week to determine if the drug is causing the hypercalcemia or if it's due to another cause (e. g., too little calcitriol). Monitoring patients with elevated PTH: monitor as above, but also determine PTH levels at 4-6 weeks after starting calcitriol. If still elevated increase dose by 1-2 ng/kg/day, but do not exceed 6. 6 ng/kg/day unless monitoring ionized calcium. If higher daily doses are required (5-7 ng/kg/day), a pulsed-dosing strategy may be considered. This is usually about 20 ng/kg given twice weekly PO at bedtime on an emp-ty stomach. (Nagode 2005) For subacute and chronic maintenance treatment of hypocalcemia: a) Initially, 20-30 ng/kg/day PO divided twice a day for 3-4 days, then 5-15 ng/kg/day divided twice a day (Chew and Nagode 2000) For primary idiopathic seborrhea (especially in spaniel breeds): a) 10 ng/kg PO once daily. Give as far away from the main meal as possible. (Kwochka 1999) CATS: T! T o suppress secondary hyperparathyroidism in CRF: a) 1. 65-3. 63 ng/kg PO daily (Polzin, Os borne et al. 2000) b) 2. 5-3. 5 ng/kg PO once daily (Chew 2003) c) See the dog dose in “c” above (Nagode 2005) monitoring Serum calcium, phosphate, creatinine. Baseline and at one week T! and 1 month after starting treatment; then monthly thereafter Urine calcium baseline and as needed T! Serum PTH levels T! Clinical efficacy (T! e. g., improved appetite, activity level, slowed progression of disease)

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

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CAl CIUm 125 laboratory Considerations No specific concerns noted; see Monitoring Doses DOg ST! /CATS: For hyperphosphatemia associated with chronic renal failure: a) In conjunction with a low-phosphorus diet: Initial therapy at 60-90 mg/kg/day, with food or mixed with food, or just pri-or to each meal. Individualize dose to achieve desired serum phosphorus concentrations. Perform serial serum phospho-rus evaluations at 2-4 week intervals. Decrease dose if serum calcium exceeds normal limits; additional aluminum-based phosphate binders should be used if hyperphosphatemia persists. (Polzin, Osborne et al. 2005) monitoring Initially at 10- 14 day intervals; once “stable”, at 4- 6 week intervals: Serum phosphorus (after a 12T! -hour fast) Serum ionized calcium T! Client Information Give with meals; either just before or mixed into food T! The veterinarian may prescribe additional doses to be adminis-T! tered between meals if additional calcium is required, give only with meals unless the veterinarian instructs to do so Use of this medication will require ongoing laboratory T! monitoring Chemistry/Synonyms Calcium acetate is a white, odorless, hygroscopic powder that is freely soluble in water and slightly soluble in alcohol. Each gram contains approximately 254 mg of elemental calcium. Calcium acetate may also be known as: calcii acetas, acetato de calcio, kalcio acetates, kalciumacetat, or kalciumasetaatti, Phos Lo®. Storage/Stability The commercially available tablets, capsules and gelcaps should be stored at room temperature (25°C); excursions are permitted to 15-30°C. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Calcium Acetate Tablets: 667 mg (169 mg elemental calcium); Phos-Lo® (Nabi); (Rx) Calcium Acetate Capsules: 333. 5 mg (half-size; 84. 5 mg elemental calcium), 667 mg (169 mg elemental calcium); Phos Lo® (Nabi); (Rx) Calcium Acetate Gelcaps: 667 mg (169 mg elemental calcium); Phos Lo® (Nabi); (Rx) Calcium EDTA — see Edetate Calcium Disodiumc Alcium s Alts c Alcium glucon A te c Alcium glucept Ate c Alcium chloridec Alcium l Act Ate (kal-see-um) essential cati On nutrient Prescriber Highlights Used to treat or prevent hypocalcemia; or as an oral T T antacid Contraindicated in V-fib or hypercalcemia T T Must NOT give IV too rapidly T T Must monitor therapy carefully depending on condition, T T etc. Drug interactions & incompatibilities prevalent T T Uses/Indications Calcium salts are used for the prevention or treatment of hypocal-cemic condi tions. Pharmacology/Actions Calcium is an essential element that is required for many functions within the body, including proper nervous and musculoskeletal sys-tem function, cell membrane and capillary perme ability, and acti-vation of enzymatic reactions. Pharmacokinetics Calcium is absorbed in the small intestine in the ionized form only. Presence of vitamin D (in active form) and an acidic p H is nec-essary for oral absorption. Parathormone (parathyroid hormone) increases with resultant increased calcium absorption in calcium deficiency states and decreases as serum calcium levels rise. Dietary factors (high fiber, phytates, fatty acids), age, drugs (corticoster-oids, tetracyclines), disease states (steatorrhea, uremia, renal osteo-dystrophy, achlorhydria), or decreased serum calcitonin levels may all cause reduced amounts of calcium to be absorbed. After absorption, ionized calcium enters the extracellular flu-id and then is rapidly incorporated into skeletal tissue. Calcium administration does not necessarily stimulate bone formation. Approxi mately 99% of total body calcium is found in bone. Of cir-culating calcium, approximately 50% is bound to serum proteins or complexed with anions and 50% is in the ionized form. T otal se-rum cal cium is dependent on serum protein concentrations. T otal serum calcium changes by approximately 0. 8 mg/dl for every 1. 09 g/dl change in serum albumin. Calcium crosses the placenta and is dis tributed into milk. Calcium is eliminated primarily in the feces, contributed by both unabsorbed calcium and calcium excreted into the bile and pancre-atic juice. Only small amounts of the drug are excreted in the urine as most of the cation filtered by the glomeruli is reabsorbed by the tubules and ascending loop of Henle. Vitamin D, parathormone, and thiazide diuretics decrease the amount of calcium excreted by the kidneys. Loop diuretics (e. g., furosemide), calcitonin, and so-matotropin increase calcium renal excretion.

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126 CAl CIUm Contraindications/Precautions/Warnings Calcium is contraindicated in patients with ventricular fibrillation or hypercalcemia. Parenteral calcium should not be administered to pa tients with above normal serum calcium levels. Calcium should be used very cautiously in patients receiving digitalis glycosides, or having cardiac or renal disease. Calcium chloride, because it can be acidifying, should be used with caution in patients with respiratory failure, respiratory acidosis, or renal disease. In dogs, calcium gluconate diluted 1:1 has been regarded as safe to administer subcutaneously for the treatment of primary hy-poparathyroidism in the past, but there are now several case reports of severe tissue reactions (pyogranulomatous panniculitis, adipocyte mineralization, etc. ) at the injection site; use with caution, particu-larly when using with calcitriol. Adverse Effects Hypercalcemia can be associated with calcium therapy, particularly in patients with cardiac or renal disease; animals should be ade-quately monitored. Other effects that may be seen include GI irrita-tion and/or constipation after oral administration, mild to severe tissue reactions after IM or SC administration of calcium salts and venous irritation after IV administration. Calcium chloride may be more irritating than other parenteral salts and is more likely to cause hy potension. T oo rapid intravenous injection of calcium can cause hypotension, cardiac arrhythmias and cardiac arrest. Should calcium salts be infused perivascularly, stop the infusion; treatment then may include: infiltrating the affected area with nor-mal saline, corticosteroids administered locally, applying heat and el evating the area, and infiltrating the affected area with 1% pro-caine and hyaluronidase. Reproductive/Nursing Safety Although parenteral calcium products have not been proven safe to use during pregnancy, they are often used before, during, and after parturition in cows, ewes, bitches, and queens to treat parturient pa-resis secondary to hypocalcemia. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity Unless other drugs are given concurrently that enhance the absorp-tion of calcium, oral overdoses of calcium containing products are unlikely to cause hypercalcemia. Hy percalcemia can occur with par-enteral therapy or oral therapy in combination with vitamin D or in creased parathormone levels. Hypercalcemia should be treated by withholding calcium therapy and other calcium elevating drugs (e. g., vitamin D analogs). Mild hypercalcemia generally will resolve without further intervention when renal function is adequate. More serious hypercalcemia (>12 mg/dl) should generally be treated by hydrating with IV normal saline and administering a loop diuretic (e. g., furosemide) to increase both sodium and calcium ex cretion. Potassium and magnesium must be monitored and re-placed as necessary. ECG should also be monitored during treat-ment. Corticosteroids, and in humans calcitonin and hemodialysis, have also been employed in treating hypercalcemia. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving calcium and may be of significance in veterinary patients: CAl CIUm CHANNEl bl OCKERS T! (e. g., diltiazem, verapamil, etc. ): Intra-venous calcium may antagonize the effects of cal cium-channel blocking agents DIg Ox INT! : Patients on digitalis therapy are more apt to develop ar-rhythmias if receiving IV calcium—use with caution m Ag NESIUm T! (oral): With oral calcium may lead to increased serum magnesium and/or cal cium, particularly in patients with renal failure. m Ag NESIUm SUl FATET! : Parenteral calcium can neutralize the effects of hy permagnesemia or magnesium toxicity secondary to paren-teral magnesium sulfate NEUROm USCUl AR bl OCKERS T! (e. g., tubocurarine, metubine, gallamine, pancuronium, atracurium, and vecuronium ): Parenteral calcium may reverse the effects of nondepolarizing neuromuscular blocking agents; calcium has been reported to prolong or enhance the ef-fects of tubocurarine TETRACy Cl INES, Fl UOROQUINOl ONEST! (oral): Oral calcium can reduce the amount of tetracyclines or fluoroquinolones absorbed from the GI tract; separate dosages by two hours if possible POTASSIUm SUPPl Em ENTST! : Patients receiving both parenteral cal-cium and potassium supplementation may have an increased chance of developing cardiac arrhythmias—use cautiously THIAz IDE DIURETICST! : Used in conjunction with large doses of cal-cium may cause hypercalcemia VITAm IN AT! : Excessive intake of vitamin A may stimulate calcium loss from bone and cause hypercalcemia. VITAm IN DT! : Concurrent use of large doses of vitamin D or its analogs may cause enhanced calcium absorption and induce hypercalcemia laboratory Considerations SERUm AND URINAR y m Ag NESIUm T! : Parenteral calcium may cause false-negative results for serum and urinary magnesium when us-ing the Titan yellow method of determination. Doses DOg ST! For hypocalcemia:a) Calcium gluconate injection: 94-140 mg/kg IV slowly to ef-fect (intraperitoneal route may also be used). Monitor respi-rations and cardiac rate and rhythm during administra tion. (USPC 1990) b) For acute hypocalcemia: Calcium gluconate 10% injection: Warm to body temperature and give IV at a rate of 50-150 mg/kg (0. 5-1. 5 m L/kg) over 20-30 minutes. If brady cardia develops, halt infusion. Following acute crisis, infuse 10-15 m L (of a 10% solu tion) per kg over a 24-hour period. Long-term therapy may be accomplished by increasing dietary calcium and using vitamin D. Calcium lactate may be given orally at a rate of 0. 5-2 g/day. (Seeler and Thurmon 1985) c) Calcium gluconate 10% 0. 5-1. 5 m L/kg or calcium chloride 10% 1. 5-3. 5 m L (total) IV slowly over 15 minutes; monitor heart rate or ECG during infusion. If ST segment eleva tion or Q-T interval shortening occur, temporarily discontinue infu-sion and reinstate at a slower rate when resolved. Maintenance therapy is dependent on cause of hypocalcemia. Hypopara-thyroidism is treated with vitamin D analogs (refer to DHT monograph) with or without oral calcium supplementation. (Russo and Lees 1986) d) For emergency treatment of tetany and seizures secondary to hypoparathyroidism: Cal cium gluconate 10%: 0. 5-1. 5 m L/ kg (up to 20 m L) over 15-30 minutes. May repeat at 6-8 hour intervals or give as continuous infusion at 10- 15 mg/ kg/hour. Monitor ECG and stop infusion if S-T segment el-evates, Q-T interval shortens, or arrhythmias occur. For long-term therapy (with DHT—refer to that monograph), calcium

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CAl CIUm 127 supplementation may occasionally be useful. Calcium glu-conate at 500-750 mg/kg/day divided three times daily, or calcium lactate at 400-600 mg/kg/day divided three times daily, or calcium carbonate 100-150 mg/kg/day divided twice daily. Monitor serum calcium and adjust as necessary. (Kay and Richter 1988) e) For emergency treatment: Calcium gluconate 10% 5-15 mg/ kg (0. 5-1. 5 m L/kg) slowly to effect over a ten minute period, or calcium chloride 10% (extremely caustic if administered extravascularly) 5-15 mg/kg (0. 15-0. 5 m L/kg); dose is the same but volume is N that of calcium gluconate; monitor heart rate or ECG (if possible) during infusion. If brady-cardia or Q-T interval shortening occurs, temporarily dis-continue infusion. Short-term treatment immediately after correction of tetanty: Either give a constant rate infusion of calcium gluconate 10% at 60-90 mg/kg/day (6. 5-9. 75 m L/ kg/day) added to the fluids or give the daily dosage SC in 3-4 divided doses per day after diluting with an equal volume of saline. (Crystal 2004) For hyperkalemic cardiotoxicity:a) Secondary to uremic crisis: Correct metabolic acidosis, if present, with sodium bicarbon ate (bicarbonate may also be beneficial even if acidosis not present). Calcium gluconate (10%) indicated if serum K+ is >8 m Eq/L. Give at an approx-imate dose of 0. 5-1 m L/kg over 10-20 minutes; monitor ECG. Rapidly corrects arrhythmias but effects are very short (10-15 minutes). IV glucose (0. 5-1 g/kg body weight with or without insulin) also bene ficial in increasing intracellular K+ concentrations. (Polzin and Osborne 1985) CATST! : For hypocalcemia:a) Calcium gluconate injection: 94-140 mg/kg IV slowly to ef-fect (intraperitoneal route may also be used). Monitor respi-rations and cardiac rate and rhythm during administra tion. (USPC 1990) b) For acute hypocalcemia secondary to hypoparathyroidism: Using 10% calcium gluconate injection, give 1-1. 5 m L/kg IV slowly over 10-20 minutes. Monitor ECG if possible. If bradycardia, or Q-T interval shortening occurs, slow rate or temporarily discontinue. Once life-threatening signs are controlled, add calcium to IV fluids and administer as a slow infusion at 60-90 mg/kg/day (of elemental calcium). This converts to 2. 5 m L/kg ev ery 6-8 hours of 10% cal-cium gluconate. Carefully monitor serum calcium (once to twice daily) during this period and adjust dose as required. Begin oral calcium initially at 50-100 mg/kg/day divided 3-4 times daily of elemental calcium and dihydrotachysterol once animal can tolerate oral therapy. Give DHT initially at 0. 125-0. 25 mg PO per day for 2-3 days, then 0. 08-0. 125 mg per day for 2-3 days and finally 0. 05 mg PO per day un-til further dosage adjustments are necessary. As cat's serum calcium is stabilized, intravenous calcium may be reduced and discontinued if tolerated. Stable serum calcium levels (8. 5-9. 5 mg/dl) are usually achieved in about a week. Con-tinue to monitor and adjust dosages of DHT and calcium to lowest levels to maintain normocalcemia. (Peterson and Randolph 1989) ( Note: refer to the DHT monograph for fur-ther information. ) c) For hypocalcemia secondary to phosphate enema toxicity or puerperal tetany: follow the guidelines for use of intravenous calcium in “b” above. (Peterson and Randolph 1989) d) For emergency treatment: Calcium gluconate 10% 5-15 mg/ kg (0. 5-1. 5 m L/kg) slowly to effect over a ten minute period, or calcium chloride 10% (extremely caustic if administered extravascularly) 5-15 mg/kg (0. 15-0. 5 m L/kg); dose is the same but volume is N that of calcium gluconate; monitor heart rate or ECG (if possible) during infusion. If brady-cardia or Q-T interval shortening occurs, temporarily dis-continue infusion. Short-term treatment immediately after correction of tetanty: Either give a constant rate infusion of calcium gluconate 10% at 60-90 mg/kg/day (6. 5-9. 75 m L/ kg/day) added to the fluids or give the daily dosage SC in 3-4 divided doses per day after diluting with an equal volume of saline. (Crystal 2004) CATTl ET! For hypocalcemia:a) Calcium gluconate injection: 150-250 mg/kg IV slowly to effect (intraperitoneal route may also be used). Monitor res-pirations and cardiac rate and rhythm during administra-tion. (USPC 1990) b) Calcium gluconate 23% injection: 250-500 m L IV slowly, or IM or SC (divided and given in several locations, with mas-sage at sites of injection) (Label directions; Calcium Gluc. Injection 23%—T ech America) c) 8-12 grams of calcium IV infused over a 5-10 minute pe-riod; use a product containing magnesium during the last month of pregnancy if subclinical hypomagnesemia is de-tected. (Allen and Sansom 1986) HORSEST! For hypocalcemia:a) Calci um gluconate injection: 150-250 mg/kg IV slowly to effect (intraperitoneal route may also be used). Monitor res-pirations and cardiac rate and rhythm during administra-tion. (USPC 1990) b) Calcium gluconate 23% injection: 250-500 m L IV slowly, or IM or SC (divided and given in several locations, with mas-sage at sites of injection) (Label directions; Calcium Glucon-ate Injection 23%—T ech America) c) For lactation tetany: 250 m L per 450 kg body weight of a standard commercially available solution that also contains magnesium and phosphorous IV slowly while auscultating heart. If no improvement after 10 minutes, repeat. Intensity in heart sounds should be noted, with only an infrequent ex-trasystole. Stop infusion immediately if a pronounced change in rate or rhythm is detected. (Brewer 1987) SHEEP & g OATS:T! For hypocalcemia:a) Sheep: Calcium gluconate injection: 150-250 mg/kg IV slowly to effect (intraperitoneal route may also be used). Monitor respirations and cardiac rate and rhythm during admin istration. (USPC 1990) b) Sheep: Calcium gluconate 23% injection: 25-50 m L IV slowly, or IM or SC (divided and given in several locations, with massage at sites of injection) (Label directions; Calcium Gluconate Injection 23%—T ech America) SWINE:T! For hypocalcemia:a) Calcium gluconate injection: 150-250 mg/kg IV slowly to effect (intraperitoneal route may also be used). Monitor res-pirations and cardiac rate and rhythm during administra-tion. (USPC 1990) b) Calcium gluconate 23% injection: 25-50 m L IV slowly, or IM or SC (divided and given in several locations, with mas-sage at sites of injection) (Label directions; Calcium Glu-conate Injection 23%—T ech America)

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128 CAl CIUm b IRDS:T! For hypocalcemic tetany: a) Calcium gluconate: 50-100 mg/kg IV slowly to effect; may be diluted and given IM if a vein cannot be located (Clubb 1986) For egg-bound birds:a) Initially, calcium gluconate 1% solution 0. 01-0. 02 m L/g IM. Provide moist heat (80-85°F) and allow 24 hours for bird to pass egg. (Nye 1986) REPTIl ES:T! For egg binding in combination with oxytocin (oxytocin: 1-10 IU/kg IM. ): a) Calcium glubionate: 10-50 mg/kg IM as needed until calci-um levels back to normal or egg bind ing is resolved. Use care when giving multiple injections. Calcium/oxytocin is not as ef fective in lizards as in other species. (Gauvin 1993) monitoring Serum calcium T! Serum magnesium, phosphate, and potassium when indicated T! Serum PTH (parathormone) if indicated T! Renal function tests initially and as required T! ECG during intravenous calcium therapy if possible T! Urine calcium if hypercalcuria develops T! Chemistry Several different salts of calcium are available in various formula-tions. Calcium glucep tate and calcium chloride are freely soluble in water; calcium lactate is soluble in water; calcium glu conate and cal-cium glycerophosphate are sparingly soluble in water, and calcium phosphate and car bonate are insoluble in water. Calcium gluconate for injection has a p H of 6-8. 2 and calcium chloride for injection has a p H of 5. 5-7. 5. T o determine calcium content per gram of various calcium salts: Calcium Acetate: 253 mg (12. 7 m Eq) Calcium Carbonate: 400 mg (20 m Eq)Calcium Chloride: 270 mg (13. 5 m Eq)Calcium Citrate: 211 mg (10. 6 m Eq)Calcium Gluceptate: 82 mg (4. 1 m Eq)Calcium Gluconate: 90 mg (4. 5 m Eq)Calcium Glycerophosphate: 191 mg (9. 6 m Eq)Calcium Lactate: 130 mg (6. 5 m Eq)Calcium Phosphate Dibasic Anhydrous: 290 mg (14. 5 m Eq)Dihydrate: 230 mg (11. 5 m Eq)Calcium Phosphate Tribasic: 400 mg (20 m Eq) Storage/Stability/Compatibility Calcium gluconate tablets should be stored in well-closed con tainers at room temperature. Calcium lactate tablets should be stored in tight containers at room tem perature. Calcium gluconate injection, calcium gluceptate injection, and calcium chloride injection should be stored at room temperature and protected from freezing. Calcium chloride for injection is reportedly compatible with the fol-lowing intravenous solutions and drugs: amikacin sulfate, ascorbic acid, bretylium tosylate, cephapirin sodium, chloramphenicol so-dium succinate, dopamine HCl, hydrocortisone sodium succinate, isoproterenol HCl, lidocaine HCl, methicillin sodium, norepineph-rine bitartrate, penicillin G potassium/sodium, pentobarbital so-dium, phenobarbital sodium, sodium bicarbonate, verapamil HCl, and vitamin B-complex with C. Calcium chloride for injection compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or solutions: fat emulsion 10%, dobutamine HCl, oxytetracy-cline HCl, and tetracycline HCl. Compatibility is dependent upon factors such as p H, con centration, temperature and diluent used. Calcium chloride for injection is reportedly incompatible with the fol-lowing solutions or drugs: amphotericin B, cephalothin sodium, and chlorpheniramine maleate. Calcium gluconate for injection is reportedly compatible with the fol-lowing intravenous solutions and drugs: sodium chloride for injec-tion 0. 9%, lactated Ringer's injection, dextrose 5%-20%, dex trose-lactated Ringer's injection, dextrose-saline combinations, amikacin sulfate, aminophylline, ascorbic acid injection, bretylium tosylate, cephapirin sodium, chloramphenicol sodium succinate, corticotro-pin, dimenhydrinate, erythromycin gluceptate, heparin sodium, hy-drocortisone sodium succinate, lidocaine HCl, methicillin sodium, norepinephrine bitartrate, penicillin G potas sium/sodium, pheno-barbital sodium, potassium chloride, tobramycin sulfate, vancomy-cin HCl, vera pamil and vitamin B-complex with C. Calcium gluconate compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or so-lutions: phosphate salts, oxytetracycline HCl, prochlorperazine edi-sylate, and tetracycline HCl. Compatibility is dependent upon fac-tors such as p H, concentration, temperature and diluent used. Calcium gluconate is reportedly incompatible with the following so-lutions or drugs: intravenous fat emulsion, amphotericin B, cefa-mandole naftate, cephalothin sodium, dobutamine HCl, methyl-prednisolone sodium succinate, and metoclopramide HCl. Consult specialized references or a hospital pharmacist for more specific information. Dosage Forms/Regulatory Status VETERINAR y­APPROVED PRODUCTS: (not necessarily a complete list) Parenteral Products: Calcium Gluconate (as calcium borogluconate) 23% [230 mg/m L; 20. 7 mg (1. 06 m Eq) calcium per m L]; in 500 m L bottles; Am Tech® Calcium Gluconate 23% Solution (Phoenix Scientific); (OTC), Cal-cium Gluconate 23% (Agri Pharm, Agri Labs, Aspen, Bimeda, Durvet, Phoenix Pharmaceutical, Vet T ek, Vetus); (OTC), Cal-Nate 1069® (Butler); (OTC). Depending on the product, approved for use in cattle, horses, swine, sheep, cats, and dogs. No withdrawal times are required. Calcium Gluconate oral 40 g-42 g calcium/300 m L tube. Supple-ment for use pre and post calving. Cal Supreme Gel® (Bimeda); (OTC)Calcium Chloride 35% w/w or 47% w/v equivalent to 170 mg cal-cium/m L (127 mg per gm) in 300 m L (400 g) tube. Clearcal 50® (Vedco); (OTC) Products are also available that include calcium, phosphorus, po-tassium and/or dextrose; refer to the individual product's labeling for specific dosage information. Trade names for these products in clude: Norcalciphos®—Pfizer, and Cal-Dextro ® Special, #2, C, and K—Fort Dodge; (Rx). Oral Products : No products containing only calcium (as a salt) are available commercially with vet erinary labeling. There are several products (e. g., Pet-Cal® and Osteoform® Improved ) that contain cal-cium with phosphorous and vitamin D (plus other ingredients in some preparations).

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CAPTOPRIl 129 HUm AN­APPROVED PRODUCTS: (not a complete list) Parenteral Products : Calcium Gluconate Injection 10% [100 mg/m L; 9 mg (0. 47 m Eq) calcium per m L] in 10 m L amps, 10 and 50 m L, 100 m L, and 200 m L vials; generic; (Rx) Calcium Chloride Injection 10% [100 mg/m L; 27. 2 mg (1. 36 m Eq) calcium per m L] in 10 m L amps, vials, and syringes; generic; (Rx) Oral Products : Calcium Gluconate (9. 3% calcium) Tablets: 500 mg (45 mg cal-cium), 650 mg (58. 5 mg calcium), 975 mg (87. 75 mg calcium), 1 gram (90 mg of calcium); generic; (OTC) Calcium Lactate (13% calcium) Tablets: 325 mg (42. 25 mg calci-um), 650 mg (84. 5 mg calcium); Capsules (13% calcium), 500 mg (96 mg calcium), Cal-Lac® (Bio T ech); generic; (OTC) Also available are calcium carbonate tablets, suspension and cap-sules, calcium acetate tablets, calcium citrate tablets, and tricalcium phosphate tablets. Camphorated Tincture of Opium — See Paregoric c Aptopril (kap-toe-pril) Capoten® angi O tensin-c Onverting enzyme (ace) inhibit Or Prescriber Highlights First available ACE inhibitor; use largely supplanted by T T enalapril & other newer ACE inhibitors Shorter duration of activity & more adverse effects than T T other newer ACE inhibitors Uses/Indications The principle uses of captopril in veterinary medicine, at present, are as a va sodilator in the treatment of CHF and in the treatment of hypertension. Because of fewer adverse ef fects, enalapril and benazepril have largely supplanted the use of this drug in veteri-nary medicine. Pharmacology/Actions Captopril prevents the formation of angiotensin-II (a potent va-soconstrictor) by competing with angiotensin-I for the enzyme angiotensin-converting enzyme (ACE). ACE has a much higher af-finity for captopril than for angiotensin-I. Because angiotensin-II concentrations are decreased, aldosterone secretion is reduced and plasma renin activity is increased. The cardiovascular effects of captopril in patients with CHF include decreased total peripheral re sistance, 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 out put, stroke volume, and exercise tolerance. Renal blood flow can be increased with little change in hepatic blood flow. Pharmacokinetics In dogs, approximately 75% of an oral dose is absorbed but food in the GI tract reduces bioavailability by 30-40%. It is distributed to most tissues (not the CNS) and is 40% bound to plasma proteins in dogs. The half-life of captopril is about 2. 8 hours in dogs and less than 2 hours in humans. Its duration of effect in dogs may only persist for 4 hours. The drug is metabolized and re nally excreted. More than 95% of a dose is excreted renally, both as unchanged (45-50%) drug and as metabolites. Patients with significant renal dysfunction can have significantly prolonged half-lives. Contraindications/Precautions/Warnings Captopril is contraindicated in patients who have demonstrated hypersensitivity with ACE inhibitors. It should be used with cau-tion and under close supervision in pa tients with renal insufficien-cy; doses may need to be reduced. Captopril should also be used with caution in patients with hyponatremia or sodium depletion, coronary or cerebrovascular insufficiency, preexisting hematologic abnormalities or a collagen vas cular disease (e. g., SLE). Patients with severe CHF should be monitored very closely upon initiation of therapy. Adverse Effects There have been some reports of hypotension, renal failure, hyper-kalemia, vomiting and diarrhea developing in dogs after captopril administration. Captopril may have a higher incidence of gastro-intestinal effects in dogs than other available ACE inhibitors. Al-though seen in people, skin rashes (4-7% incidence) and neutro-penia/agranulocytosis (rare) have not been reported in dogs. Reproductive/Nursing Safety Captopril apparently crosses the placenta. High doses of ACE in-hibitors in rodents have caused decreased fetal weights and increas-es in fetal and maternal death rates; no teratogenic effects have been reported to date, but use during pregnancy should occur only when the potential benefits of therapy outweigh the risks to the offspring. In humans, the FDA categorizes this drug as category C for use dur-ing the first trimester of pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in hu-mans; or there are no animal reproduction studies and no adequate studies in humans. ) During the second and third trimesters, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is catego-rized as in class: C (These 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. ) Captopril enters milk in concentrations of about 1% of that found in maternal plasma. Overdosage/Acute Toxicity In overdose situations, the primary concern is hypotension; sup-portive treatment with volume expansion with normal saline is rec-ommended to correct blood pressure. Dogs given 1. 5 gm/kg orally developed emesis and decreased blood pressure. Dogs receiving doses greater than 6. 6 mg/kg q8h may develop renal failure. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving captopril and may be of significance in veterinary patients: ANTACIDST! : Reduced oral absorption of captopril may occur if giv-en concomitantly with antacids; it is sug gested to separate dosing by at least two hours

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130 CARb ENICIll IN INDANyl SODIUm CIm ETIDINE:T! Used concomitantly with captopril has caused neuro-logic dysfunction in two human pa tients DIg Ox INT! : Levels may increase 15- 30% when captopril is added, automatic reduction in dosage is not recommended, but monitor-ing of serum digoxin levels should be performed DIURETICST! : Concomitant diuretics may cause hypotension if used with captopril; titrate dosages carefully NON­STEROIDAl ANTIINFl Amm ATOR y Ag ENTS T! (NSAIDs ): May reduce the clinical efficacy of captopril when it is being used as an anti-hypertensive agent POTASSIUm T! or POTASSIUm SPARINg DIURETICS (e. g., spironolactone ): Hyperkalemia may develop with captopril PROb ENECIDT! : Can decrease renal excretion of captopril and pos-sibly enhance the clinical and toxic effects of the drug VASODIl ATORST! (e. g., prazosin, hydralazine, nitrates ): Concomitant va-sodilators may cause hypotension if used with captopril; titrate dosages carefully laboratory Considerations Captopril may cause a false positive T! urine acetone test (sodium nitro prusside reagent). When using T! iodohippurate sodium I123/I134 or Technetium Tc99 penten­ tate renal imaging in patients with renal artery stenosis, ACE inhib-itors may cause a reversible decrease in localization and excretion of these agents in the affected kidney which may lead confusion in test interpretation. Doses Note : Because of fewer adverse effects in dogs, longer duration of ac-tivity, and/or veterinary label ing/dosage forms, enalapril and other newer ACE inhibitors have largely supplanted the use of this drug in veterinary medicine. DOg S:T! a) 1-2 mg/kg PO q8h (Kittleson 2000) b) 0. 5-2 mg/kg PO q8-12h (Bonagura and Muir 1986) CATS:T! a) 1/4 to one-half 12. 5 mg tablet PO q8-12h (Bonagura 1989) b) For dilative, restrictive or hypertrophic cardiomyopathy: 0. 55-1. 54 mg/kg PO q8-12h (Kittleson 2000) monitoring Clinical signs of CHFT! Serum electrolytes, creatinine, BUN, urine protein T! CBC with differential; periodic T! Blood pressure (if treating hypertension or signs associated with T! hypotension arise). Client Information Give medication on an empty stomach unless otherwise instruct-T! ed. Do not abruptly stop or reduce therapy without veterinarian's approval. Contact veterinarian if vomiting or diarrhea persist or are severe, or if animal's condition deteriorates. Chemistry/Synonyms Related to a peptide isolated from the venom of a South American pit viper, captopril occurs as a slightly sulfurous smelling, white to off-white, crystalline powder. It is freely soluble in water or alcohol. Captopril may also be known as: captoprilum, or SQ-14225; many trade names are available. Storage/Stability Captopril tablets should be stored in tight containers at tempera-tures not greater than 30°C. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: T! None The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS:T! Captopril Tablets 12. 5 mg, 25 mg, 50 mg, and 100 mg; Capoten® (PAR); generic; (Rx) Captopril and Hydrochlorothiazide Tablets: 15 mg hydrochlorothi-azide and 25 mg captopril; 15 mg hydrochlorothiazide and 50 mg captopril; 25 mg hydrochlorothiazide and 25 mg captopril; 25 mg hydrochlorothiazide and 50 mg captopril. Captopril and Hydro-chlorothiazide Tablets (Teva); Capozide® 25/25 Tablets, Capozide® 50/25 Tablets, Capozide® 50/15 Tablets, Capozide® 25/15 Tablets (B-M Squibb); (Rx) c Arbenicillin ind Anyl sodium (kar-ben-i-sill-in in-da-neel) Geocillin® e Xtended-a cti On Oral penicillin Prescriber Highlights “Antipseudomonal” oral carboxypenicillin that may be T T useful for treating susceptible UTI's or bacterial prostati-tis in small animals Blood levels too low to treat other systemic infections T T Inactivates aminoglycosides T T in vitro; may have ramifica-tions when used together for UTI Uses/Indications Carbenicillin was used parenterally in the treatment of systemic Pseu domonas aeruginosa infections in small animals, usually in com-bination with an appropriate aminoglycoside agent, but in the USA the injectable is no longer available and most clinicians use ticarcillin or piperacillin in its place. Because the oral form is poorly absorbed and the drug has a rapid elimination half-life, oral therapy is only indicated for the treatment of susceptible urinary tract (and possibly prostate) infections as levels are too low in serum and other tissues for adequate therapy in other systemic Pseudomonas in fections. Pharmacology/Actions The alpha-carboxypenicillins, sometimes called anti-pseudomonal penicillins, in clude both carbenicillin and ticarcillin. These agents have similar spectrums of activity as the aminopenicillins (ampicil-lin, etc. ) including increased activity against many strains of gram-negative aerobes not covered by either the natural penicillins or penicillinase-resistant penicillins, including some strains of E. coli, Klebsiella, and Haemophilus. Additionally, they have activity against several gram-negative organisms of the family Enterobacteriaceae in-cluding many strains of Pseudomonas aeruginosa and Acinetobacter. Like the natural penicillins, they are susceptible to inactivation by beta-lactamase-producing bacteria (e. g., Staph aureus). Although not as active as the natural peni cillins, they do have some activity against many anaerobic bacteria including Clostridial organisms.

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CARb ENICIll IN INDANyl SODIUm 131 Pharmacokinetics The oral form (indanyl sodium) of the drug is rapidly, but incom-pletely, absorbed (see above) with only 30-40% of an oral dose ab-sorbed in humans. Peak levels of the indanyl sodium salt are at-tained in humans about 30 minutes after administration, but it is rapidly hy drolyzed into the base. Attainable serum levels after oral therapy are generally too low to treat systemic infections, but high levels are achieved in the urine. The volume of distribution is reportedly 0. 18-0. 2 L/kg in dogs and cats, and 0. 29-0. 4 L/kg in the horse. The drug is 29-60% bound to serum proteins (human). Car benicillin is thought to cross the placenta and is found in small quantities in milk. In cattle, mastitic milk levels of carbenicillin are approximately twice those found in normal milk, but are too low to treat most causal organisms. Carbenicillin is eliminated primarily by the kidneys, via both tu-bular secretion and glomerular fil tration. Concurrent probenecid administration can slow elimination and increase blood levels. In humans, about 2-5% of the drug is metabolized by hydrolysis to inactive compounds. The half-life in dogs and cats is reportedly 45-75 minutes and 60-90 minutes in the horse. Clearance is 1. 8 m L/kg/min in the dog and 4. 6 m L/kg/min in the horse. Contraindications/Precautions/Warnings Penicillins are contraindicated in patients with a history of hyper-sensitivity to them. Because there may be cross-reactivity, use peni-cillins cautiously in patients who are documented hypersensitive to other beta-lactam antibiotics (e. g., cephalosporins, cefamycins, carbapenems). Adverse Effects Adverse effects with the penicillins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, neu-tropenia, agranulocytosis, thrombocytopenia, leukopenia, anemias, lymphadenopathy, or full-blown anaphylaxis. In humans, it is esti-mated that up to 15% of patients hypersensitive to cephalosporins will also be hypersensitive to penicillins. The incidence of cross-re-activity in veterinary patients is unknown. When given orally, penicillins may cause GI effects (anorexia, vomiting, diarrhea). Because the penicillins may also alter gut flora, antibiotic-associated diarrhea can occur and allow the proliferation of resistant bacteria in the colon (superinfections). Neurotoxicity (e. g., ataxia in dogs) has been associated with very high doses or very prolonged use. Al though the penicillins are not considered hepatotoxic, elevated liver enzymes have been re ported. Other effects reported in dogs include tachypnea, dyspnea, edema and tachycardia. Reproductive/Nursing Safety Penicillins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems associ-ated with these drugs. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. )Overdosage/Acute Toxicity Acute oral carbenicillin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving carbenicillin and may be of significance in veterinary patients: Am INOgly COSIDEST! : In vitro studies have demonstrated that peni-cillins can have synergistic or addi tive activity against certain bacteria when used with aminoglycosides b ACTERIOSTATIC ANTIb IOTICS T! (e. g., chloramphenicol, erythromycin, tetracyclines ): With penicillins are generally not recommend-ed, particularly in acute infections where the organism is pro-liferating rapidly as penicillins tend to perform better on actively growing bacteria PROb ENECIDT! : Competitively blocks the tubular secretion of most penicillins thereby increasing serum levels and serum half-lives, but may also lower urine levels laboratory Considerations As penicillins and other beta-lactams can inactivate T! aminoglyco­ sides in vitro (and in vivo in patients in renal failure), serum con-centrations of aminoglycosides may be falsely decreased if the patient is also receiving beta-lactam antibiotics and the serum is stored prior to analysis. It is recommended that if the assay is delayed, samples be frozen and, if possible, drawn at times when the beta-lactam antibiotic is at a trough. The significance of this interaction when using oral carbenicillin in patients with normal renal function is in doubt. Doses DOg S:T! For susceptible infections in sites where therapeutic levels may be achieved (bladder/urine, and possibly prostate):a) For UTI: 22-33 mg/kg PO q8h for 7-10 days (Greene and Watson 1998) CATS:T! For susceptible infections in sites where therapeutic levels may be achieved (bladder/urine, and possibly prostate):a) For UTI: 22-33 mg/kg PO q8h for 7-10 days (Greene and Watson 1998) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Mice, Rats: 100 mg/kg PO q12h (Adamcak and Otten 2000) b IRDS:T! For susceptible infections in Psittacines:a) 100-200 mg/kg PO twice daily; N tablet added to 4 oz drink-ing water. Crush tablets and gav age or hide in mash or pal-atable soft food item. If adding to drinking water, disguise bit ter taste by adding Tang® or a Pina Colada mix to water. (Mc Donald 1989) b) 200 mg/kg, PO for 5-10 days. Crush tablets and apply to favorite food (e. g., cooked sweet potato works well) or mix in mash or hand-feeding formula. (Clubb 1986) monitoring Because penicillins usually have minimal toxicity associated with T! their use, monitoring for efficacy is usually all that is required un-less toxic signs develop. Serum levels and therapeutic drug moni-toring are not routinely done with these agents.

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

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CARb OPl ATIN 133 the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) As methimazole can enter milk and have deleterious effects on offspring, switch to milk replacer if carbimazole or methimazole are required for nursing dams. Overdosage Acute toxicity that may be seen with overdosage include those that are listed above under Adverse Effects. Agranulocytosis, hepatopa-thy, and thrombocytopenias are perhaps the most serious effects that may be seen. Treatment consists of following standard proto-cols in handling an oral ingestion (empty stomach if not contrain-dicated, administer charcoal, etc. ) and to treat symp tomatically and supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving carbimazole and may be of significance in veterinary patients: b UPROPION!! : Potential for increased risk for hepatotoxicity; in-creased monitoring (LFT's) necessary DIg Ox IN!! : Carbimazole may decrease digoxin efficacy WARFARIN!! : Potential for decreased anticoagulant efficacy if carbi-mazole added Doses See also Methimazole. Usually, carbimazole dosages are twice that of methimazole. CATS:T! For hyperthyroidism:a) 10-15 mg total dose daily per cat in divided doses for 1-3 weeks will produce a euthyroid state for most patients. Then adjust dosage for the patient to the lowest effective dose. Most cats will need dosing at least once daily. (Debuf 1991) b) Initially, give 5 mg (total dose) q8h for 2-3 weeks. Then ad-just. May need to increase dose in approximately 10% of cats (be sure owner was compliant with previous dose). Most cats require 5 mg PO q12h to maintain euthyroidism. (Peterson 2000) monitoring During first 3 months of therapy (baseline values and every 2-3 weeks): CBC, platelet counts T! Serum TT! 4 If indicated by clinical signs: liver function tests, ANAT! After stabilized (at least 3 months of therapy): TT!4 at 3-6 month intervals Other diagnostic tests as dictated by adverse effects T! Client Information It must be stressed to owners that this drug will decrease exces-T! sive thyroid hormones, but does not cure the condition Adherence with the treatment regimen is neces sary for success T! Chemistry/Synonyms A thioimidazole-derivative antithyroid drug, carbimazole occurs as a white to creamy white powder having a characteristic odor. It is slightly soluble in water and soluble in alcohol. Carbimazole may also be known as: carbimazolum, Basolest®, Camazol®, Carbimazole®, Carbazole®, Carbistad®, Cazole®, Neo Tomizol®, Neo-Mercazole®, Neo-Thyreostat®, Thyrostat®, Tyrazol®, or Neo-morphazole®. Storage/Stability Unless otherwise labeled, carbimazole tablets should be stored at room temperature in well-closed containers. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: There are no approved products in the USA; elsewhere it may be available as: Carbimazole Tablets: 5 mg & 20 mg. Trade names include Neo-Car-bimazole®, Carbazole®, Neo Mercazole®, etc. c Arbopl A tin (kar-boe-pla-tin) Paraplatin® antine Oplastic Prescriber Highlights Platinum antineoplastic agent used for a variety of carci-T T nomas & sarcomas Unlike cisplatin, may be used in cats T T Contraindications: History of hypersensitivity to it or other T T platinum agents; severe bone marrow depression Caution: Hepatic/renal disease, hearing impairment, ac-T T tive infection Primary adverse effects: GI, Bone marrow depression. T T Nadir (neutrophils/platelets) in dogs about 14 days; in cats (neutrophils) about 17-21 days Fetotoxic T T Must be given IVT T May adversely affect vaccinations (safety/efficacy)T T Uses/Indications Like cisplatin, carboplatin may be useful in a variety of veterinary neoplastic dis eases including squamous cell carcinomas, ovarian carcinomas, mediastinal carcinomas, pleural ade nocarcinomas, nasal carcinomas and thyroid adenocarcinomas. Carboplatin's pri-mary use currently in small animal medicine is in the adjunctive treatment (post amputation) of osteogenic sarcomas. Its effective-ness in treating transitional cell carcinoma of the bladder has been disappointing; however, carboplatin may have more efficacy against melanomas than does cisplatin. Carboplatin, unlike cisplatin, appears to be relatively safe to use in cats. Carboplatin may be considered for intralesional use in condi-tions such as equine sarcoids or in treating adenocarcinoma in birds. Whether carboplatin is more efficacious than cisplatin for cer-tain cancers does not appear to be de cided at this point, but the drug does appear to have fewer adverse effects (less renal toxicity and re duced vomiting) in dogs. Pharmacology/Actions Carboplatin's exact mechanism of action is not fully understood. Both carboplat in's and cisplatin's properties are analogous to those of bifunctional alkylating agents producing in ter-and intrastrand cross-links in DNA, thereby inhibiting DNA replication, RNA transcrip-tion, and protein synthesis. Carboplatin is cell-cycle nonspecific.

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134 CARb OPl ATIN Pharmacokinetics After IV administration, carboplatin is well distributed through-out the body; highest concentrations are found in the liver, kidney, skin and tumor tissue. The metabolic fate and elimination of car-boplatin are complex and the discussion of this aspect of the drug's pharmacokinet ics is beyond the scope of this reference. Suffice it to say, the parent drug degrades into platinum and platinum-com-plexed compounds that are primarily eliminated by kidneys. In dogs, almost one half of the dose is excreted in the urine within 24 hours and approximately 70% of the platinum ad ministered is secreted in the urine after 72 hours. Contraindications/Precautions/Warnings Carboplatin is contraindicated in patients hypersensitive to it or other platinum-containing compounds. It is also contraindicated in patients with severe bone marrow suppression. Patients with severe carboplatin-induced myelosuppression should be allowed to recover their counts before additional therapy. Caution is advised in patients with active infections, hearing im-pairment or preexisting renal or hepatic disease. Dosage may need adjustment in patients with reduced renal function. One suggested dosage adjustment (Kitchell 2002) for cats, small dogs and those with real function follows: Cats usually dosed at 180-240 mg/m2 depending on the size and general health of the patient. Dogs usually dosed at 300 mg/m 2, but in dogs <10 lb. : 200 mg/m2; 10-20 lb. : 250 mg/m2; >20 lb. : 300 mg/m2. Dogs with se-rum creatinine levels of 2. 5-3 mg/dl are dosed at 200 mg/m2 and if creatinine is 2-2. 5 mg/dl: 250 mg/m2. Dogs with a creatinine greater than 3 mg/dl are not dosed with carboplatin. Do not give carboplatin IM or SC. Adverse Effects Established adverse effects in dogs include anorexia, vomiting (GI effects are uncommon) and dose-related bone marrow suppression that is exhibited primarily as thrombocytopenia and/or neutropenia. The nadir of platelet and neutrophil counts generally occur about 14 days post treatment in dogs. Recov ery is generally seen by day 21. In cats, thrombocytopenia occurs infrequently, but the neutrophil nadir occurs about 21 days post treatment. Recovery usually occurs by day 28 in cats. Hepatotoxicity (increased serum bilirubin and liver enzymes) is seen in about 15% of human patients treated with carboplatin. Other potential adverse effects include: nephrotoxicity, neuropathies and ototoxicity. These effects occur with carboplatin therapy much less frequently than with cisplatin therapy. Anaphylactoid reactions have been reported rarely in humans that have received platinum-containing compounds (e. g., cisplatin). Hyperuricemia may occur after therapy in a small percentage of patients. Reproductive/Nursing Safety Carboplatin is fetotoxic and embryotoxic in rats and the risks of its use during pregnancy should be weighed with its potential benefits. In humans, the FDA categorizes this drug as category D for use dur-ing pregnancy (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. ) It is unknown whether carboplatin enters maternal milk. In hu-mans, it is recommended to discontinue nursing if the mother is receiving the drug. Overdosage/Acute Toxicity There is limited information available. An overdose of carboplatin would be expected to cause aggravated effects associated with the drug's bone marrow nephro-and liver toxicity. Monitor for neuro-toxicity, ototoxicity, hepatotoxicity and nephrotoxicity. Treatment is basically supportive; no specific antidote is avail-able. Plasmapheresis or hemodialysis could potentially be of benefit in removing the drug. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving carboplatin and may be of significance in veterinary patients: Am INOgly COSIDEST! : Potential for increased risk of nephrotoxicity or ototoxicity CISPl ATINT! : Human patients previously treated with cis platin have an increased risk of developing neurotoxicity or ototoxicity after receiving carboplatin myl EOSUPPRESSIVE DRUg ST! : The leukopenic or thrombocytopenic effects secondary to carboplatin may be enhanced by other my-elosuppressive medications RADIATION THERAPy T! : Potential for increased hematologic toxicity VACCINEST! : Live or killed virus vaccines administered after carbo-platin therapy may not be as effective as the immune response to these vaccines may be modified by carboplatin therapy; carbopla-tin may also potentiate live virus vaccines replication and increase the adverse effects associated with these vac cines Doses Note : Do not confuse cisplatin and carboplatin dosages; cisplatin dosages are much lower. For more information on cancer chemotherapy, 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). DOg S:T! As adjunctive treatment of osteogenic sarcoma:a) 300 mg/m2 BSA IV every 21 days (Bergman, Mac Ewen et al. 1996) b) 300 mg/m2 BSA IV (admixed with D5W and given IV over 15 minutes) usually within 7 days after amputation. Addition-al treatments given every 21 days for a total of 4 treatments (Johnston 1997) As adjunctive treatment of osteogenic sarcoma, melanomas, or various carcinomas:a) Large Dogs: 350 mg/m2 BSA IV (diluted in dextrose) every 3 weeks Small Dogs: 300 mg/m2 BSA IV (diluted in dextrose) every 3 weeks (London and Frimberger 1997) CATS:T! As adjunctive treatment of osteogenic sarcoma, melanomas or various carcinomas: a) 210 mg/m2 BSA IV (diluted in dextrose) every 3 weeks (Lon-don and Frimberger 1997) b) 180-260 mg/m2 IV every 21 days (Kitchell and Dhaliwal 2000) For Squamous cell carcinoma of the nasal planum (intra tumor administration): a) Give 100 mg/m2 BSA intratumorally (Kitchell and Dhaliwal 2000) b) 1. 5 mg (in a purified sesame oil)/cm3 of tissue (including gross tumor and a margin of normal tissue) injected intra-

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CARNITINE 135 tumorally once a week for 4 weeks (Donecker, Sams et al. 1986) b IRDS:T! For adenocarcinoma: a) 5 mg/kg IV over 3 minutes every 14-21 days (Tully 2006) monitoring CBCT! Serum electrolytes, uric acid T! Baseline renal and hepatic function tests T! Client Information Clients should fully understand the potential toxicity of this agent T! and, ideally, should give informed consent for its use. As carboplatin (and any platinum containing metabolites) is T! principally excreted in the urine over several days after treatment, clients should be warned to avoid direct contact with patient's urine. Chemistry/Synonyms Carboplatin, like cisplatin, is a platinum-containing antineoplastic agent. It occurs as white to off-white crystalline powder having a solubility of 14 mg/m L in water and is insoluble in al cohol. The commercially available powder for injection contains equal parts of mannitol and carbo platin. After reconstitution with sterile water for injection, a resulting solution of 10 mg/m L of car boplatin has a p H of 5-7 and an osmolality of 94 m Osm/kg. Carboplatin may also be known as: cis-Diammine-1,1-cyclob-utanedicarboxylato-platinum, carboplatinum; CBDCA; JM-8; or NSC-241240; many trade names are available. Storage/Stability/Compatibility/Preparation The powder for injection should kept stored at room temperature and protected from light. After reconstitution, solutions containing 10 mg/m L are stable for at least 8 hours. Some sources say that the solution is stable for up to 24 hours and can be refrigerated, but because there are no preser vatives in the solution, the manufacturer recommends dis-carding unused portions after 8 hours. Pre vious recommendations to avoid the use of solutions to dilute carbo platin containing so-dium chloride are no longer warranted as only a minimal amount of carboplatin is converted to cisplatin in these solutions. Because aluminum can displace platinum from carboplatin, the solution should not be prepared, stored or administered where aluminum-containing items can come into contact with the solu-tion. Should carboplatin come into contact with aluminum, a black precipitate will form and the product should not be used. Directions for reconstitution for the 50 mg vial: Add 5 m L of ei-ther sterile water for injec tion, normal saline injection or D 5W that will provide a solution containing 10 mg/m L. May infuse directly (usually over 15 minutes) or further dilute. Visually inspect after re constitution/dilution for discoloration or particulate matter. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Carboplatin Powder for reconstitution and IV Injection: 50 mg, 150 mg, and 450 mg vials (contains mannitol); Paraplatin® (Bristol- Myers Squibb Oncology); generic; (Rx)c Arnitine levoc Arnitine l-c Arnitine (kar-ni-teen) Carnitor® nutrient Prescriber Highlights Nutrient required for normal fat utilization & energy T T metabolism May be useful in certain cardiomyopathies (including T T doxorubicin induced) in dogs Use only L (levo-) forms T T Preferably give with meals T T Uses/Indications Levocarnitine may be useful as adjunctive therapy of dilated cardio-myopathy in dogs. Up to 90% of dogs with dilated cardiomyopa-thy may have a carnitine deficiency. Levocarni tine may also protect against doxorubicin-induced cardiomyopathy and reduce risks of myocardial infarction. It may be beneficial in the adjunctive treat-ment of valproic acid toxicity. In cats, levocarnitine has been recommended as being useful as an adjunctive therapy in feline hepatic lipidosis by facilitating he-patic lipid metabolism. Its use for this indication is controversial. Pharmacology/Actions Levocarnitine is required for normal fat utilization and energy me-tabolism in mammalian species. It serves to facilitate entry of long-chain fatty acids into cellular mitochondria where they can be used during oxidation and energy production. Severe chronic deficiency is generally a result of an inborn ge-netic defect where levocarnitine utilization is impaired and not the result of dietary insufficiency. Effects seen in levocarnitine defi-ciency may include hypoglycemia, progressive myasthenia, hepato-megaly, CHF, cardiomegaly, hepatic coma, neurologic disturbances, encephalopathy, hypotonia and lethargy. Pharmacokinetics In humans, levocarnitine is absorbed via the GI with a bioavailabil-ity of about 15%, but is absorbed rapidly in the intestine via passive and active mechanisms. Highest levels of levocarnitine are found in skeletal muscle. Levocarnitine is distributed in milk. Exoge nously administered levocarnitine is eliminated by both renal and fecal routes. Plasma levocarnitine levels may be increased in patients with renal failure. Contraindications/Precautions/Warnings Levocarnitine may also be known as Vita min B T. Products labeled as such may have both D and L racemic forms. Use only Levo-(L-) forms as the D-form may competitively inhibit L-uptake with a resulting deficiency. Adverse Effects Adverse effect profile is minimal. Gastrointestinal upset is the most likely effect that may be noted and is usually associated with high dosages but is usually mild and limited to loose stools or possibly diarrhea; nausea and vomiting are possible. Human patients have reported increased body odor.

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

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CARPROFEN 137 Pharmacology/Actions Like other NSAIDs, carprofen exhibits analgesic, antiinflamma-tory, and an tipyretic activity probably through its inhibition of cyclooxygenase, phospholipase A 2 and inhibition of prostaglandin synthesis. Carprofen is more sparing of COX-1 in vitro and in dogs appears to have fewer COX-1 effects (GI distress/ulceration, plate-let inhibition, renal damage) when compared to older non-COX-2 specific agents. COX-2 specificity appears to be species, dose, and tissue dependent. Carprofen in horses or cats does not seem to be as COX-2 specific as it is in dogs. Pharmacokinetics When administered orally to dogs, carprofen is approximately 90% bioavail able. Peak serum levels occur between 1- 3 hours post dos-ing. The drug is highly bound to plasma proteins (99%) and has a low volume of distribution (0. 12-0. 22 L/kg). Carprofen is extensive-ly me tabolized in the liver primarily via glucuronidation and oxida-tive processes. About 70- 80% of a dose is eliminated in the feces; 10-20% eliminated in the urine. Some enterohepatic recycling of the drug occurs. Elimination half-life of carprofen in the dog is approxi-mately 13-18 hours with the S form having a longer half-life than the R form. In horses, the half-life of carprofen is reportedly 22 hours. Contraindications/Precautions/Warnings Carprofen is contraindicated in dogs with bleeding disorders (e. g., Von Willebrand's) or those that have had prior serious reactions to it or other propionic-class antiinflammatory agents. It should be used with caution in geriatric patients or those with preexisting chronic diseases (e. g., inflammatory bowel disease, renal or hepatic insufficiency). If discontinuing carprofen and switching to another NSAID, a one day wash-out period has been recommended (Boothe 2005). Adverse Effects Although adverse effects appear to be uncommon with carprofen use in dogs, they can occur. Mild gastrointestinal effects are the most likely to appear, but serious effects (hepatocellular damage and/or renal disease; hematologic and serious gastrointestinal ef-fects) have been reported. Reported incidence of hepatopathy is approximately 0. 05% of dogs treated. Geriatric dogs or dogs with chronic diseases (e. g., inflammatory bowel disease, renal or hepatic insufficiency) may be at greater risk for developing toxicity while receiving this drug. Al though not proven statistically significant, Labrador Retrievers have been associated with G of the initially re-ported cases associated with the reported hepatic syndrome; but it is not believed that this breed has any greater chance of developing this adverse effect than others. Before initiating therapy, pre-treat-ment patient evaluation and discussion with the owner regarding the potential risks versus ben efits of therapy are strongly advised. Reproductive/Nursing Safety The manufacturer states that the safe use of carprofen in dogs less than 6 weeks of age, pregnant dogs, dogs used for breeding pur-poses, or lactating bitches has not been established. Carprofen has been given to pregnant rats at dosages of up to 20 mg/kg during day 7-15 of gestation. While no teratogenic effects were noted in pups, the drug did delay parturition with an increased number of dead pups at birth. Overdosage/Acute Toxicity In dog toxicologic studies, repeated doses of up to 10X resulted in little adversity. Some dogs exhibited hypoalbuminemia, melena or slight increases in ALT. However, post-market ing surveillance sug-gests that there may be significant interpatient variability in re-sponse to acute or chronic overdoses. There were 2296 exposures to carprofen reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) dur-ing 2005-2006. In these cases 2066 were dogs with 90 showing clinical signs and the remaining 229 cases were cats with 11 show-ing clinical signs. Common findings in dogs recorded in decreasing frequency included vomiting, anorexia, lethargy, bloody vomitus and diarrhea. Common findings in cats recorded in decreasing fre-quency included vomiting, anorexia, dehydration, abdominal pain and absent bowel movements. 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 carprofen's use with other ulcerogenic drugs (e. g., corticos­ teroids or other NSAIDs ). The following drug interactions have either been reported or are theoretical in humans or animals receiving carprofen and may be of significance in veterinary patients: ASPIRINT! : When aspirin is used concurrently with carprofen, plas-ma levels of carprofen could decrease and an increased likelihood of GI adverse effects (blood loss) could occur. Concomitant ad-ministration of aspirin with carprofen cannot be recommended. CORTICOSTEROIDST! : Concomitant administration with NSAIDs may significantly increase the risks for GI adverse effects DIg Ox INT! : Carprofen may increase serum levels of digoxin; use with caution in patients with severe cardiac failure FUROSEm IDET! : Carprofen may reduce the saluretic and diuretic ef-fects of furosemide HIg Hly PROTEIN b OUND DRUg S T! (e. g., phenytoin, valproic acid, oral anti­ coagulants, other antiinflammatory agents, salicylates, sulfonamides, sulfonylurea antidiabetic agents ): Because carprofen is highly bound to plasma proteins (99%), it potentially could displace other highly bound drugs; increased serum levels and duration of actions may occur. Although these interactions are usually of little concern clinically, use together with caution. m ETHOTREx ATET! : Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate; use together with extreme caution PHENOb ARb ITAl, RIFAm PIN, T! or OTHER HEPATIC ENzym E INDUCINg Ag ENTS : As carprofen hepatotoxicity may be mediated by its he-patic metabolites, these drugs should be avoided if carprofen is required PROb ENECIDT! : May cause a significant increase in serum levels and half-life of carprofen laboratory Considerations In dogs, carprofen may lower T! Total T4 and TSH levels, but ap-parently does not affect free concentrations of T 4. Doses DOg S:T! As an antiinflammatory/analgesic: a) 4. 4 mg/kg PO; may be given once daily or divided and given as 2. 2. mg/kg twice daily; round dose to nearest half caplet increment. For postoperative pain, administer approximately 2 hours before the procedure. Injectable is dosed as the oral products, but administered SC. (Package Insert; Rimadyl®— Pfizer)

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

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CARVEDIl Ol 139 c Arvedilol (kar-vah-da-lol) Coreg® beta & alpha-1 adrenergic bl Ocker Prescriber Highlights Non-selective Beta-adrenergic blocker with selective T T alpha1-adrenergic blocking activity that could be useful for treating heart failure in dogs; use is controversial Very limited veterinary experience T T Negative inotrope that may prohibit its use in severely T T symptomatic patients; potentially could decompensate patient Additional adverse effects that may demonstrate intoler-T T ance include lassitude, inappetence, & hypotension Expense may be an issue T T Uses/Indications Carvedilol may be useful as adjunctive therapy in the treatment of heart failure (dilated cardiomyopathy) in dogs. There is a fair amount of controversy at present among veterinary cardiologists as to whether this drug will find a therapeutic niche. Pharmacology/Actions Carvedilol is a non-selective, beta-adrenergic blocker with selective alpha1-adrenergic blocking activity. Despite their negative inotro-pic effects, chronic dosing of beta blockers in human patients with dilated cardiomyopathy can be useful in reducing both morbidity and mortality. Patients in heart failure, chronically activate their sympathetic nervous system, thereby leading to tachycardia, activa-tion of the renin-angiotensin-aldosterone system, down-regulation of beta-receptors, induction of myocyte necrosis and myocyte en-ergy substrate and calcium ion handling. By giving beta-blockers, these negative effects may be reversed or diminished. As carvedilol also inhibits alpha1-adrenergic activity, it can cause vasodilation and reduce afterload. Carvedilol has free-radical scavenging and antidysrhythmic effects that could be beneficial in heart failure pa-tients. Pharmacokinetics In dogs, a pilot study (Arsenault, Boothe et al. 2003) showed carve-dilol's bioavailability after oral dosing averaged about 23% in the 4 dogs studied, but in 3 of the 4, bioavailability ranged from 3-10%. Volume of distribution averaged about 1. 4 L/kg; elimination half-life was about 100 minutes. At least 15 different metabolites of carvedilol have been identified after dosing in dogs. Hydroxylation of the carbazolyl ring and glucuronidation of the parent compound are the most predominant processes of metabolism in dogs. In humans, carvedilol is rapidly and extensively absorbed but due to a high first-pass effect, bioavailability is about 30%. The drug is extensively bound to plasma proteins (98%). It is extensively metabolized and the R(+) enantiomer is metabolized 2-3 times greater than the S(-) form during the first pass. Both the R(+) and S(-) enantiomers have equal potency as non-specific beta-or al-pha-adrenergic blockers. CYP2D6 and CYP2C9 are the P450 isoen-zymes most responsible for hepatic metabolism. Some of these metabolites have pharmacologic activity. Metabolites are primarily excreted via the bile and feces. Elimination half-life of carvedilol in humans is about 8-9 hours. Contraindications/Precautions/Warnings In humans, carvedilol is contraindicated in class IV decompensated heart failure, bronchial asthma, 2nd or 3rd degree A V block, sick sinus syndrome (unless artificially paced), severe bradycardia, car-diogenic shock or hypersensitivity to the drug. Dogs with equiva-lent conditions should not receive the drug. Adverse Effects Veterinary experience is very limited and an accurate portrayal of adverse effects in dogs has yet to be elucidated. T oo rapid beta blockade can cause decompensation in patients with heart failure; cautious dosage titration is mandatory. Dogs that do not tolerate the medication may show signs of inappetence, lassitude, or hy-potension. Bronchospasm has been reported in humans. Because the drug is extensively metabolized in the liver, patients with hepatic insufficiency should receive the drug with caution. In humans, carvedilol has on rare occasions, caused mild hepatocel-lular injury. Reproductive/Nursing Safety In humans, the FDA categorizes carvedilol as a category C drug for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). In rats and rabbits, carvedilol increased post-implantation loss. It is unknown if carvedilol enters maternal milk in dogs, but it does enter milk in rats. Use with caution in nursing patients. Overdosage/Acute Toxicity The acute oral LD50 in healthy rats and mice is greater than 8 grams/ kg. Clinical signs associated with large overdoses include: severe hypotension, cardiac insufficiency, bradycardia, cardiogenic shock and death due to cardiac arrest. Gut emptying protocols should be considered if ingestion was recent. In humans, bradycardia is treated with atropine, and cardiovascular function supported with glucagon and sympathomimetics (e. g., dobutamine, epinephrine, etc. ). Contact an animal poison control center for specific informa-tion in the case of overdose. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving carvedilol and may be of significance in veterinary patients: b ETA­bl OCKERST! (other ): Use with carvedilol may cause additive effects CAl CIUm CHANNEl bl OCKERS T! (e. g., diltiazem, verapamil ): Carvedilol may rarely cause hemodynamic compromise in patients taking diltiazem or verapamil CIm ETIDINET! : May decrease metabolism and increase AUC of carvedilol Cl ONIDINET! : Carvedilol may potentiate the cardiovascular effects of clonidine Cy Cl OSPORINET! : Carvedilol may increase cyclosporine levels DIg Ox INT! : Carvedilol can increase (in humans) digoxin plasma concentrations by approximately 15% Fl UOx ETINE, P AROx ETINE, QUINIDINE T! : May increase R(+)-carve-dilol concentrations and increase alpha-1 blocking effects (vasodilation) INSUl IN; ORAl ANTIDIAb ETIC Ag ENTS T! : Carvedilol may enhance the blood glucose lowering effects of insulin or other antidiabetic agents RIFAm PINT! : Can decrease carvedilol plasma concentrations by as much as 70%

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140 CASPOFUNg IN ACETATE RESERPINET! : Drugs such as reserpine can cause increased bradycar-dia and hypotension in patients taking carvedilol laboratory Considerations No specific laboratory interactions or considerations noted Doses DOg S:T! a) A reasonable target plasma carvedilol concentration is 50-100 ng/m L. Based upon prior studies and the small series of dogs studied in this study, doses of 0. 5 mg/kg PO twice daily should result in beta-blockade, but maximum beta-blockade may require doses of >0. 7-0. 9 mg/kg. Because of bioavailability variations, plasma monitoring, clinical trials and uptitration protocols may be beneficial. (Gordon, Boothe et al. 2004) monitoring Clinical efficacy T! Adverse effects T! Plasma drug levels (see Doses above)T! Client Information Give this medication exactly as veterinarian prescribes. Do not stop T! the medication without the approval and guidance of veterinarian Contact veterinarian if animal's condition worsens while receiv-T! ing this medication, or if it shows signs of reduced appetite, fa-tigue or listlessness, and dizziness or unsteadiness Medication is best given with food T! Veterinarians should inform clients of the relative “investigation-T! al” nature of this medication in veterinary patients Chemistry/Synonyms A non-selective beta-adrenergic blocker with selective alpha1-adrenergic blocking activity, carvedilol occurs as a white to off-white crystalline powder that is practically insoluble in water, dilute acids, and gastric or intestinal fluids. It is sparingly soluble in ethanol. The compound exhibits polymorphism and contains both R(+) and S(-) enantiomers. It is a basic, lipophilic compound. Carvedilol may also be known as: BM-14190, carvedilolum, Cardilol®, Cardiol®, Carloc®, Carvil®, Carvipress®, Coreg ®, Coritensil®, Coropres®, Dilatrend®, Dilbloc®, Dimitone®, Divelol ®, Eucardic®, Hybridil®, Kredex®, or Querto®. Storage/Stability Carvedilol tablets and extended release capsules should be stored below 30°C (86°F) and protected from moisture. They should be dispensed in tight, light-resistant containers. An oral suspension with documented 90 day stability may be compounded to accurately dose dogs (Gordon, Boothe et al. 2006). Powder 25 mg tablets and add enough de-ionized water to make a paste, allowing the tablet coating to dissolve. Then suspend in a commercially available simple syrup to a concentration of either 2 mg/m L or 10 mg/m L. Store in amber bottles at temperatures not exceeding 25°C and protect from light for up to 90 days. Shake well before administering. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUm AN­l Ab El ED PRODUCTS: Carvedilol Oral Tablets: 3. 125 mg, 6. 25 mg, 12. 5 mg, and 25 mg; Coreg ® (Glaxo Smith Kline); (Rx) Carvedilol Extended-Release Capsules: 10 mg, 20 mg, 40 mg & 80 mg; Coreg CR® (Glaxo Smith Kline); (Rx) c Aspofungin Acet Ate (kas-poe-fun-jin) Cancidas® parenteral antifungal Prescriber Highlights Parenteral antifungal that has potential for treating inva-T T sive aspergillosis or disseminated candidal infections in companion animals Very limited clinical experience in veterinary medicine T T Very Expensive T T Uses/Indications Caspofungin has potential for treating invasive aspergillosis or dis-seminated candidal infections in companion animals although little, if any, information on its use in dogs or cats is available. Pharmacology/Actions Caspofungin represents the echinocandins, a new class of antifungal agent. These drugs inhibit beta-glucan synthase, thereby blocking the synthesis of beta-(1,3)-D-glucan, a component found in cell walls of filamentous fungi. Caspofungin has activity against Aspergillus and Candida species and is effective in treating pneumonia caused by Pneumocystis carinii. Because it contains very little beta-glucan syn-thase, Cryptococcus neoformans infections are not effectively treated with caspofungin. Pharmacokinetics No information was located on the pharmacokinetics of caspo-fungin in dogs or cats. In humans, the drug is not appreciably absorbed from the gut and must be administered IV. Protein binding (primarily to albu-min) is high (97%) and the drug is distributed to tissues over a 36-48 hour period. Caspofungin is slowly metabolized via hydro-lysis and N-acetylation. It also spontaneously degrades chemically. Caspofungin exhibits polyphasic elimination, but little drug is ex-creted or biotransformed during the first 30 hours post-administra-tion. Elimination half-life for the primary phase is about 10 hours; the secondary phase between 40-50 hours. Excretion, consisting mostly as metabolites, is via the feces and urine. Only small amounts (1-2%) are excreted unchanged into the urine. Contraindications/Precautions/Warnings No specific information is available for veterinary patients. Caspofungin is contraindicated in human patients hypersensitive to it. Dosage adjustment is recommended in humans with moderate hepatic impairment. No information is available for use in patients with significant hepatic impairment; avoid use. Reproductive/Nursing Safety In humans, the FDA categorizes caspofungin as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Studies with caspofungin performed in pregnant rats and rabbits

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CEFACl OR 141 demonstrated changes in fetal ossification. The drug should be avoided during the first trimester of pregnancy unless the benefits associated with treating outweigh the risks. Although no data is available, because the drug is not apprecia-bly absorbed from the gut, it would be expected that caspofungin would be safe to administer during lactation. Adverse Effects An adverse effect profile for animals has not been determined. In humans, caspofungin is generally well tolerated. Histamine-mediated signs have occurred (rash, facial swelling, pruritus) and anaphylaxis has been reported. Intravenous site reactions (pain, redness, phlebitis) have occurred. Hepatic dysfunction has been re-ported but frequency is unknown. Overdosage/Acute Toxicity Limited information is available. Dosages of 210 mg (about 3x) in humans were well tolerated. Some monkeys receiving 5-8 mg/kg (approx. 4-6X) over 5 weeks developed sites of microscopic sub-capsular necrosis on their livers. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving caspofungin and may be of significance in veterinary patients: CARb Am Az EPINET! : Reduced caspofungin plasma levels Cy Cl OSPORINET! : Increased caspofungin plasma levels and increased risk of hepatic enzyme increases DEx Am ETHASONET! : Reduced caspofungin plasma levels PHENy TOINT! : Reduced caspofungin plasma levels RIFAm PINT! : Reduced caspofungin plasma levels laboratory Considerations No specific concerns noted; see Monitoring Doses DOg ST! /CATS: No published doses for dogs or cats were located and the use of this medication in these patients must be considered highly investigational. Although not labeled for use in human pediat-ric patients, one study performed in immunocompromised hu-man pediatric patients administered doses of 0. 8-1. 6 mg/kg in patients weighing less than 50 kg and 50-75 mg (total dose) in those weighing more than 50 kg. The drug was well tolerated in both groups. monitoring Clinical efficacy T! Periodic liver function tests, CBC, serum electrolytes T! Client Information This medication is appropriate for inpatient use only T! Clients should understand the investigational nature and the as-T! sociated expense of using this drug on veterinary patients Chemistry/Synonyms Caspofungin acetate is a semisynthetic echinocandin compound produced from a fermentation product of Glarea lozoyensis. It oc-curs as a white to off-white powder that is freely soluble in water and slightly soluble in ethanol. The commercially available lyophilized powder for injection also contains acetic acid, sodium hydroxide, mannitol and sucrose. Caspofungin may also be known as: caspofungina, caspofungine, caspofungini, kaspofungiinia, kaspofungina, L-743873, MK-0991, or Cancidas®. Storage/Stability/Compatibility The commercially available product should be stored refrigerated (2-8°C). Refer to the package insert for very specific directions on preparing the solution for intravenous use. Do not use if the solution is cloudy or has precipitated. It is rec-ommended not to mix or infuse with any other medications and not to use with intravenous solutions containing dextrose. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Caspofungin Acetate Powder for Injection: 50 mg, & 70 mg in sin-gle-use vials; Cancidas® (Merck); (Rx) cef Aclor (sef-a-klor) Ceclor® Oral 2nd generati On cephal Osp Orin Prescriber Highlights Oral 2nd generation cephalosporin that is more active T T against some gram-negative bacteria then first genera-tion (e. g., cephalexin) cephalosporins Potentially useful when an oral cephalosporin is desired T T to treat bacterial infections that are susceptible to cefa-clor, but resistant to first generation cephalosporins Limited clinical experience in veterinary medicine T T Adverse effects most likely seen in small animals would T T be GI-related Uses/Indications Cefaclor may potentially be useful when an oral cephalosporin is desired to treat infections that are susceptible to it but resistant to first generation cephalosporins such as cephalexin or cefadroxil. Little information is available with regard to its clinical use in small animals, however. Pharmacology/Actions Cefaclor, like other cephalosporins, is bactericidal and acts via in-hibiting cell wall synthesis. Its spectrum of activity is similar to that of cephalexin, but it is more active against gram-negative bacteria including strains of E. coli, Klebsiella pneumoniae, and Proteus mira-bilis. For more information on cephalosporin pharmacology and spectrums of activity, refer to the Cephalosporin monograph. Pharmacokinetics Limited information is available on the pharmacokinetics of cefa-clor in dogs and none was located for cats. In dogs, about 75% of an oral dose is absorbed, but an apparent first-pass effect reduces bioavailability to about 60%. Cefaclor is distributed to many tis-sues, but levels are lower in interstitial fluid than those found in serum. Very high levels are excreted into the urine unchanged. Bile levels are higher than those found in serum. Dogs appear to metab-olize a greater percentage of cefaclor than do rats, mice, or humans. Approximate elimination half-life is about 2 hours in dogs. In humans, cefaclor is well absorbed after oral administration; food delays, but does not appreciably alter the amount absorbed. The drug is widely distributed, crosses the placenta and enters breast milk. Up to 85% of a dose is excreted unchanged into the

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

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CEFADROx Il 143 cef Adroxil (sef-a-drox-ill) Cefa-Drops®, Duricef® Oral 1st-generati On cephal Osp Orin Prescriber Highlights Oral 1st generation cephalosporin T T May be administered with food (especially if GI upset T T occurs) Most likely adverse effects are GI in nature T T May need to reduce dose in renal failure T T May be expensive when compared to generic cephalexin T T Uses/Indications Cefadroxil is approved for oral therapy in treating susceptible infec-tions of the skin, soft tissue, and genitourinary tract in dogs and cats. The veterinary oral tablets have been discontinued (in the USA), but human-labeled oral capsules and tablets are still available. Pharmacology/Actions A first generation cephalosporin, cefadroxil exhibits activity against the bacteria usually covered by this class. First generation cepha-losporins are usually bactericidal and act via inhibition of cell wall synthesis. While there may be differences in MIC's for individual first gen-eration cephalosporins, their spectrums of activity are quite similar. They generally possess excellent coverage against most gram-posi-tive pathogens; variable to poor coverage against most gram-neg-ative pathogens. These drugs are very active in vitro against groups A beta-hemolytic and B Streptococci, non-ente rococcal group D Streptococci (S. bovis), Staphylococcus intermedius and au-reas, Proteus mirabilis and some strains of E. coli, Klebsiella spp., Actinobacillus, Pasturella, Haemophilus equigenitalis, Shigella and Salmonella. With the exception of Bacteroides fragilis, most anaer-obes are very sus ceptible to the first generation agents. Most spe-cies of Corynebacteria are susceptible, but C. equi ( Rhodococcus) is usually resistant. Strains of Staphylococcus epidermidis are usually sensitive to the parenterally administered 1st generation drugs, but may have variable susceptibilities to the oral drugs. The following bacteria are regularly resistant to the 1st generation agents: Group D strepto cocci/enterococci (S. faecalis, S. faecium), Methicillin-resistant Staphylococci, indole-positive Pro teus spp., Pseudomonas spp., Enterobacter spp., Serratia spp. and Citrobacter spp. Pharmacokinetics Cefadroxil is reportedly well absorbed after oral administration to dogs without regard to feeding state. After an oral dose of 22 mg/kg, peak serum levels of approxi mately 18. 6 micrograms/m L occur within 1-2 hours of dosing. Only about 20% of the drug is bound to canine plasma proteins. The drug is excreted into the urine and has a half-life of about 2 hours. Over 50% of a dose can be recov-ered unchanged in the urine within 24 hours of dosing. In cats, the serum half-life has been reported as approximately 3 hours. Oral absorption of cefadroxil in adult horses after oral suspen-sion was administered was character ized as poor and erratic. In a study done in foals (Duffee, Christensen, and Craig 1989), oral bio-availability ranged from 36-99. 8% (mean=58. 2%); mean elimina-tion half-life was 3. 75 hours af ter oral dosing. Contraindications/Precautions/Warnings Cephalosporins are contraindicated in pa tients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam an tibiotics (e. g., penicillins, cefamy-cins, carbapenems). Oral systemic antibiotics should not be administered in patients with septicemia, shock or other grave illnesses as absorption of the medication from the GI tract may be significantly delayed or di minished. Parenteral routes (preferably IV) should be used for these cases. Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in patients documented to be hypersensitive to penicillin-class an-tibiotics is controversial. In hu mans, it is estimated that up to 15% of patients hypersensitive to penicillins will also be hypersensi tive to cephalosporins. The incidence of cross-reactivity in veterinary patients is unknown. When given orally, cephalosporins may cause GI effects (anorex-ia, vomiting, diarrhea). Adminis tering the drug with a small meal may help alleviate these effects. Because the cephalosporins may al-ter gut flora, antibiotic-associated diarrhea can occur and allow the proliferation of resistant bacteria in the colon (superinfections). While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with normal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use of cephalosporins have been associated with neurotoxicity, neu tropenia, agranulocytosis, throm-bocytopenia, hepatitis, positive Comb's test, interstitial nephritis, and tubular necrosis. Except for tubular necrosis and neurotoxicity, these effects have an immuno logic component. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems asso-ciated with these drugs. However, use only when the potential ben-efits outweigh the risks. In humans, the FDA categorizes this drug as 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. ) Cephalosporins can be distributed into milk, but are unlikely to pose much risk to nursing offspring; diarrhea is possible. Overdosage/Acute Toxicity Acute oral cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefadroxil and may be of significance in veterinary patients: PROb ENECIDT! : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives

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

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CEFAz Ol IN SODIUm 145 While there may be differences in MIC's for individual first generation cephalosporins, their spectrums of activ ity are quite similar. They possess generally excellent coverage against most gram-positive pathogens; variable to poor coverage against most gram-negative pathogens. These drugs are very active in vitro against groups A beta-hemolytic and B Streptococci, non-entero-coccal group D Streptococci (S. bovis), Staphylococcus intermedius and aureas, Proteus mirabilis and some strains of E. coli, Klebsiella spp., Actinobacillus, Pasturella, Haemophilus equigenitalis, Shigella and Salmonella. With the exception of Bacteroides fragilis, most an-aerobes are very susceptible to the first generation agents. Most spe-cies of Corynebacteria are susceptible, but C. equi (Rhodococcus) is usually resistant. Strains of Staphylococcus epidermidis are usually sensitive to the parenterally ad ministered 1st generation drugs, but may have variable susceptibilities to the oral drugs. The follow ing bacteria are regularly resistant to the 1st generation agents: Group D streptococci/enterococci (S. faecalis, S. faecium), Methicillin-resistant Staphylococci, indole-positive Proteus spp., Pseudomonas spp., Enterobacter spp., Serratia spp. and Citrobacter spp. Pharmacokinetics Cefazolin is not appreciably absorbed after oral administration and must be given parenterally to achieve therapeutic serum levels. Absorbed drug is excreted unchanged by the kidneys into the urine. Elimination half-lives may be significantly prolonged in patients with severely diminished renal function. In dogs, peak levels occur in about 30 minutes after IM admin-istration. The apparent volume of distribution at steady state is 700 m L/kg, total body clearance of 10. 4 m L/min/kg with a serum elimi-nation half-life of 48 minutes. Approximately 64% of the clearance can be attributed to renal tubular secretion. The drug is approxi-mately 16-28% bound to plasma proteins in dogs. In horses, the apparent volume of distribution at steady state is 190 m L/kg, total body clearance of 5. 51 m L/min/kg with a se-rum elimination half-life of 38 minutes when given IV and 84 min-utes after IM injection (gluteal muscles). Cefazolin is about 4-8% bound to equine plasma proteins. Because of the significant tubular secretion of the drug, it would be expected that probenecid admin-istration would alter the kinetics of cefazolin. One study performed in horses (Donecker, Sams, and Ashcroft 1986), did not show any effect, but the authors concluded that the dosage of probenecid may have been sub-therapeutic in this species. In calves, the volume of distribution is 165 m L/kg, and had a terminal elimination half-life of 49- 99 minutes after IM administration. Contraindications/Precautions/Warnings Cephalosporins are contraindicated in pa tients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam an tibiotics (e. g., penicillins, cefamy-cins, carbapenems). Patients in renal failure may need dosage adjustments. Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in patients documented to be hypersensitive to penicillin-class antibiotics is controversial. In hu mans, it is estimated 1-15% of patients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary pa-tients is unknown. Cephalosporins can cause pain at the injection site when adminis-tered intramuscularly, although this effect occurs less with cefazolin than with other agents. Sterile abscesses or other severe local tissue re actions are possible but are much less common. Thrombophlebitis is also possible after IV ad ministration of these drugs. While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with normal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neu-rotoxicity, neutropenia, agranulocy tosis, thrombocytopenia, hepa-titis, positive Comb's test, interstitial nephritis, and tubular necro-sis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component. Cefazolin may be more likely than other cephalosporins to cause seizures at very high doses. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems asso-ciated with these drugs. However, use only when the potential ben-efits outweigh the risks. In humans, the FDA categorizes this drug as 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. ) Cefazolin is distributed into milk and could potentially alter neonatal gut flora. Use with caution in nursing dams. Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems, but other effects are possible (see Adverse Effects section). Very high doses given IV rapidly could potentially cause seizures. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefazolin and may be of significance in veterinary patients: NEPHROTOx IC DRUg ST! : The concurrent use of parenteral amino-glycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, ce-phalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well docu-mented with cephaloridine (no longer marketed). Nevertheless, use caution. PROb ENECIDT! : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives. laboratory Considerations Except for cefotaxime, cephalosporins may cause false-positive T! urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. When using the Jaffe reaction to measure T! serum or urine creatinine, cephalosporins (not cef tazidime or cefotaxime) in high dosages may falsely cause elevated values. In humans, particularly with azotemia, cephalosporins have T! caused a false-positive direct Coombs' test. Cephalosporins may also cause falsely elevated T! 17­ketosteroid val-ues in urine.

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

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CEFEPIm E HCl 147 cefepime hcl (sef-eh-pim) Maxipime® 4th generati On cephal Osp Orin Prescriber Highlights Injectable 4th generation cephalosporin that is more T T active against some gram-negative & gram-positive bac-teria than 3rd generation cephalosporins Potentially useful for treating neonatal foals & dogs with T T serious infections Limited clinical experience in veterinary medicine T T Adverse effects most likely seen in small animals T T or foals would be GI-related (diarrhea)Treatment may be very expensive T T Uses/Indications Cefepime is a semi-synthetic 4th generation cephalosporin with enhanced activity against many gram-negative and gram-positive pathogens. It potentially may be useful in treating serious infections in dogs or foals particularly when aminoglycosides, fluoroquinolo-nes or other more commonly used beta-lactam drugs are ineffective or contraindicated. Pharmacology/Actions Cefepime, like other cephalosporins, is usually bactericidal and acts by inhibiting cell wall synthesis. It is classified as a 4th-generation cephalosporin, implying increased gram-negative activity (particu-larly against Pseudomonas) and better activity against many gram-positive bacteria than would be seen with the 3rd generation agents. It rapidly penetrates into gram-negative bacteria and targets pen-icillin-binding proteins (PBPs). Cefepime does not readily induce beta-lactamases and is highly resistant to hydrolysis by them. Cefepime has activity against many gram-positive aerobes in-cluding many species and strains of Staphylococci and Streptococci. It is not clinically effective in treating infections caused by entero-cocci, L. monocytogenes, or methicillin-resistant staphylococci. Cefepime has good activity against many gram-negative bacte-ria and has better activity than other cephalosporins against many Enterobacteriaceae including Enterobacter spp., E. coli, Proteus spp. and Klebsiella. Its activity against Pseudomonas is similar to, or slightly less than, that of ceftazidime. Cefepime also has activity against certain atypicals like Mycobacterium avium-intracellulare complex. Some anaerobes are sensitive to cefepime, but Clostridia and Bacteroides are not. For more information on cephalosporin pharmacology and spectrums of activity, refer to the Cephalosporin monograph. Pharmacokinetics Cefepime is not absorbed from the GI tract and must be admin-istered parenterally. In dogs, cefepime's volume of distribution at steady state is approximately 0. 14 L/kg, elimination half-life about 1. 1 hours and clearance 0. 13 L/kg/hr. In neonatal foals, cefepime's volume of distribution at steady state is approximately 0. 18 L/kg, elimination half-life about 1. 65 hours and clearance 0. 08 L/kg/hr. In humans, volume of distribution is about 18 L in adults; 20% of the drug is bound to plasma proteins. Elimination half-life isabout 2 hours. Approximately 85% of a dose is excreted unchanged into the urine, less than 1% is metabolized. Contraindications/Precautions/Warnings No specific information is available for veterinary patients. Cefepime is contraindicated in human patients hypersensitive to it or other cephalosporins. Dosage adjustment is recommended in humans with severe renal impairment. Adverse Effects As usage of cefepime in animals has been very limited, a compre-hensive adverse effect profile has not been determined. There are some reports of dogs or foals developing loose stools or diarrhea after receiving cefepime. IM injections may be painful (alleviated by using 1% lidocaine as diluent). Human patients generally tolerate cefepime well. Injection site inflammation and rashes occur in approximately 1% of treated patients. Gastrointestinal effects (dyspepsia, diarrhea) occur in less than 1% treated patients. Hypersensitivity reactions including ana-phylaxis are possible. Rarely, patients with renal dysfunction who have received cefepime without any dosage adjustment will develop neurologic effects (see Overdosage). Reproductive/Nursing Safety Studies performed in pregnant mice, rats, and rabbits demonstrat-ed no overt fetal harm. In humans, the FDA categorizes cefepime as 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. ) Cefepime enters maternal milk in very low concentrations. Although probably safe for nursing offspring, the potential for ad-verse effects cannot be ruled out, particularly alterations to gut flora with resultant diarrhea. Overdosage/Acute Toxicity No specific information was located for acute toxicity in veterinary patients. Humans with impaired renal function receiving inadvertent overdoses have developed encephalopathy, seizures and neuromus-cular excitability. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefepime and may be of significance in veterinary patients: Am INOgly COSIDEST! : Potential for increased risk of nephrotoxicity— monitor renal function laboratory Considerations Cefepime may cause false-positive T! urine glucose determinations when using the copper reduction method (Benedict's solution, Fehling's solution, Clinitest ®); tests utilizing glucose oxidase (Tes-Tape ®, Clinistix ®) are not affected by cephalosporins In humans, particularly with azotemia, cephalosporins have T! caused a false-positive direct Coombs' test Doses DOg S:T! For susceptible infections:a) 40 mg/kg IV q6h (Gardner and Papich 2001)

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

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CEFOPERAz ONE SODIUm 149 Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefixime and may be of significance in veterinary patients: PROb ENECIDT! : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives SAl ICyl ATEST! : May displace cefixime from plasma protein binding sites; clinical significance is unclear laboratory Considerations Cefixime may cause false-positive T! urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinit-est®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. If using the nitroprusside test for determining T! urinary ketones, ce-fixime may cause false-positive results. Doses DOg S:T! For susceptible infections: a) For infectious endocarditis when documented resistance against or other contraindications for fluoroquinolones and aminoglycosides: 10 mg/kg PO q12h (De Francesco 2000) b) For UTI: 5 mg/kg PO once to twice daily for 7-14 days For respiratory, systemic infections: 12. 5 mg/kg PO q12h for 7-14 days (Greene and Watson 1998) c) 5 mg/kg PO once to twice a day (Boothe 1999) CATS:T! For susceptible infections:a) 5-12. 5 mg/kg PO q12h (Lappin 2002a) monitoring Efficacy T! Adverse effects T! Client Information Can be given without regard to meals T! Give as directed for as long as veterinarian recommends, even if T! patient appears well Chemistry/Synonyms An oral 3rd generation semisynthetic cephalosporin antibiotic, ce-fixime is available commercially as the trihydrate. Cefixime occurs as a white to slightly yellowish white crystalline powder with a char-acteristic odor and a p Ka of 3. 73. Solubility in water is p H depen-dent. At a p H of 3. 2, 0. 5 mg/m L is soluble and 18 mg/m L at p H 4. 2. The oral suspension is strawberry flavored and after reconstitution has p H of 2. 5-4. 2. Cefixime may also be known as: cefiximum, CL-284635, FK-027, FR-17027 and Suprax®; many internationally registered trade names are available. Storage/Stability Cefixime powder for suspension should be stored at room tempera-ture in tight containers. After reconstitution of the oral suspension, refrigeration is not required, but it should be discarded after 14 days whether refrigerated or not. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Powder for Oral Suspension: 100 mg/5 m L in 50 m L, & 75 m L; Su-prax® (Lupin Pharma); (Rx) cefoper Azone sodium (sef-oh-per-a-zone) Cefobid® 3rd generati On cephal Osp Orin Prescriber Highlights 3rd generation parenteral cephalosporin; has reasonably T T good activity against Pseudomonas aeruginosa Potentially could cause hypersensitivity reactions, throm-T T bocytopenia, Vitamin K defi ciency/bleeding, or diarrhea Causes pain on IM injection; give IV over 15T T -30 minutes (or more)May need to reduce dose in hepatic failure or consider T T other drugs Uses/Indications Cefoperazone is used to treat serious infections, particularly sus-ceptible Enterobacteriaceae not susceptible to other less expensive agents or when aminoglycosides are not indicated (due to their po-tential toxicity). Pharmacology/Actions Cefoperazone is a third generation injectable cephalosporin agent and, like other cephalosporins, it inhibits bacteria cell wall synthe-sis. Cefoperazone is considered bactericidal and relatively resistant to bacterial beta-lactamases. The third gen eration cephalosporins retain much of the gram-positive activity of the first and second-generation agents, but in comparison, have much expanded gram-negative activity. As with the 2nd generation agents, enough vari-ability exists with individual bacterial sensitivities that suscepti bility testing is necessary for most bacteria. Usually only ceftazidime and cefoperazone are active against most strains of Pseudomonas aeruginosa. Pharmacokinetics Cefoperazone is not absorbed after oral administration and must be given par enterally. It is widely distributed throughout the body; CSF levels are low if meninges are not in flamed. Cefoperazone crosses the placenta and enters maternal milk in low concentra-tions; no docu mented adverse effects to offspring have been noted. Unlike most cephalosporins, cefoperazone is principally excreted in the bile; elimination half-lives are approximately 2 hours in hu-mans. Dosage adjustments generally are not required for patients with renal insufficiency. In dogs, cefoperazone has a volume of distribution of 0. 233 L/kg and a clearance of 2 m L/kg/minute. IM bioavailability is only about 40%. Elimination half-life is approximately 2. 1 hours in the dog. Contraindications/Precautions/Warnings Only prior allergic reaction to cephalosporins contraindicates ce-foperazone's use. In humans documented hypersensitive to peni-cillin, up to 16% may also be allergic to cephalosporins; the veteri-nary significance of this is un clear. Because cefoperazone is excreted in the bile, patients with significant hepatic disease or biliary ob-

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

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CEFOTAx Im E SODIUm 151 Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Cefoperazone Sodium Powder for Injection: 1 g & 2 g in vials and piggyback units; Cefobid ® (Roerig); (Rx) Cefoperazone Sodium Injection: 1 g and 2 g premixed, frozen in 50 m L containers, and 10 g in bulk package; Cefobid ® (Roerig); (Rx) cefot Axime sodium (sef-oh-taks-eem) Claforan® 3rd generati On cephal Osp Orin Prescriber Highlights 3rd generation parenteral cephalosporin T T Potentially could cause hypersensitivity reactions, granu-T T locytopenia, or diarrhea Causes pain on IM injection; give IV over 3T T -5 minutes (or more)May need to reduce dose in renal failure T T Uses/Indications In the United States, there are no cefotaxime products approved for veterinary species but it has been used clinically in several species when an injectable 3rd generation cephalosporin may be indicated. Pharmacology/Actions Cefotaxime is a third generation injectable cephalosporin agent and, like other cephalosporins, inhibits bacteria cell wall synthe-sis. It is usually bactericidal and it is a time-dependent antibiot-ic. Cefotaxime has a relatively wide spectrum of activity against both gram-positive and gram-negative bacteria. While less ac-tive against Staphylococcus spp. than the first generation agents, it still has significant activity against those and other gram-positive cocci. Cefotaxime, like the other 3rd generation agents, has ex-tended coverage of gram-negative aerobes particularly in the fam-ily Enterobacteriaceae, including Klebsiella spp., E. coli, Salmonella, Serratia marcescens, Proteus spp., and Enterobacter spp. Cefotaxime's in vitro activity against Pseudomonas aeruginosa is variable and results are usually disappointing when the drug is used clinically against this organism. Many anaerobes are also susceptible to ce-fotaxime including strains of Bacteroides fragilis, Clostridium spp., Fusobacterium spp., Peptococcus spp., and Peptostrep tococcus spp. Because 3rd generation cephalosporins exhibit specific activi-ties against bacteria, a 30 microgram cefotaxime disk should be used when performing Kirby-Bauer disk susceptibility tests for this an tibiotic. Pharmacokinetics Cefotaxime is not appreciably absorbed after oral administration and must be given parenterally to attain therapeutic serum levels. After administration, the drug is widely distributed in body tissues including bone, prostatic fluid (human), aqueous humor, bile, as-citic and pleural fluids. Cefotaxime crosses the placenta and activity in amniotic fluid either equals or exceeds that in maternal serum. Cefotaxime distributes into milk in low concentrations. In humans, approximately 13-40% of the drug is bound to plasma proteins. Unlike the first generation cephalosporins (and most 2nd gen-eration agents), cefotaxime will enter the CSF in therapeutic levels (at high dosages) when the patient's meninges are inflamed. Cefotaxime is partially metabolized by the liver to de-sacetylcefotaxime which exhibits some an tibacterial activity. Desacetylcefotaxime is partially degraded to inactive metabolites by the liver. Cefotaxime and its metabolites are primarily excreted in the urine. Because tubular secretion is in volved in the renal ex-cretion of the drug, in several species probenecid has been demon-strated to prolong the serum half-life of cefotaxime. Pharmacokinetic parameters in certain veterinary species fol-low: In dogs, the apparent volume of distribution at steady state is 480 m L/kg, and a total body clearance of 10. 5 m L/min/kg after intra venous injection. Serum elimination half-lives of 45 minutes when given IV, 50 minutes after IM in jection, and 103 minutes after SC injection have been noted. Bioavailability is about 87% after IM injection and approximately 100% after SC injection. In cats, total body clearance is approximately 3 m L/min/kg after intravenous injection and the serum elimination half-life is about 1 hour. Bioavailability is about 93-98% after IM injection. Contraindications/Precautions/Warnings Cephalosporins are contraindicated in pa tients with a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hyper-sensitive to other beta-lactam an tibiotics (e. g., penicillins, cefamy-cins, carbapenems). Patients in renal failure may need dosage adjustments. Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in patients documented to be hypersensitive to penicillin-class antibiotics is controversial. In hu mans, it is estimated 1-15% of patients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary pa-tients is unknown. Cephalosporins can cause pain at the injection site when admin-istered intramuscularly. Sterile ab scesses or other severe local tis-sue reactions are also possible but are much less common. Throm-bophlebitis is also possible after IV administration of these drugs. Because the cephalosporins may also alter gut flora, antibiotic-associated diarrhea can occur and allow the proliferation of resis-tant bacteria in the colon (superinfections). While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with normal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neu-rotoxicity, neutropenia, agranulocy tosis, thrombocytopenia, hepa-titis, positive Comb's test, interstitial nephritis, and tubular necro-sis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but neither have there been any documented teratogenic problems asso ciated with these drugs. However, use only when the potential benefits outweigh the risks. In humans, the FDA categorizes this cefotaxime as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate

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152 CEFOTAx Im E SODIUm studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Most of these agents (cephalosporins) are excreted in milk in small quantities. Modification/alteration of bowel flora with resul-tant diarrhea is theoretically possible. Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems, but other effects are possible (see Adverse effects section). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefotaxime and may be of significance in veterinary patients: Am INOgly COSIDES/NEPHROTOx IC DRUg ST! : The concurrent use of par-enteral aminoglycosides or other nephrotoxic drugs (e. g., ampho-tericin B) with cephalosporins is somewhat controversial. Poten-tially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well docu mented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have syner-gistic or additive activity against certain bacteria when used with aminoglycosides, but they should not be mixed together (admin-ister separately). PROb ENECIDT! : Competitively blocks the tubular secretion of most cephalosporins, thereby increasing serum levels and serum half-lives laboratory Considerations In humans, particularly with azotemia, cephalosporins have T! caused a false-positive direct Coombs' test. Cephalosporins may cause falsely elevated T! 17­ketosteroid values in urine. Cefotaxime like most other cephalosporins, may cause a T! false­ positive urine glucose determi nation when using the cupric sulfate solution test (e. g., Clinitest®), Benedict's solution or Fehling's solution. Doses DOg S:T! For susceptible infections: a) For soft tissue infections: 22 mg/kg IV, IM or SC q8h for 7 days or less or 50 mg/kg IV or IM q12h for 7 days or less. For orthopedic infections: 20-40 mg/kg IV, IM or SC q6-8h for 7 days or less. For severe bacteremia: 20-80 mg/kg IV q6h or 10-50 mg/kg IV q4-6h for as long as necessary (Greene and Watson 1998) b) 25-50 mg/kg IV, IM or SC q8h (Riviere 1989); (Vaden and Papich 1995) c) For sepsis: 20-80 mg/kg IV, IM q8h (T ello 2003a) d) For CNS infections (spinal cord): 25 mg-50 mg/kg IV, IM q8h (Dickinson 2003) CATS:T! For susceptible infections: a) For severe bacteremia: 20-80 mg/kg IV or IM q6h as long as necessary (Greene and Watson 1998) b) 25-50 mg/kg IV, IM or SC q8h (Vaden and Papich 1995), (Lappin 2002a)c) For sepsis: 20-80 mg/kg IV, IM q8h (T ello 2003b) For CNS infections (spinal cord): 25 mg-50 mg/kg IV, IM q8h (Dickinson 2003) HORSES:T! For susceptible infections:a) Foals: 40 mg/kg IV q6h (Giguere 2003a) b) For meningitis in foals: 40 mg/kg IV 3-4 times a day (Furr 1999) c) Foals: 15-30 mg/kg IV or IM q6-12h (Brumbaugh 1999) b IRDS:T! For susceptible infections:a) For most birds: 50-100 mg/kg IM three times a day; may be used with aminoglycosides, but nephro toxicity may occur. Reconstituted vial good for 13 weeks if frozen. (Clubb 1986) b) 75-100 mg/kg IM or IV q6-8h (Hoeffer 1995) c) Ratites (young birds): 25 mg/kg IM 3 times daily (Jenson 1998) d) 75-100 mg/kg IM or IV q4-8h (Hess 2002a) e) 75 mg/kg IM q8h (Tully 2002) REPTIl ES:T! For susceptible infections:a) 20-40 mg/kg IM once daily for 7-14 days (Gauvin 1993) b) Chelonians: 20-40 mg/kg IM q24h (Johnson 2002) c) Nebulized antibiotic therapy: 100 mg twice daily (Raiti 2003) monitoring Because cephalosporins usually have minimal toxicity associ-T! ated with their use, monitoring for efficacy is usually all that is required. Patients with diminished renal function may require intensified T! renal monitoring. Chemistry/Synonyms A semisynthetic, 3rd generation, aminothiazolyl cephalosporin, ce-fotaxime sodium oc curs as an odorless, white to off-white crystalline powder with a p K a of 3. 4. It is sparingly soluble in water and slightly soluble in alcohol. Potency of cefotaxime sodium is expressed in terms of cefo taxime. One gram of cefotaxime (sodium) contains 2. 2 m Eq of sodium. Cefotaxime sodium may also be known as: cefotaximum natri-cum, CTX, HR-756, RU-24756 and Claforan®; many other trade names are available internationally. Storage/Stability/Compatibility Cefotaxime sodium sterile powder for injection should be stored at temperatures of less than 30°C; protected from light. The com-mercially available frozen injection should be stored at temperatures no greater than-20°C. Depending on storage conditions, the pow-der or solutions may darken which may indicate a loss in potency. Cefotaxime is not stable in solutions with p H >7. 5 (sodium bicar-bonate). All commonly used IV fluids and the following drugs are report-edly compatible with cefotaxime: clindamycin, metronidazole and verapamil. Compatibility is dependent upon factors such as p H, concentration, temperature, and diluent used; consult specialized references or a hospital pharmacist for more specific in formation.

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CEFOTETAN DISODIUm 153 Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Cefotaxime Sodium Powder for Injection: 500 mg, 1 g (as cefotaxi-me), 2 g, and 10 g in vials, infusion bottles & ADD-Vantage system vials; Claforan® (Hoechst Marion Roussel); generic; (Rx) Cefotaxime Sodium for Injection: 1 g and 2 g in premixed, frozen 50 m L & infusion bottles; Claforan® (Hoechst Marion Roussel); (Rx) cefotet An disodium (sef-oh-tee-tan) Cefotan® 2nd generati On cephal Osp Orin (cephamycin) Prescriber Highlights 2nd to 3rd generation parenteral cephalosporin (ce-T T phamycin) similar to cefoxitin Pharmacokinetic profile better and may be more effec-T T tive against E. coli in dogs than cefoxitin Contraindications: Hypersensitivity to it or cephalosporins T T Adverse Effects: Unlikely; potentially could cause T T bleeding If severe renal dysfunction, may need to increase time T T between doses Uses/Indications Cefotetan may be a reasonable choice for treating serious infec-tions caused by susceptible bacteria, including E. coli or anaerobes. It appears to be well tolerated in small animals and may be given less frequently than cefoxitin. Pharmacology/Actions Often categorized as a 2nd or 3rd generation cephalosporin, cefo-tetan is usually bactericidal and acts by inhibiting mucopeptide synthesis in the bacterial cell wall. Cefotetan's in vitro activity against aerobes include E. coli, Proteus, Klebsiella, Salmonella, Staphylococcus and most Streptococcus. It has efficacy against most strains of the fol-lowing anaer obes: Actinomyces, Clostridium, Peptococcus, Peptostreptococcus and Propionibacterium. Many strains of Bacteroides are still sensitive to cefotetan. Cefotetan is generally ineffective against Pseudomonas aerugi-nosa and Enterococci. Because 2nd generation cephalosporins exhibit specific ac-tivities against bacteria, a 30-microgram cefoxitin disk should be used when performing Kirby-Bauer disk susceptibility tests for this antibi otic. Pharmacokinetics Cefotetan is not appreciably absorbed after oral administration and must be given parenterally to achieve therapeutic serum lev-els. The drug is well distributed into most tissues, but only has limited penetration into the CSF. Cefotetan is primarily excreted unchanged by the kid neys into the urine via both glomerular fil-tration (primarily) and tubular secretion. Elimination half-lives may be significantly prolonged in patients with severely dimin-ished renal function. Contraindications/Precautions/Warnings Cephamycins are contraindicated in pa tients who have a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented to be hypersensitive to other beta-lactam an tibiotics (e. g., penicil-lins, cephalosporins, carbapenems). Adverse Effects There is little information on the adverse effect profile of this medica tion in veterinary species, but it appears to be well toler-ated. In humans, less than 5% of patients re port adverse effects. Because cefotetan contains an N-methylthiotetrazole side chain (like cefopera zone), it may have a greater tendency to cause hema-tologic effects (e. g. hypoprothrombinemia) or disulfiram-like reac-tions (vomiting, etc) than other parenteral cephalosporins. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in patients documented to be hypersensitive to penicillin-class antibiotics is controversial. In hu mans, it is estimated 1-15% of patients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary pa-tients is unknown. Cephalosporins can cause pain at the injection site when admin-istered intramuscularly. Sterile abscesses or other severe local tissue re actions are also possible but are less common. Thrombophlebitis is also possible after IV ad ministration of these drugs. Even when administered parenterally, cephalosporins may alter gut flora and antibiotic-associated diarrhea or the proliferation of resistant bacteria in the colon (superinfections) can occur. While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with normal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neurotoxicity, neutropenia, agranulocy tosis, throm-bocytopenia, hepatitis, positive Comb's test, interstitial nephritis, and tubular necrosis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component. Reproductive/Nursing Safety Safe use during pregnancy has not been established; use only when justified. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrat-ed risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but ad-equate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters) Cefotetan enters ma ternal milk in small quantities. Alteration of bowel flora with resultant diarrhea is theoretically possible. Overdosage/Acute Toxicity Unlikely to cause adverse effects, unless massive or chronically over-dosed; seizures possible. Treat symptomatically. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefotetan and may be of significance in veterinary patients: Al COHOl:T! A disulfiram reaction is possible Am INOgly COSIDES/NEPHROTOx IC DRUg S:T! The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been

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

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CEFOx ITIN SODIUm 155 Adverse Effects Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, lymph-adenopathy, or full-blown anaphylaxis. The use of cephalosporins in patients documented to be hypersensitive to penicillin-class antibiotics is controversial. In hu mans, it is estimated 1-15% of patients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary pa-tients is unknown. Cephalosporins can cause pain at the injection site when admin-istered intramuscularly. Sterile abscesses or other severe local tissue re actions are also possible but are less common. Thrombophlebitis is also possible after IV ad ministration of these drugs. Even when administered parenterally, cephalosporins may alter gut flora and antibiotic-associated diarrhea or the proliferation of resistant bacteria in the colon (superinfections) can occur. While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with normal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neurotoxicity, neutropenia, agranulocy tosis, throm-bocytopenia, hepatitis, positive Comb's test, interstitial nephritis, and tubular necrosis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems asso-ciated with these drugs; however, use only when the potential ben-efits outweigh the risks. In humans, the FDA categorizes this drug as 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. ) Cefoxitin can be distributed into milk in low concentrations. It is unlikely to pose significant risk to nursing offspring. Overdosage/Acute Toxicity Acute oral cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefoxitin and may be of significance in veterinary patients: Am INOgly COSIDES/NEPHROTOx IC DRUg ST! : The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well docu mented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have synergistic or additive activity against certain bacteria when used with aminoglycosides, but they should not be mixed together (administer separately). PROb ENECIDT! : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives. laboratory Considerations Except for cefotaxime, cephalosporins may cause false-positive T! urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. When using the Jaffe reaction to measure T! serum or urine creatinine, cephalosporins (not cef tazidime or cefotaxime) in high dosages may falsely cause elevated values. In humans, particularly with azotemia, cephalosporins have T! caused a false-positive direct Coombs' test. Cephalosporins may also cause falsely elevated T! 17­ketosteroid val-ues in urine. Doses DOg S:T! For susceptible infections: a) For mixed infections (e. g., aspiration pneumonia, bowel per-foration): 30 mg/kg SC q8h; 30 mg/kg IV q4-6h (Trepanier 1999) b) For sepsis: 30 mg/kg IV q5h (Hardie 2000) c) For soft tissue infections: 30 mg/kg SC q8h or 30 mg/kg IV q5h For bacteremia: 15-30 mg/kg IV, IM SC q6-8h For orthopedic infections: 22 mg/kg IV, IM q6-8h Use for all indications above as long as necessary to control initial infection, then switch to oral drugs for longer therapy. (Greene and Watson 1998) d) For Gram+ infections: 10 mg/kg q8h IV, IM or SC For Gram-infections: 20 mg/kg q8h IV, IM or SC (Aucoin 2000) e) For septic shock: 20 mg/kg IV q8h (T ello 2003a) CATS:T! For susceptible infections:a) For systemic infections: 25-30 mg/kg IV or IM q8h; use for as long as necessary to control initial infection, then switch to oral drugs for longer therapy (Greene and Watson 1998) b) For sepsis: 30 mg/kg IV q5h (Hardie 2000) c) 30 mg/kg IV q8h (Vaden and Papich 1995) d) For Gram+ infections: 10 mg/kg q8h IV, IM or SC For Gram-infections: 20 mg/kg q8h IV, IM or SC (Aucoin 2000) e) For septic shock: 20 mg/kg IV q8h (T ello 2003a) HORSES:T! For susceptible infections:a) Foals: 20 mg/kg IV q4-6h (Caprile and Short 1987); (Brum-baugh 1999) monitoring Because cephalosporins usually have minimal toxicity associated T! with their use, monitoring for efficacy is usually all that is re-quired. Patients with diminished renal function may require intensified T! renal monitoring. Chemistry/Synonyms Actually a cephamycin, cefoxitin sodium is a semisynthetic an-tibiotic that is derived from cephamycin C that is produced by Streptomyces lactamdurans. It occurs as a white to off-white, some-what hygroscopic powder or granules with a faint but characteristic odor. It is very soluble in water and only slightly soluble in alcohol. Each gram of cefoxitin sodium contains 2. 3 m Eq of sodium.

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

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CEFTAz IDIm E 157 Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefpodoxime and may be of significance in veterinary patients: Am INOgly COSIDES/NEPHROTOx IC DRUg ST! : The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well docu mented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have synergistic or additive activity against certain bacteria when used with aminoglycosides, but they should not be mixed together (administer separately). ANTACIDST! : Drugs that can increase stomach p H may decrease the absorption of the drug H­2 ANTAg ONISTST! (ranitidine, famotidine, etc. ): Drugs that can in-crease stomach p H may decrease the absorption of the drug PROb ENECIDT! : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives PROTON PUm P INHIb ITORST! (e. g., omeprazole ): Drugs that can in-crease stomach p H may decrease the absorption of the drug laboratory Considerations Cefpodoxime may cause false-positive T! urine glucose determina­ tions when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose ox idase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. If using the nitroprusside test for determining T! urinary ketones, cefpodoxime may cause false-posi tive results. Doses DOg S:T! a) For susceptible skin infections: 5-10 mg/kg PO once daily. Should be administered for 5-7 days or 2-3 days beyond cessation of clinical signs, up to a maximum of 28 days. Treatment of acute infections should not be continued for more than 3-4 days if no response to therapy is seen. May be given with or without food. (Label information; Simplicef®— Pfizer) b) For staphylococcal skin infections: 5-10 mg/kg PO q12h (Campbell 1999); (Mac Donald 2002b) c) For susceptible infections: 5-10 mg/kg PO twice daily (Boothe 1999) CATS:T! a) For susceptible skin and soft tissue infections: 5 mg/kg PO q12h or 10 mg/kg PO once daily ( Note : Extrapolated from human dosage) (Greene and Watson 1998) monitoring Clinical efficacy T! Client Information Can be given without regard to meals (in humans presence of T! food enhances absorption). Give as directed for as long as veterinarian recommends, even if T! patient appears well. Chemistry/Synonyms An orally administered semisynthetic 3rd generation cephalosporin, cefpodoxime proxetil is a prodrug that is hydrolyzed in vivo to cef-podoxime. The esterified form (proxetil) en hances lipid solubility and oral absorption. Cefpodoxime proxetil may also be known as: CS-807; R-3763, U-76252, U-76253, Banan®, Biocef®, Cefodox ®, Cepodem ®, Garia®, Instana®, Kelbium®, Orelox®, Otreon®, Podomexef®, Simplicef®, or Vantin®. Storage/Stability/Compatibility Tablets and unreconstituted powder should be stored at 20-25°C in well-closed containers. After reconstitution, the oral suspension should be stored in the refrigerator and discarded after 14 days. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Cefpodoxime Proxetil Tablets: 100 mg & 200 mg; Simplicef® (Pfiz-er); (Rx). Approved for use in dogs. HUm AN­l Ab El ED PRODUCTS: Cefpodoxime Proxetil Tablets: 100 mg & 200 mg; Vantin® (Pharma-cia & Upjohn), generic (Putney); (Rx) Cefpodoxime Proxetil Granules for Suspension: 50 mg/5 m L & 100 mg/5 m L in 50 m L, 75 m L & 100 m L bottles; Vantin® (Pharmacia & Upjohn), generic (Putney); (Rx) ceft Azidime (sef-taz-i-deem) Ceptaz®, Fortaz®, Tazicef® 3rd generati On cephal Osp Orin Prescriber Highlights 3rd generation cephalosporin used parenterally for gram-T T negative infections Particularly useful in reptiles T T Could cause hypersensitivity reactions, granulocytopenia/T T thrombocytopenia, diarrhea, mild azotemia May cause pain on IM injection; SC injection probably T T less painful May need to reduce dose in renal failure; use with T T caution Check drug-lab interactions T T Uses/Indications Ceftazidime is potentially useful in treating serious gram-negative bacterial infections particularly against susceptible Enterobacteriaceae including Pseudomonas aeruginosa, that are not susceptible to other, less-expensive agents, or when aminogly-cosides are not indicated (due to their potential toxicity). It is of particular interest for treating gram-negative infections in reptiles due to a very long half-life. Pharmacology/Actions Ceftazidime is a third generation injectable cephalosporin agent. It is bactericidal and acts via its inhibition of enzymes responsible for bacterial cell wall synthesis. The third generation cephalosporins re-tain much of the gram-positive activity of the first and second gen-eration agents, but, have much expanded gram-negative activity. As with the 2nd generation agents, enough variability exists with indi-vidual bacterial sensitivities that susceptibility testing is necessary for most bacteria. Ceftazidime is considered an anti-pseudomonal

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

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CEFTIOFUR CR y STAll INE FREE ACID 159 Client Information Clients may be instructed to administer this drug SC for outpa-T! tient therapy. Be certain they understand the storage and stability issues before dispensing. Chemistry/Synonyms A semi-synthetic, third-generation cephalosporin antibiotic, cef-tazidime occurs as a white to cream-colored crystalline powder that is slightly soluble in water (5 mg/m L) and insoluble in alcohol, chloroform and ether. The p H of a 0. 5% solution in water is be-tween 3 and 4. Ceftazidime may also be known as ceftazidimum, GR-20263, or LY-139381, Fortaz®, Ceptaz®, Tazicef®, and Tazidime®; there are many international trade names. Storage/Stability/Compatibility Commercially available powders for injection should be stored at 15-30°C (59-86°F) and protected from light. The commercially available frozen ceftazidime for injection should be stored at tem-peratures no higher than-20°C (-4°F). The commercial products containing the sodium carbonate (Fortaz®, Tazicef®, Tazidime®) all release carbon dioxide (effer-vesce) when reconstituted and are supplied in vials under negative pressure; do not allow pressure to normalize before adding diluent. The product containing arginine (Ceptaz®), does not effervesce. Once reconstituted, the solution retains potency for 24 hours (18 hours for arginine formulation) at room temperature and 7 days when refrigerated. Solutions frozen in the original glass vial after reconstitution with sterile water are stable for 3 months when stored at-20°C (-4°F). While no stability data was located, veteri-narians have anecdotally reported efficacy when individual dosages are frozen in plastic syringes. Once thawed, they should not be re-frozen. Thawed solutions are stable for 8 hours at room tempera-ture and 4 days when refrigerated. Ceftazidime is compatible with the following diluents when being prepared for IM (or SC) injection: sterile or bacteriostatic water for injection, 0. 5% or 1% lidocaine. Once reconstituted it is compatible with the more commonly used IV fluids, including: D5W, normal saline or half-normal saline, Ringer's, or lactated Ringer's. Do not use sodium bicarbonate solution for a diluent; it is not recommended to mix with aminoglycosides, vancomycin or metronidazole. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Ceftazidime Powder for Injection: (with sodium carbonate) 500 mg, 1 g, 2 g, and 6 g in 20 m L & 100 m L vials, infusion packs, ADD-Vantage vials & piggyback vials; Fortaz® & Ceptaz® (Glaxo Smith-Kline); Tazicef® (Smith Kline Beecham/Bristol-Myers); Tazidime® (Lilly); (Rx) Ceftazidime Injection: 1 g & 2 g premixed, frozen in 50 m L & Gal-axy containers; Fortaz® (Glaxo Wellcome); Tazicef® (Smith Kline Beecham/Bristol-Myers Squibb); (Rx)ceftiofur cryst Alline free Acid (sef-tee-oh-fur) Excede® 3rd generati On cephal Osp Orin Prescriber Highlights Veterinary-only 3rd generation cephalosporin labeled for T T use in cattle & swine Potentially could cause hypersensitivity reactions, granu-T T locytopenia, thrombocytopenia, or diarrhea Administered SC at the posterior aspect of ear in cattle; T T administered IM in swine Shake well prior to use T T Monograph by Elaine Lust, Pharm D Uses/Indications In beef, lactating and non-lactating cattle, ceftiofur crystalline free acid (CCFA) is labeled for the treatment of bovine respiratory dis-ease (BRD, shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni and for the control of respiratory disease in cattle at high risk of developing BRD associated with M. haemolytica, P. multocida, and H. somni. In swine, Ceftiofur CFA is labeled for the treatment of swine respiratory disease (SRD) associated with Actinobacillus pleuro-pneumoniae, Pasteurella multocida, Haemophilus parasuis, and Streptococcus suis. Pharmacology/Actions Ceftiofur is a 3rd generation cephalosporin antibiotic active against a variety of gram-positive and gram-negative bacteria and like oth-er cephalosporins, inhibits bacteria cell wall synthesis; it is usually bactericidal and is a time-dependent antibiotic. After administration, the parent compound (ceftiofur) is rapidly cleaved into furoic acid and desfuroyl ceftiofur (active). Desfuroylceftiofur inhibits cell wall synthesis (at stage three) of suscepti ble multiplying bacteria and exhibits a spectrum of activ-ity similar to that of cefotaxime. Parent ceftiofur and the primary metabolite are equally potent and assays to measure microbial sen-sitivity (plasma and tissue levels) are based on ceftiofur equivalents referred to as CE. The protein binding activity of ceftiofur creates a “reservoir effect” to maintain active levels at the site of infection. In cattle, ceftiofur has a broad range of in vitro activity against a variety of pathogens including many species of Pasturella, Streptococcus, Staphylococcus, Salmonella, and E. coli. In Swine, ceftiofur CFA at a single IM dosage of 2. 27 mg/lb (5 mg/kg) BW provides concentrations of ceftiofur and desfuroylceft-iofur-related metabolites in plasma that are multiples above the MIC90 for an extended period of time for the swine respiratory disease (SRD) label pathogens Actinobacillus pleuropneumoniae, Pasteurella multocida, Haemophilus parasuis and Streptococcus suis. Pharmacokinetics In cattle, subcutaneous administration of ceftiofur CFA, in the middle third of the posterior aspect of the ear (middle third of the ear) of beef and non-lactating dairy cattle, or in the posterior aspect of the ear where it attaches to the head (base of the ear) of beef, non-lactating dairy, and lactating dairy cattle, provides therapeutic concentrations of ceftiofur and desfuroylceftiofur-related metabo-

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

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CEFTIOFUR HCl 161 Cephalosporins may also cause falsely elevated T! 17­ketosteroid val-ues in urine. Doses CATTl E:T! beef and lactating cattle treatment dose: Administer as a single SC injection in the posterior aspect of the ear where it attaches to the head at the base of the ear to cattle at 3 mg per lb (6. 6 mg ceftiofur equivalents/kg) body weight (1. 5 m L sterile suspension per 100 lb body weight). The approved site of injection in lactat-ing dairy cattle is at the base of the ear (BOE). (Excede ® Sterile Suspension; Package Insert—Pfizer) beef and non­lactating dairy cattle treatment dose: Administer as a single SC injection in the middle third of the posterior aspect of the ear at a dosage of 6. 6 mg ceftiofur equivalents/kg body weight (1. 5 m L sterile suspension per 100 lb body weight). Most animals will respond to treatment within 3-5 days. If no improvement is observed, the diagnosis should be reevaluated. Administration of ceftiofur free acid into the ear arteries is likely to result in sudden death in cattle. beef and non­lactating dairy cattle control dose: Administer as a SC injection either in the middle third of the posterior aspect of the ear or in the posterior aspect of the ear where it attaches to the head (base of the ear) to beef and non-lactating dairy cattle at a dosage of 6. 6 mg ceftiofur equivalents (CE)/kg body weight (1. 5 m L sterile suspension per 100 lb body weight). See package in-sert for graphics depicting locations of injection and anatomical landmarks to avoid. (Excede ® Sterile Suspension; Package Insert—Pfizer) SWINE:T! Administer by IM injection in the post-auricular region of the neck as a single dosage of 2. 27 mg ceftiofur equivalents (CE)/lb (5 mg CE/kg) body weight (BW). This is equivalent to 1 m L ster-ile suspension per 44 lb (20 kg) BW. No more than 2 m L should be injected in a single injection site Injection volumes in excess of 2 m L may result in violative resi-dues. Pigs heavier than 88 lb (40 kg) will require more than one injection. Most animals will respond to treatment within 3-5 days. If no improvement is observed, the diagnosis should be reevaluated. (Excede ® For Swine; Package Insert—Pfizer) monitoring Because cephalosporins usually have minimal toxicity associated with their use, monitoring for efficacy is usually all that is required. Some clinicians recommend weekly CBC monitoring of small ani-mals receiving ceftiofur. Patients with diminished renal function may require intensified renal monitoring. Serum levels and thera-peutic drug monitoring are not routinely done with these agents. Chemistry/Synonyms Ceftiofur CFA has a molecular weight of 523. 58. Ceftiofur may also be known as CM-31916, ceftiofuri, or Excede ®. Storage/Stability Ceftiofur CFA cattle and swine products should be stored at con-trolled room temperature 20-25 °C (68-77°F). Shake well before using. Contents should be used within 12 weeks after the first dose is removed. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Ceftiofur Crystalline Free Acid equivalent to 200 mg/m L ceftiofur (in a Miglyol ® cottonseed oil based suspension) in 100 m L vials; Ex-cede® (Pfizer). Approved for use in beef, lactating and non-lactating cattle. If used in an extra-label manner, contact FARAD (see ap-pendix) for guidance in determining withdrawal times for milk or meat. Ceftiofur Crystalline Free Acid equivalent to 100 mg/m L ceftiofur (in a Miglyol ® cottonseed oil based suspension) in 100 m L vials; Ex-cede® for Swine (Pfizer); HUm AN­l Ab El ED PRODUCTS: None ceftiofur hcl (sef-tee-oh-fur) Excenel®, Spectramast® 3rd generati On cephal Osp Orin Prescriber Highlights A veterinary-only 3rd generation cephalosporin T T Potentially could cause hypersensitivity reactions, granu-T T locytopenia, thrombocytopenia, or diarrhea Causes pain on IM injection to small animals T T May need to reduce dose in renal failure T T Monograph by Elaine Lust, Pharm D Uses/Indications In swine, ceftiofur HCl injection is labeled for the treatment and control of swine bacterial respiratory disease (swine bacterial pneumonia) associated with Actinobacillus (Haemophilus) pleu-ropneumoniae, Pasteurella multocida, Salmonella choleraesuis and Streptococcus suis. In cattle, ceftiofur HCl is labeled for the treatment of the fol-lowing bacterial diseases: Bovine respiratory disease (BRD, ship-ping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni; Acute bovine inter-digital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus; and acute metritis (0-14 days post-partum) associated with bacterial organisms susceptible to ceftiofur. The intramammary syringe for dry dairy cattle (Spectramast DC®) is labeled for the treatment of subclinical mastitis in dairy cattle at the time of dry off associated with Staphylococcus aureus, Streptococcus dysgalactiae, and Streptococcus uberis. The intramam-mary syringe for lactating dairy cattle (Spectramast LC®) is labeled for the treatment of clinical mastitis in lactating dairy cattle associ-ated with coagulase-negative staphylococci, Streptococcus dysgalac-tiae, and Escherichia coli. Pharmacology Ceftiofur is a 3rd generation cephalosporin antibiotic active against a variety of gram-positive and gram-negative bacteria and like oth-er cephalosporins inhibits bacteria cell wall synthesis; it is usually bactericidal and is a time-dependent antibiotic. After administration, the parent compound (ceftiofur) is rapidly cleaved into furoic acid and desfuroyl ceftiofur (active). Desfuroylceftiofur inhibits cell wall synthesis (at stage three) of suscepti ble multiplying bacteria and exhibits a spectrum of activ-ity similar to that of cefotaxime. Parent ceftiofur and the primary metabolite are equally potent and assays to measure microbial sen-sitivity (plasma and tissue levels) are based on ceftiofur equivalents

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

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CEFTIOFUR HCl 163 gistic or additive activity against certain bacteria when used with aminoglycosides, but they should not be mixed together (admin-ister separately). PROb ENECIDT! : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives laboratory Considerations Note T! : Ceftiofur is structurally similar to cefotaxime and it is not known if these interactions occur with ceftiofur. Except for cefotaxime, cephalosporins may cause false-positive T! urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. When using the Jaffe reaction to measure T! serum or urine creatinine, cephalosporins (not cef tazidime or cefotaxime) in high dosages may falsely cause elevated values. In humans, particularly with azotemia, cephalosporins have T! caused a false-positive direct Coombs' test. Cephalosporins may also cause falsely elevated T! 17­ketosteroid val-ues in urine. Doses SWINE:T! a) Administer IM at 3 to 5 mg/kg body weight (1 m L of sterile suspension per 22 to 37 lb body weight). Treatment should be repeated at 24-hour intervals for a total of three consecu-tive days. (Excenel ® RTU; Package Insert—Pfizer) CATTl E:T! For bovine respiratory disease and acute bovine interdigital necrobacillosis: a) Administer IM or SC at 1. 1 to 2. 2 mg/kg (1 to 2 m L sterile suspension per 100 lb) daily for a total of three consecutive days. Additional treatments may be administered on Days 4 and 5 for animals which do not show a satisfactory response. For or BRD only, administer IM or SC 2. 2 mg/kg every other day on Days 1 and 3 (48h interval). Do not inject more than 15 m L per injection site. (Excenel ® RTU; Package Insert— Pfizer) For acute post-partum metritis: a) Administer by IM or SC 2. 2 mg/kg (2 m L sterile suspension per 100 lb ) daily for five consecutive days. Do not inject more than 15 m L per injection site. (Excenel ® RTU; Package Insert—Pfizer) For neonatal salmonellosis: a) Ceftiofur HCl 5 mg/kg IM once daily for 5 days (Fecteau, House et al. 2002) For the treatment of subclinical mastitis in dairy cattle at time of dry off associated with Staphylococcal aureus, Streptococcus dys-galactiae or Streptococcus uberis: a) Infuse one syringe of Spectramast® DC into each affected quarter at the time of dry off. (Spectramast® DC; Package Insert—Pfizer) For the treatment of clinical mastitis in lactating dairy cattle associated with coagulase-negative staphylococci Streptococcus dysgalactiae or E. coli:a) Infuse one syringe of Spectromast® LC into each affected quarter. Repeat this treatment in 24 hours. For extended duration therapy, once daily treatment may be repeated for up to 8 consecutive days. (Spectramast® LC Package Insert— Pfizer)monitoring Because cephalosporins usually have minimal toxicity associated with their use, monitoring for efficacy is usually all that is required. Some clinicians recommend weekly CBC monitoring of small ani-mals receiving ceftiofur. Patients with diminished renal function may require intensified renal monitoring. Serum levels and ther-apeutic drug monitoring are not routinely performed with these agents. Chemistry/Synonyms Ceftiofur HCl is a semisynthetic 3rd generation cephalosporin. Ceftiofur HCl is a weak acid and is acid stable and water-soluble with a molecular weight of 560. The injectable sterile suspension in a ready to use formulation that contains ceftiofur hydrochloride equivalent to 50 mg ceftiofur, 0. 50 mg phospholipon, 1. 5 mg sorbi-tan monooleate, 2. 25 mg sterile water for injection, and cottonseed oil. Both Spectramast® products are sterile, oil based suspensions of ceftiofur HCl. Ceftiofur HCl may also be known as U-64279A, ceftiofuri hy-drochloridium or Excenel RTU®. Storage/Stability The ready-to-use injectable product should be stored at controlled room temperature 20 to 25 °C (68 to 77 °F). Shake well before us-ing; protect from freezing. The intramammary syringes should be stored at controlled room temperature 20 to 25 °C (68 to 77 °F). Protect from light. Store plastets in carton until used. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Ceftiofur HCL Sterile Suspension for injection, 50 mg/m L in 100 m L vials; Excenel RTU® (Pharmacia/Upjohn); (Rx). Approved for use in cattle and swine. Slaughter withdrawal = 3 days in cattle, and 4 days in swine. There is no required milk discard time. Ceftiofur HCl Sterile Suspension for Intramammary Infusion in Dry Cows 500 mg ceftiofur equivalents (as the HCl) per 10 m L syringe (plastets) in packages of 12 syringes with 70% isopropyl alcohol pads; Spectramast® DC (Pfizer); (Rx) Slaughter withdrawal for cattle = 16 days (no slaughter withdrawal required for neonatal calves born from treated cows) Ceftiofur HCl Sterile Suspension for Intramammary Infusion in Lactating Cows 125 mg ceftiofur equivalents (as the HCl) per 10 m L syringe (plastets) in packages of 12 syringes with 70% isopropyl alcohol pads; Spectramast® LC (Pfizer); (Rx) Cattle slaughter with-drawal = 2 days; milk discard = 72 hours HUm AN­l Ab El ED PRODUCTS: None

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

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CEFTIOFUR SODIUm 165 Reproductive/Nursing Safety The effects of ceftiofur on the reproductive performance, pregnan-cy, and lactation of cattle, dogs, horses, swine, sheep, and goats have not been determined. Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy have not been firmly established, but neither have there been any documented teratogenic problems asso ciated with these drugs. However, use only when the potential benefits outweigh the risks. Most of these agents (cephalosporins) are excreted in milk in small quantities. Modification/alteration of bowel flora with resul-tant diarrhea is theoretically possible. When dosed as labeled, there are no milk withdrawal times necessary for ceftiofur products in dairy cattle. Overdosage/Acute Toxicity Cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). However, overdoses in food animals may result in significantly extended withdrawal times, contact FARAD (see ap-pendix) for assistance. Drug Interactions Although the manufacturer does not list any drug interactions on the label for ceftiofur, the following drug interactions have either been reported or are theoretical in humans or animals receiving in-jectable 3rd generation cephalosporins and may be of significance in veterinary patients receiving ceftiofur: Am INOgly COSIDES/NEPHROTOx IC DRUg ST! : The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well docu mented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have synergistic or additive activity against certain bacteria when used with aminoglycosides, but they should not be mixed together (administer separately). PROb ENECIDT! : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives. laboratory Considerations Note T! : Ceftiofur is structurally similar to cefotaxime and it is not known if these interactions occur with ceftiofur. Except for cefotaxime, cephalosporins may cause false-positive T! urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins.. When using the Jaffe reaction to measure T! serum or urine creatinine, cephalosporins (not cef tazidime or cefotaxime) in high dosages may falsely cause elevated values. In humans, particularly with azotemia, cephalosporins have T! caused a false-positive direct Coombs' test. Cephalosporins may also cause falsely elevated T! 17­ketosteroid val-ues in urine. Doses CATTl E:T! a) Administer to cattle by IM or SC injection at 1. 1 to 2. 2 mg/ kg of body weight (1-2 m L reconstituted sterile solution per 100 lbs body weight). Treatment should be repeated at 24-hour intervals for a total of three consecutive days. Ad-ditional treatments may be given on days four and five for animals which do not show a satisfactory response (not re-covered) after the initial three treatments. (Package Insert; Naxcel®—Pfizer) SWINE:T! a) Administer to swine by IM injection at 3 to 5 mg/kg of body weight (1m L of reconstituted sterile solution per 22 to 37 lbs body weight). Treatment should be repeated at 24-hour in-tervals for a total of three consecutive days. (Package Insert; Naxcel®—Pfizer) SHEEPT! /g OATS: a) Administer to sheep/goats by IM injection at 1. 1 to 2. 2 mg/kg of body weight (1-2 m L reconstituted sterile solution per 100 lbs body weight). Treatment should be repeated at 24 hour intervals for a total of three consecutive days. Addition-al treatments may be given on days four and five for animals which do not show a satisfactory response (not recovered) after the initial three treatments. When used in lactating does, the high end of the dosage is recommended. (Package Insert; Naxcel®—Pfizer) HORSES:T! a) Administer to horses by IM injection at the dosage of 1 to 2 mg ceftiofur per pound (2. 2 to 4. 4 mg/kg) of body weight (2-4 m L reconstituted sterile solution per 100 lbs body weight). A maximum of 10 m L may be administered per in-jection site. Repeat treatment at 24-hour intervals, continued for 48 hours after symptoms have disappeared. Do not ex-ceed 10 days of treatment. (Package Insert; Naxcel®—Pfizer) b) 1-2 mg/kg IV or IM q12-24h (Bertone 2003b) c) For Lyme disease: 2. 2-4. 4 mg/kg IV q12 hours via a long-term catheter (Divers 1999) d) Foals: 2. 2-4. 4 mg/kg IV or IM q12-24h (Brumbaugh 1999) e) For strangles: Early in infection when only fever and depres-sion are present: ceftiofur sodium 2. 2 mg/kg IM q12-24h. If lymphadenopathy noted in otherwise healthy and alert horse do not treat. If lymphadenopathy present and horse is de-pressed, febrile, anorexic and especially if dyspneic, treat as above. (Foreman 1999) f) For intrauterine infusion: 1 gram. Little science is available for recommending doses, volume infused, frequency, di-luents, etc. Most treatments are commonly performed every day or every other day for 3-7 days. (Perkins 1999) g) Foals: 2. 2-5 mg/kg IM q12h (Giguere 2003a) DOg S:T! a) For susceptible UTI's: 2. 2 mg/kg SC once daily for 5-14 days Administer to dogs by subcutaneous injection at the dos-age of 1 mg ceftiofur per pound (2. 2 mg/kg) of body weight (0. 1 m L reconstituted sterile solution per 5 lbs body weight). Treatment should be repeated at 24-hour intervals for 5-14 days. (Package Insert; Naxcel®—Pfizer) b) 10 mg/kg once to twice daily (q12-24h) SC (Aucoin 2000) c) For UTI: 2. 2 mg/kg SC once daily for 5-14 days For systemic, soft tissue infections: 2. 2 mg/kg q12h or 4. 4 mg/kg q24h SC for 5-14 days For sepsis, bacteremia: 4. 4 mg/kg q12h SC for 2-5 days (Greene and Watson 1998) d) For neonatal septicemia: 2. 5 mg/kg SC q12h for no longer than 5 days (Davidson 2004a)

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

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CEFTRIAx ONE SODIUm 167 Pharmacokinetics Ceftriaxone is not absorbed after oral administration and must be given par enterally. It is widely distributed throughout the body; CSF levels are higher when meninges are in flamed. Ceftriaxone crosses the placenta and enters maternal milk in low concentra-tions; no docu mented adverse effects to offspring have been noted. Ceftriaxone is excreted by both renal and non-renal mechanisms; in humans, elimination half-lives are approximately 6-11 hours. In dogs, ceftriaxone bioavailability after IM or SC administra-tion equal that of IV, but peak levels occur much faster after IM (approximately 30 minutes) than SC (80 minutes). Peak levels are higher with IM administration than SC, but total area under the curve is similar for both routes. Elimination half-life is longer af-ter SC administration (1. 73 hrs) than either IM (1. 17 hrs) or IV administration (0. 88 hrs). The authors of the study (Rebuelto, Albarellos et al. 2002) concluded that once or twice daily IM or SC injections of 50 mg/kg should be adequate to treat most susceptible infections in dogs. Contraindications/Precautions/Warnings Only prior allergic reaction to cephalosporins contraindicates cef-triaxone's use. In humans documented hypersensitive to penicillin, up to 16% may also be allergic to cephalosporins. The veterinary significance of this is unclear. Although bleeding times have only been reported rarely in hu-mans, ceftriaxone should be used with caution in patients with vi-tamin K utilization or synthesis abnormalities (e. g., severe hepatic dis ease). Patients in renal failure may need dosage adjustments; but are not generally required unless severely uremic, or with concomitant hepatic impairment. Adverse Effects Because veterinary usage of ceftriaxone is very limited, an ac-curate adverse effect profile has not been determined. The fol-lowing adverse effects have been reported in humans and may or may not apply to veterinary patients: hematologic effects, includ-ing eosinophilia (6%), thrombocytosis (5%), leukopenia (2%) and, more rarely, anemia, neutropenia, lymphopenia and throm-bocytopenia. Approximately 2-4% of humans get diarrhea. Very high dosages (100 mg/kg/day) in dogs have caused a “sludge” in bile. Hypersensitivity reactions (usually a rash) have been noted. Increased serum concentrations of liver enzymes, BUN, creatinine, and urine casts have been described in about 1-3% of patients. When given IM, pain may be noted at the injection site. Reproductive/Nursing Safety No teratogenic effects were demonstrated in studies in pregnant mice and rats given up to 20X labeled doses of ceftriaxone. In hu-mans, the FDA categorizes this drug as category B 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. ) Ceftriaxone is distributed into milk in low concentrations and is unlikely to pose much risk to nursing offspring. Overdosage/Acute Toxicity Limited information available; overdoses should be monitored and treated symptomatically and supportively if required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ceftriaxone and may be of significance in veterinary patients:Am INOgly COSIDES/NEPHROTOx IC DRUg ST! : The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e. g., amphotericin B) with cephalosporins is somewhat controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well docu mented with cephaloridine (no longer marketed). In vitro studies have demonstrated that cephalosporins can have synergistic or additive activity against certain bacteria when used with aminoglycosides. CAl CIUm T! : Concomitant use with calcium containing solutions have caused fatal calcium-ceftriaxone precipitates in lungs and kidneys of neonatal humans. Do not mix with calcium or admin-ister calcium-containing solutions or products within 48 hours of ceftriaxone administration. laboratory Considerations When using Kirby-Bauer disk diffusion procedures for testing T! sus ceptibility, a specific 30 micrograms ceftriaxone disk should be used. A cephalosporin-class disk containing cephalothin should not be used to test for ceftriaxone susceptibility. An inhibition zone of 18 mm or more indicates susceptibility; 14-17 mm, in-termediate; and 13 mm or less, resistant. When using a dilution susceptibility procedure, an organism with T! a MIC of 16 micrograms/m L or less is considered susceptible and 64 micrograms/m L or greater is considered resistant. With either method, infections caused by organisms with intermediate sus-ceptibility may be effectively treated if the infection is limited to tissues where the drug is concentrated or if a higher than normal dose is used. Ceftriaxone, like most other cephalosporins, may cause a T! false­ positive urine glucose determina tion when using the cupric sulfate solution test (e. g., Clinitest®). Ceftriaxone in very high concentrations (50 micrograms/m L or T! greater) may cause falsely elevated serum creatinine levels when manual methods of testing are used. Automated methods do not appear to be affected. Doses DOg S:T! a) For meningitis/borreliosis: 15-50 mg/kg (maximum single dose in humans is 1 gram) IV or IM q12h for 4-14 days For preoperative/intraoperative use: 25 mg/kg (maximum single dose in humans is 1 gram) IM or IV one time For skin, genitourinary infections: 25 mg/kg IM once daily (q24h) for 7-14 days (Greene and Watson 1998) b) For infectious endocarditis and documented resistance against or other contraindications for fluoroquinolones and aminoglycosides in dogs: 20 mg/kg IV q12h (De Francesco 2000) c) 15-50 mg/kg (route not specified) once daily (Trepanier 1999) CATS:T! For systemic infections: a) 25-50 mg/kg IV, IM or Intraosseous q12h as long as neces-sary (Greene and Watson 1998) HORSES:T! For susceptible infections: a) 25-50 mg/kg q12h IV or IM ( Note : This is a human dose and should be used as a gen eral guideline only) (Walker 1992) b) 20 mg/kg IV q12h (Brumbaugh 1999)

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

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CEFUROx Im E 169 Contraindications/Precautions/Warnings No specific information is available for veterinary patients. In hu-mans, cefuroxime is contraindicated in patients hypersensitive to it or other cephalosporins. Dosage adjustment is recommended in humans with severe renal impairment. Adverse Effects As usage of cefuroxime in animals has been limited, a comprehen-sive adverse effect profile has not been determined. A six-month toxicity study of oral cefuroxime axetil given at dosages ranging from 100 mg/kg/day to 1600 mg/kg day in Beagles demonstrated little adversity associated with cefuroxime. At the highest dosing levels (approximately 80X), some vomiting and slight suppression of body weight gain were noted. Minor reductions in neutrophils and red cells, with increases in prothrombin times were also seen. When used clinically in dogs, gastrointestinal effects (inap-petance, vomiting, diarrhea) would be the most likely expected ad-verse effects, but incidence rates are not known. Cefuroxime is generally well tolerated in human patients. Injection site inflammation can occur when cefuroxime is used in-travenously. Gastrointestinal effects (nausea, diarrhea) may occur, but are not frequently reported. Eosinophilia and hypersensitivity reactions (including anaphylaxis) are possible. Neurologic effects (hearing loss, seizures), pseudomembranous colitis, serious derma-tologic reactions (TEN, Stevens-Johnson syndrome, etc. ), hema-tologic effects (pancytopenia, thrombocytopenia), and interstitial nephritis have all been reported rarely in humans. Reproductive/Nursing Safety Studies performed in pregnant mice at dosages of up to 6400 mg/kg and rabbits at 400 mg/kg demonstrated no adverse fetal effects. In humans, the FDA categorizes cefuroxime as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the 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. ) Cefuroxime enters maternal milk in low concentrations. Although probably safe for nursing offspring the potential for ad-verse effects cannot be ruled out, particularly alterations to gut flora with resultant diarrhea. Overdosage/Acute Toxicity Beagles receiving daily dosages of up to 1600 mg/kg/day orally tol-erated cefuroxime well (see Adverse Effects). Cerebral irritation with seizures has been reported with large overdoses in humans. Plasma levels of cefuroxime can be reduced with hemodialysis or peritoneal dialysis. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cefuroxime and may be of significance in veterinary patients: Am INOgly COSIDEST! : Potential for increased risk of nephrotoxicity— monitor renal function; however, aminoglycosides and cepha-losporins may have synergistic or additive actions against some gram-negative bacteria (Enterobacteriaceae) FUROSEm IDE, TORSEm IDET! : Possible increased risk of nephrotoxicity PROb ENECIDT! : Reduced renal excretion of cefaclor laboratory Considerations Cefuroxime may cause false-positive T! urine glucose determinations when using the copper reduction method (Benedict's solution, Fehling's solution, Clinitest ®); tests utilizing glucose oxidase (Tes-Tape ®, Clinistix ®) are not affected by cephalosporins In humans, particularly with azotemia, cephalosporins have !! caused a false-positive direct Coombs' test Doses DOg S: T! For susceptible infections: a) For soft tissue infections: 10 mg/kg PO q12h for 10 days. For systemic infections: 15 mg/kg IV q8h. For meningitis: 30 mg/kg IV q8h. Note : All dosages extrapolated from human dos-ages. (Greene, Hartmannn et al. 2006) For surgery prophylaxis: a) 20 mg/kg IV 30 minutes prior to surgery and every 2 hours during surgery. (Greene, Hartmannn et al. 2006) monitoring Clinical efficacy T! Monitor renal function in patients with renal insufficiency T! Client Information Give the oral tablets with food as it may enhance the absorption T! of the drug Avoid crushing tablets; a strong, bitter taste results even if mixed T! into food; if tablets must be crushed, give with dairy products such as milk or chocolate milk to improve absorption and palatability Give as directed by the veterinarian; even if animal appears well, T! continue treating for the full duration prescribed Contact veterinarian if animal develops severe vomiting/diarrhea T! or rash/itching Chemistry/Synonyms Cefuroxime axetil occurs as a white or almost white, powder that is insoluble in water and slightly soluble in dehydrated alcohol. Cefuroxime sodium occurs as a white or almost white, hygro-scopic powder that is freely soluble in water. Cefuroxime may also be known as: CCI-15641, cefuroxim, cefu-roxima, cefuroximum, cefuroksiimi, or cefuroksimas; many inter-nationally registered trade names are available. Storage/Stability/Compatibility Cefuroxime axetil tablets should be stored in tight containers at room temperature (15-30°C); protect from excessive moisture. The powder for suspension should be stored at 2-30°C. Once reconstituted, it should be kept refrigerated (2-8°C) and any un-used suspension discarded after 10 days. The powder for injection of infusion should be stored at room temperature (15-30°C). The powder may darken, but this does not indicate any loss of potency. When reconstituted with sterile water to a concentration of 90 mg/m L, the resulting solution is stable for 24 hours at room temperature; 48 hours if refrigerated. If further diluted into a compatible IV solution such as D5W, normal saline or Ringer's, the resulting solution is stable for 24 hours at room tem-perature; up to 7 days if refrigerated. Drugs that are reportedly compatible when mixed with cefu-roxime for IV use include, clindamycin, furosemide and metron-idazole. Drugs that may be given at a Y-site with a cefuroxime in-fusion running include, morphine, hydromorphone, and propofol. Aminoglycosides, ciprofloxacin, or ranitidine should not be ad-mixed with cefuroxime. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None HUm AN­l Ab El ED PRODUCTS: Cefuroxime Axetil Tablets (film coated): 125 mg, 250 mg, & 500 mg; Ceftin® (Glaxo Wellcome), generic; (Rx)

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

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CEPHAl Ex IN 171 Rarely, cephalexin has been implicated in causing toxic epider-mal necrolysis in cats. While cephalosporins (particularly cephalothin) have the po-tential for causing nephrotoxicity at clinically used doses in patients with normal renal function, risks for the occurrence of this adverse effect appear minimal. High doses or very prolonged use has been associated with neu-rotoxicity, neutropenia, agranulocy tosis, thrombocytopenia, hepa-titis, positive Coomb's test, interstitial nephritis, and tubular necro-sis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component. Reproductive/Nursing Safety Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy has not been firmly established, but nei-ther have there been any documented teratogenic problems asso-ciated with these drugs. However, use only when the potential ben-efits outweigh the risks. In humans, the FDA categorizes cephalexin 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. ) Small amounts of cephalexin may be distributed into maternal milk; it could potentially affect gut flora in neonates. Overdosage/Acute Toxicity Acute oral cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible (see Adverse Effects section). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cephalexin and may be of significance in veterinary patients: PROb ENECIDT! : Competitively blocks the tubular secretion of most cephalosporins thereby increasing serum levels and serum half-lives laboratory Considerations Except for cefotaxime, cephalosporins may cause false-positive T! urine glucose determinations when using cupric sulfate solution (Benedict's Solution, Clinitest®). T ests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins. When using the Jaffe reaction to measure T! serum or urine creatinine, cephalosporins (not cef tazidime or cefotaxime) in high dosages may falsely cause elevated values. In humans, particularly with azotemia, cephalosporins have T! caused a false-positive direct Coombs' test. Cephalosporins may also cause falsely elevated 17­ketosteroid values in urine. Doses DOg S:T! For susceptible infections: a) For susceptible Staph infections: 30 mg/kg PO q12h (may not be adequate dose for non-UTI's caused by E. coli) (Campbell and Rosin 1998) b) For pyoderma: 22-35 mg/kg PO q12h or 22 mg/kg PO q8h For respiratory infections: 20-40 mg/kg PO q8h; For soft tis-sue infections: 30-50 mg/kg PO q12h For systemic infections: 25-60 mg/kg PO q8h For orthopedic infections: 22-30 mg/kg PO q6-8h for 28 days For above doses, guideline for duration of therapy is treat for 5-7 days beyond resolution of clinical disease or preferably negative culture (Greene and Watson 1998) c) For Gram-positive infections: 22 mg/kg PO twice daily For Gram-negative infections: 30 mg/kg PO three times daily (Aucoin 2000) d) For treating infectious otitis: 22 mg/kg PO q12h (Kwochka 2002) e) For pyometra/metritis: 10-30 mg/kg PO q8-12h (Fresh-man 2002a) f) For UTI: 30-40 mg/kg PO q8h. For acute urethrocystitis, treatment may be 7-10 days for chronic urethrocystitis, up to 4 weeks of treatment may be necessary; for pyelonephritis, 4-8 weeks may be adequate (Brovida 2003) g) For neonates: 10-30 mg/kg PO (weak neonates should be given via stomach tube) twice daily-three times daily (Fresh-man 2002b) h) For juvenile cellulitis in 3-16 week old puppies: 20 mg/kg PO three times daily (Macintire 2004) i) For recurrent pyoderma: 22 mg/kg PO q12h (use at q8h for deep pyoderma) (Hillier 2006b) j) For superficial and deep pyoderma: 22-33 mg/kg PO two to three times daily (Beale and Murphy 2006) CATS:T! For susceptible infections:a) For soft tissue infections: 30-50 mg/kg PO q12h For systemic infections: 35 mg/kg PO q6-8h. For above doses, guideline for duration of therapy is treat for 5-7 days beyond resolution of clinical disease or preferably negative culture (Greene and Watson 1998) b) 22 mg/kg PO q8h; administer with food if GI upset occurs (Vaden and Papich 1995) c) For Gram+ infections: 22 mg/kg PO twice daily d) For Gram-infections: 30 mg/kg PO three times daily (Au-coin 2000) e) 20-40 mg/kg PO q8h (Lappin 2002a) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: 11-22 mg/kg PO q8h (Ivey and Morrisey 2000) b) Guinea pigs: 50 mg/kg IM q24h (Adamcak and Otten 2000) FERRETS:T! For susceptible infections:a) 15-25 mg/kg PO 2-3 times daily (Williams 2000) HORSES:T! For susceptible infections:a) 30 mg/kg PO q8h (Davis, Salmon et al. 2005) b) 22- 33 mg/kg PO q6h (Br umbaugh 1987) b IRDS:T! For susceptible infections:a) 35-50 mg/kg PO four times daily (using suspension); most preps are well accepted (Clubb 1986) b) 40-100 mg/kg q6h PO (Hoeffer 1995) c) Ratites: 15-22 mg/kg PO three times daily; For megabacte-riosis: 50 mg/kg PO 4 times daily for 5 days (Jenson 1998)

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

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CETIRIz INE HCl 173 monitoring Because cephalosporins usually have minimal toxicity associated T! with their use, monitoring for efficacy is usually all that is re-quired. Patients with diminished renal function may require intensified T! renal monitoring. Serum levels and therapeutic drug monitoring are not routinely done with these agents. Chemistry/Synonyms An intramammary semi-synthetic cephalosporin antibiotic, cep-hapirin sodium occurs as a white to off-white, crystalline powder having a faint odor. It is very soluble in water and slightly sol uble in alcohol. Each gram of the injection contains 2. 36 m Eq of so-dium. After reconstitution, the solution for injection has a p H of 6. 5-8. 5. Cephapirin sodium may also be known as: BL-P-1322, cefapirin, cefapirinum natricum, Brisfirina®, Cefa-Dri®, Cefa-Lak®, Cefaloject®, Cefatrex®, Lopitrex®, or Piricef®, To DAY ® or To MORROW®. Storage/Stability Cephapirin intramammary syringes should be stored at controlled room temperature (15-30°C); avoid excessive heat. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Cephapirin Sodium Mastitis Tube; 200 mg cephapirin per 10 m L tube; To DAY ® (Fort Dodge), Cefa-Lak® (Fort Dodge); (OTC). Ap-proved for use in lactating dairy cattle. Milk withdrawal = 96 hours; Slaughter withdrawal = 4 days. Cephapirin Benzathine Mastitis Tube; 300 mg cephapirin per 10 m L tube; To MORROW® (Fort Dodge), Cefa-Dri® (Fort Dodge); (OTC). Approved for use in dry dairy cattle. Milk withdrawal = 72 hours after calving and must not be administered within 30 days of calving; Slaughter withdrawal = 42 days. HUm AN­l Ab El ED PRODUCTS: None cetirizine hcl (she-tih-ra-zeen) Zyrtec® 2nd generati On antihistamine Prescriber Highlights Oral, relatively non-sedating antihistamine T T Limited clinical experience in veterinary medicine; rec-T T ommended dosages for dogs & cats vary widely but the drug appears well tolerated Potentially may cause vomiting, hypersalivation, or som-T T nolence in small animals Expensive when compared to 1st generation antihista-T T mines; generic products becoming available Uses/Indications Cetirizine is a H 1 receptor blocking antihistamine agent that may be useful for the adjunctive treatment of histamine-mediated pru-ritic conditions in dogs or cats. Pharmacology/Actions Cetirizine, a human metabolite of hydroxyzine, is a piperazine-class non-sedating (when compared to first generation drugs) antihista-mine. It selectively inhibits peripheral H 1 receptors. Cetirizine does not possess significant anticholinergic or anti-serotonergic effects. T olerance to its antihistaminic effects is thought not to occur. Pharmacokinetics No specific information was located for the pharmacokinetics of cetirizine in dogs. In a study performed in cats (Papich, Schooley et al. 2006) after an oral dose of 5 mg, volume of distribution was 0. 26 L/kg and clearance about 0. 3 m L/L/minute. T erminal elimination half-life was approximately 11 hours. The mean plasma concentra-tions remained above 0. 85 mcg/m L (a concentration reported to be effective for humans) for 24 hours after dosing. After oral administration to humans, cetirizine peak concentra-tions occur in about one hour. Food can delay, but not affect the extent of, absorption. It is 93% bound to human plasma proteins and brain levels are approximately 10% of those found in plasma. Approximately 80% is excreted in the urine, primarily as unchanged drug. T erminal elimination half-life is around 8 hours; antihista-minic effect generally persists for 24 hours after a dose. Contraindications/Precautions/Warnings No specific information is available for veterinary patients. In hu-mans, cetirizine is contraindicated in patients hypersensitive to it or hydroxyzine. Dosage adjustment is recommended in humans with severe renal or hepatic impairment, or older than 76 years of age. The combination product containing pseudoephedrine is not appropriate for use in dogs or cats. Adverse Effects Cetirizine appears well tolerated in dogs and cats. Vomiting or hypersalivation after dosing have been reported in some dogs. Drowsiness has been reported in small dogs at higher dosages. In humans, the primary adverse effects reported have been drowsiness (13%) and dry mouth (5%). Rarely, hypersensitivity re-actions or hepatitis have been reported. Reproductive/Nursing Safety In pregnant mice, rats, and rabbits, dosages of approximately 40X, 180X, and 220X respectively, of the human dose when compared on mg/m2 basis, caused no teratogenic effects. In humans, the FDA categorizes cetirizine as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In Beagles, approximately 3% of a dose was excreted into milk. Although probably safe for use in nursing veterinary patients, the manufacturer does not recommend using cetirizine in nursing women. Overdosage/Acute Toxicity Limited information is available. Reported minimum lethal oral doses for mice and rats are 237 mg/kg (95X human adult dose on a mg/m2 basis) and 562 mg/kg (460X human adult dose on a mg/m2 basis), respectively. Unlike the earlier non-sedating antihistamines, terfenadine and astemizole (both no longer available in the USA), cetirizine does not appreciably prolong the QT interval on ECG at high serum levels. Overdoses of cetirizine products that also contain pseudoephed-rine (Zyrtec-D 12 Hour®) may be serious. It is advised to contact an animal poison control center in this event.

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

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CHARCOAl, ACTIVATED 175 Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving charcoal and may be of significance in veterinary patients: OTHER ORAlly ADm INISTERED THERAPEUTIC Ag ENTST! : Separate by at least 3 hours the administration of any other orally administered therapeutic agents from the charcoal dose DAIRy PRODUCTST! : May reduce the adsorptive capacity of activated charcoal m INERAl OIl T! : May reduce the adsorptive capacity of activated charcoal POly ETHyl ENE gly COl; El ECTROly TE SOl UTIONS T! (e. g., Go-Lytely®): May reduce the adsorptive capacity of activated charcoal Doses DOg S & CATS:T! As a gastrointestinal absorbent:a) 10 m L of a 20% slurry (1 g of charcoal in 5 m L of water) per kg of body weight by stomach tube (Carson and Osweiler 2003) For acute poisoning: a) After decontamination of the GI tract give activated charcoal at 1-4 g/kg PO. Placement of a nasogastric tube can facili-tate administration and reduce the incidence of aspiration in the sedated/fractious animal particularly when repeated administration is desired; repeat every 4-6 hours for toxins that are recirculated through the intestinal capillary network. (Rudloff 2006b) b) 1-4 g/kg in 50-200 m L of water. Concurrent with or within 30 minutes of giving char coal, give an osmotic cathartic. Re-peated doses of activated charcoal may also bind drugs that are enterohepatically recycled. (Beasley and Dorman 1990) c) Administer in a bathtub or other easily cleanable area. Give activated charcoal at 1-5 g/kg PO (via stomach tube using either a funnel or large syringe) diluted in water at a con-centration of 1 g charcoal/5-10 m L of water. Follow in 30 minutes with sodium sulfate oral cathartic. (Bailey 1989) RUm INANTS:T! a) 1-3 grams/kg PO (1 gram of charcoal in 3-5 m L of water) via stomach tube; give saline cathartic concurrently. May re-peat in 8-12 hours. (Bailey 1986b) HORSES:T! a) Foals: 250 grams (minimum). Adult horses: up to 750 grams. Make a slurry by mixing with up to 4 L (depending on ani-mal's size) of warm water and administer via stomach tube. Leave in stomach for 20-30 minutes and then give a laxative to hasten removal of toxicants. (Oehme 1987b) monitoring Monitoring for efficacy of charcoal is usually dependent upon the T! toxin/drug that it is being used for and could include the drug/toxin's serum level, clinical signs, etc. Serum sodium, particularly if patient develops neurologic signs T! associated with hypernatremia (tremors, ataxia, seizures)Client Information This agent should generally be used with professional supervi-T! sion; if used on an outpatient basis patients must be observed for at least 4 hours after administration for signs associated with too much sodium in the blood (weakness, unsteadiness, tremors, convulsions). Should these occur, patients must immediately be seen by a veterinarian. Charcoal can easily stain fabrics T! Chemistry/Synonyms Activated charcoal occurs as a fine, black, odorless, tasteless powder that is insoluble in water or alcohol. Commercially available acti-vated charcoal products may differ in their adsorptive properties, but one gram must adsorb 100 mg of strychnine sulfate in 50 m L of water to meet USP standards. Activated charcoal may also be known as: active carbon, acti-vated carbon, carbo activatus, ad sorbent charcoal, decolorizing car-bon, or medicinal charcoal. There are many trade names available. Storage/Stability Store activated charcoal in well-closed glass or metal containers or in the manufacturer's supplied container. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: Activated charcoal 47. 5%, Kaolin 10% granules (free flowing and wettable) in 1 lb bottles, and 5 kg pails: Toxiban® Granules (Vet-A-Mix); (OTC). Labeled for use in both large and small animals. Activated charcoal 10. 4%, Kaolin 6. 25% suspension in 240 m L bot-tles: Toxiban® Suspension (Vet-A-Mix); (OTC). Labeled for use in both large and small animals. Activated charcoal 10%, Kaolin 6. 25%, sorbitol 10% suspension in 240 m L bottles: Toxiban® Suspension with Sorbitol Vet-A-Mix); (OTC). Labeled for use in small animals. Activated Charcoal 10%, Attapulgite 20%, sodium chloride 35 mg/ m L, potassium chloride 35 mg/m L Gel/Paste in 80 m L & 300 m L: D-Tox-Besc® (Agri Pharm); Activated Charcoal Gel with Electrolytes® & DVM Formula® (Bomac Plus Vet), Activated Charcoal Paste® (First Priority); (OTC). Labeled for use in small and large animals. Activated Hardwood Charcoal and thermally activated attapulgite clay (concentrations not labeled) in an aqueous gel suspen sion in 8 fl oz bottle, 60 m L tube and 300 m L tube with easy dose syringe. UAA® (Universal Animal Antidote) Gel (Vedco); (OTC). Labeled for use in dogs, cats and grain overload in ruminants. HUm AN­l Ab El ED PRODUCTS: Activated Charcoal Powder: 15 g, 30 g, 40 g, 120 g, 240 g and UD 30 g (Activated charcoal is also available in bulk powder form); ge-neric; (OTC) Activated Charcoal Liquid/Suspension with sorbitol: 15 g & 30 g in 150 m L & 50 g in 240 m L; Charco Aid® (Requa); 25 g in 120 m L & 50 g in 240 m L; Actidose® with Sorbitol (Paddock); (OTC) Activated Charcoal Liquid/Suspension without sorbitol: 15 g & 50 g in 120 m L & 240 m L; Charco Aid® 2000 (Requa); (OTC); 208 mg/ m L — 12. 5 g in 60 m L & 25 g in 120 m L; 12. 5 g in 60 m L, 15 g in 75 m L, 25 g in 120 m L, 30 g in 120 m L, 50 g in 240 m L; Actidose-Aqua® (Paddock); generic; (OTC) Activated Charcoal Granules: 15 g in 120 m L; Charco Aid® 2000 (Requa); (OTC)

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

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CHl ORAmb UCIl 177 For adjunctive therapy of lymphoreticular neoplasms, macro-globulinemia, and polycythemia vera: a) 2-6 mg/m2 PO once a day or every other day (Jacobs, Lums-den et al. 1992) b) For first level treatment of dogs of canine lymphoma where clients cannot afford, or will not accept combination chemo-therapy due to risks of toxicity: Prednisone alone (40 mg/m2 PO daily for 7 days then every other day) or in combination with chlorambucil at 6-8 mg/m2 PO every other day. Per-form a CBC every 2-3 weeks. (Ogilvie 2006) c) For lymphoproliferative disease; macroglobulinemia: 2-4 mg/m2 PO q24-48h (Gilson and Page 1994) For chronic lymphocytic leukemia: a) 20 mg/m2 PO every 1-2 weeks or 6 mg/m2 PO daily (Vail and Ogilvie 1994) For treatment of pemphigus complex: a) Prednisone 2-4 mg/kg PO divided q12h with chlorambucil 0. 2 mg/kg q24-48h (Helton-Rhodes 1994) b) Used in combination with corticosteroids. Chlorambucil 0. 1-0. 2 mg/kg once daily ini tially until marked improve-ment (or 75% improvement) of clinical signs (may require 4-8 weeks). Then alternate day dosing is begun and main-tained for several weeks. If no exac erbation, alternately de-crease chlorambucil and corticosteroids until lowest possible dose is attained. (White 2000) For adjunctive treatment of inflammatory bowel disease: a) 1. 5 mg/m2 PO every other day (Marks 2007b) CATS:T! For adjunctive treatment of inflammatory bowel disease: a) As a second choice (corticosteroids first choice) or refractory or severe IBD: Cats greater than 4kg: 2 mg (total dose) PO q48 hours (every other day) for 2-4 weeks then tapered to the lowest effective dose (2 mg per cat q72-96 hours; every 3rd to 4th day). Cats less than 4 kg are started at 2 mg (total dose) q72 hours (every 3rd day). (Moore 2004) b) 15 mg/m2 PO once per day for 4 consecutive days, repeated every 3 weeks (in combination with prednisolone) appears highly effective in managing cats with severe IBD or intesti-nal lymphoma. Alternatively, may dose at 2 mg (total dose) per cat every 4 days indefinitely. (Marks 2007b) c) For lymphocytic-plasmacytic enteritis (LPE): Chlorambucil is sometimes useful for cats that do not respond to diet, pred-nisolone and metronidazole; limited experience, but seems it should be administered with prednisolone. Two methods for dosing: 1) Initial dose is 2 mg/m2 PO for 4-7 days, then decreased to 1 mg/m2 for 7 days. If clinical signs are lessen-ing, continue daily dosing but only every other week; it is common for patients to develop anemia. 2) Large cats (>7 lb. ) 2 mg PO twice weekly; smaller cats (<7 lb) 1 mg PO twice weekly. If a clinical response will occur, it should be seen in 4-6 weeks, after which the drug is slowly tapered to the low-est effective dose. Monitor CBC's anytime the cat seems to feel bad. (Willard 2006a) For adjunctive treatment of pemphigus complex: a) Prednisolone 2-4 mg/kg PO divided q12h with chloram-bucil 0. 2 mg/kg q24-48h (Helton-Rhodes 1994) b) For generalized pemphigus foliaceous: If cats have a poor response to prednisolone alone, may add chlorambucil at 0. 1-0. 2 mg/kg PO q24-48h; has slow onset of action and can cause bone marrow depression. (Hillier 2006f)For adjunctive treatment of FIP: a) Prednisolone 4 mg/kg PO once daily with chlorambucil 20 mg/m2 every 2-3 weeks (Weiss 1994) For chronic lymphocytic leukemia: a) Chlorambucil at 2 mg/m2 PO every other day or 20 mg/m2 every other week; with or without prednisolone at 20 mg/m2 PO every other day. The authors state they have had more success with the high dose-every other week regi men. (Peter-son and Couto 1994) For lymphocytic leukemia: a) Chlorambucil 6 mg/m2 (2 mg/5. 3 kg cat) PO every other day and prednisolone 5 mg/cat/day. Supplemental cobalamin (1 m L SC q2-3 weeks) and folate/B-complex vitamins should also be given. (Simpson 2003a) For feline pemphigus foliaceous or severe feline eosinophilic granuloma complex (in combi nation with corticosteroids): a) 0. 1-0. 2 mg/kg (usually H of the 2 mg tablet or 1 mg) once daily initially until marked improvement (or 75% improve-ment) of clinical signs (may require 4-8 weeks). Then alter-nate day dosing is begun and maintained for several weeks. If no exacerbation, alternately decrease chlorambucil and corticosteroids until lowest possible dose is attained. Most cats may ultimately be maintained on alternate day steroid therapy alone. (White 2000) For idiopathic pruritus when nothing else works: a) 0. 2 mg/kg PO q24-48h. Closely monitor during treatment. (Hnilica 2003c) HORSES:T! For adjunctive therapy in treating lymphoma using the LAP protocol: a) Cytosine arabinoside 200-300 mg/m2 SC or IM once every 1-2 weeks; Chlorambucil 20 mg/m2 PO every 2 weeks (al-ternating with cytosine arabinoside) and Prednisone 1. 1-2. 2 mg/kg PO every other day. If this protocol is not effective (no response seen in 2-4 weeks) add vincristine at 0. 5 mg/m2 IV once a week. Side effects are rare. (Couto 1994) monitoring Efficacy T! CBC, Platelets once weekly (or once stable every other week) T! during therapy; once stable, dogs may require only monthly monitoring. If neutrophils are <3,000/micro L hold drug until re-covered and reduce dose by 25% or increase dosing interval. Uric acid, liver en zymes; if warranted T! Client Information Clients must understand the importance of both administering T! chlorambucil as directed and immediately reporting any signs associated with toxicity (e. g., abnormal bleeding, bruis ing, urina-tion, depression, infection, shortness of breath, etc. ) Chemistry/Synonyms A nitrogen mustard derivative antineoplastic agent, chlorambucil occurs as an off-white, slightly granular powder. It is very slightly soluble in water. Chlorambucil may also be known as: CB-1348, NSC-3088, WR-139013, chlorambucilum, chloraminophene, chlorbutinum, Chloraminophene®, Leukeran®, or Linfolysin®.

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

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CHl ORAm PHENICOl 179 Adverse Effects While the toxicity of chloramphenicol in humans has been much dis cussed, the drug is considered by most to have a low order of toxicity in adult companion animals when appropriately dosed. The development of aplastic anemia reported in humans, does not appear to be a significant problem for veterinary patients; however, a dose-related bone marrow suppression (reversible) is seen in all species, primarily with long-term therapy. Early signs of bone marrow toxicity can include vacuola tion of many of the early cells of the myeloid and erythroid series, lymphocytopenia, and neu tropenia. Other effects that may be noted include anorexia, vomiting, di-arrhea, and depression. It has been said that cats tend to be more sensitive to developing adverse reactions to chloram phenicol than dogs, but this is prob-ably more as a result of the drug's longer half-life in the cat. Cats dosed at 50 mg/kg q12h for 2-3 weeks do develop a high incidence of adverse effects and should be closely monitored when prolonged high-dose therapy is necessary. Reproductive/Nursing Safety Chloramphenicol has not been determined to be safe for use dur-ing pregnancy. The drug may decrease protein synthesis in the fe-tus, particularly in the bone marrow. It should only be used when the benefits of therapy clearly outweigh the risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduc-tion studies and no adequate studies in humans. ) In a separate sys-tem evaluating the safety of drugs in canine and feline pregnancy (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. ) Because chloramphenicol is found in milk in humans at 50% of serum levels, the drug should be given with caution to nursing bitches or queens, particularly within the first week after giving birth. Overdosage/Acute Toxicity Because of the potential for serious bone marrow toxicity, large over doses of chloramphenicol should be handled by emptying the gut using standard protocols. For more information on the toxicity of chloramphenicol, refer to the Adverse Effects section above. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chloramphenicol and may be of significance in veterinary patients ( Note : cats may be particularly susceptible to chloramphenicol's effects on the hepatic metabolism of other drugs): ANTI­ANEm IA DRUg ST! (Iron, Vitamin b12, folic acid ): Chlorampheni-col may delay hematopoietic response b ETA­l ACTAm ANTIb IOTICST! (penicillins, cephalosporins, aminoglyco­ sides ): Potential for antagonism l IDOCAINET! : Chloramphenicol may delay hepatic metabolism my El OSUPPRESSIVE DRUg ST! (e. g., cyclophosphamide ): Potential for additive bone marrow depression PENTOb ARb ITAl T! : Chloramphenicol has been demonstrated to pro-long the duration of pentobarbital anesthesia by 120% in dogs, and 260% in cats PHENOb ARb ITAl T! : Chloramphenicol may inhibit hepatic me-tabolism and phenobarbital may decrease chloramphenicol concentrations PRIm IDONE!! : Anorexia and CNS effects may occur in dogs PROPOFOl!! : Chloramphenicol may prolong anesthesia RIFAm PIN!! : May decrease serum chloramphenicol levels laboratory Considerations False-positive T! glucosuria has been reported, but the incidence is unknown. Doses DOg S:T! For susceptible infections: a) 45-60 mg/kg PO q8h; 45-60 mg/kg IM, SC or IV q6-8h (USPC 1990) b) 40-50 mg/kg IV, IM, SC or PO q8h; avoid in young animals or in breeding or pregnant animals; avoid or reduce dosage in animals with severe liver failure. (Vaden and Papich 1995) c) For urinary, rickettsial, localized soft tissue infections: 25-50 mg/kg PO q8h for 7 days. For systemic infections: 50 mg/kg PO, IV, IM, SC q6-8h for 3-5 days For severe bacteremia, sepsis: 50 mg/kg IV, IM or SC q4-6h for 3 days (Greene and Watson 1998) d) For Rocky Mountain Spotted Fever: 15-20 mg/kg q8h PO, IM or IV for 14-21 days (Sellon and Breitschwerdt 1995) e) For susceptible infectious otitis: 50 mg/kg PO q8h (Rosenk-rantz 2006b) CATS:T! For susceptible infections:a) 25-50 mg/kg PO q12h; 12-30 mg/kg IM, SC or IV q12h (USPC 1990) b) 50 mg (total dose) IV, IM, SC or PO q8h; avoid in young animals or in breeding or preg nant animals; avoid or reduce dosage in animals with severe liver failure (Vaden and Papich 1995) c) For urinary, localized soft tissue infections: 50 mg per cat (to-tal dose) PO q12h for 14 days. For systemic infections: 25-50 mg/kg PO, IV, IM, SC q12h for 14 days or less For severe bacteremia, sepsis: 50 mg per cat (total dose) PO, IV, IM or SC q6-8h for 5 days or less. (Greene and Watson 1998) RAbb ITS/RODENTS/Sm All m Amm Al S:T! a) Rabbits: 30-50 mg/kg PO, SC, IM, IV q8 - 24h (Ivey and Morrisey 2000) b) Hedgehogs: 50 mg/kg PO q12h; 30-50 mg/kg SC, IM, IV or IO q12h (Smith 2000) c) Chinchillas: 30-50 mg/kg PO, SC, IM q12h (Hayes 2000) d) Gerbils, Guinea Pigs, Hamsters, Mice, Rats: 20-50 mg/kg (succinate salt) SC q6-12h (Adamcak and Otten 2000) e) Guinea pigs for pneumonia: 30-50 mg/kg PO q12h (John-son 2006d) FERRETS:T! For proliferative colitis:a) 10-40 mg/kg q8h PO for 2 weeks or 50 mg/kg PO q12h for 10 days (Fox 1995) b) 50 mg/kg q12h PO for 14-21 days (Johnson 2006c) For susceptible infections: a) 50 mg/kg PO twice daily (using palmitate salt—may be un-available) or 50 mg/kg SC or IM twice daily (succinate salt) (Williams 2000)

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

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CHl ORDIAz EPOx IDE ± Cl IDINIUm 181 chlordi Azepoxide ± clidinium br (klor-dye-az-e-pox-ide) ± (kli-din-ee-um) Librium®, Librax® benz Odiazepine ± antimuscarinic Prescriber Highlights Benzodiazepine for behavior problems (phobias, etc. ) T T & with an antimuscarinic (clidinium) for irritable bowel syndrome in dogs Not commonly used, so little has been published on ad-T T verse effects (similar to diazepam +/-atropine)Potentially teratogenic T T Uses/Indications Chlordiazepoxide alone may be a useful adjunct to treating certain behaviors where benzodiazepines may be useful including noise phobias in dogs; inter-cat aggression and urine spraying in cats. When combined with clidinium, it may be useful symptomatic therapy for dogs with irritable bowel syndrome. Pharmacology/Actions The subcortical levels (primarily limbic, thalamic, and hypotha-lamic) of the CNS are depressed by chlordiazepoxide and other benzodiazepines thus producing the anxiolytic, seda tive, skeletal muscle relaxant and anticonvulsant effects seen. The exact mech-anism of action is un known but postulated mechanisms include: antagonism of serotonin, increased release of and/or fa cilitation of gamma-aminobutyric acid (GABA) activity, and diminished re-lease or turnover of acetylcholine in the CNS. Benzodiazepine spe-cific receptors have been located in the mammalian brain, kidney, liver, lung, and heart. In all species studied, receptors are lacking in the white matter. Clidinium bromide is an antimuscarinic with its main action to reduce GI motility and secretion similarly to atropine. Clidinium is a quaternary ammonium compound and, unlike atropine, does not cross appreciably into the CNS or the eye and should not exhibit the same extent of CNS or ocular adverse effects that atropine pos-sesses. For further information, refer to the atropine mono graph. Pharmacokinetics Chlordiazepoxide is rapidly absorbed following oral administration. It is highly lipid soluble and is widely distributed throughout the body. It readily crosses the blood-brain barrier and is fairly highly bound to plasma proteins. Chlordiazepoxide is metabolized in the liver to several metabolites, including: desmethyldiazepam (nordi-azepam), desmethylchlordiazepoxide and ox azepam, all of which are pharmacologically active and can have considerable half lives. These are eventually conjugated with glucuronide and eliminated primarily in the urine. Because of the active metabolites, serum val-ues of chlordiazepoxide are not useful in predicting efficacy. Little pharmacokinetic data for clidinium is available. The drug is incompletely absorbed from the gut (small intestine). Effects in humans are seen in about an hour; duration of effect is about 3 hours. As the compound is completely ionized in vivo, it does not enter the CNS or the eye and there fore unlike atropine does not have effects on those systems. The drug is metabolized principally in the liver, but is also excreted unchanged in the urine. Contraindications/Precautions/Warnings Use benzodiazepines cautiously in patients with hepatic or renal disease and in debilitated or geriatric patients. Chlordiazepoxide should only be administered very cautiously to patients in coma, shock or with significant respiratory depression. It is contrain-dicated in patients with known hypersensitivity to the drug. Chlordiazepoxide should be used very cautiously, if at all, in ag-gressive patients as it may disinhibit the anxiety that may help pre-vent these animals from aggressive behavior. Benzodiazepines may impair the abilities of work ing animals. If administering the drug IV (rarely warranted), be prepared to administer cardiovascu lar or respiratory support. Give IV slowly. Clidinium, like other antimuscarinic agents should not be used in patients with tachycardias sec ondary to thyrotoxicosis or cardiac insufficiency, myocardial ischemia, unstable cardiac status dur ing acute hemorrhage, GI obstructive disease, paralytic ileus, severe ul-cerative colitis, obstructive uropathy, or myasthenia gravis. Antimuscarinic agents should be used with extreme caution in patients with known or suspected GI infections. Antimuscarinic agents can decrease GI motility and prolong retention of the caus-ative agent(s) or toxin(s) resulting in prolonged effects of the toxin. Antimuscarinic agents must also be used with extreme caution in patients with autonomic neuropathy. Antimuscarinic agents should be used with caution in patients with hepatic or renal disease, geri atric or pediatric patients, hyper-thyroidism, hypertension, CHF, tachyarrhythmias, prostatic hyper-trophy, or esophageal reflux. Systemic atropine should be used cau-tiously in horses as it can de crease gut motility and induce colic in susceptible animals. It may also reduce the arrhythmogenic doses of epinephrine. Use of atropine in cattle may result in inappetence and rumen stasis that may persist for several days. Adverse Effects Chlordiazepoxide's adverse effects are similar to other benzodi-azepines, especially diazepam (they share several active metabo-lites). As there is much more infor mation with respect to diazepam in dogs or cats than chlordiazepoxide, the following is extrapo lated from diazepam information: Dogs could exhibit a contradictory response (CNS excitement) following administration of chlordi-azepoxide. The effects with regard to sedation and tranquilization are extremely variable with each dog. Cats could exhibit changes in behavior (irritability, depression, aberrant demeanor) after receiv-ing chlordiazepoxide. There have been reports of cats developing hepatic failure after receiving oral diazepam for several days. It is unknown if chlordiazepoxide also shares this effect. Clinical signs have been reported to occur 5-11 days after beginning oral thera-py. Cats that receive diazepam should have baseline liver function tests. These should be repeated and the drug discontinued if emesis, lethargy, inappetence, or ataxia develops. Clidinium's adverse effects are basically extensions of the drug's pharmacologic effects and are generally dose related. At usual doses effects tend to be mild in relatively healthy patients. More severe effects tend to occur with high or toxic doses. GI effects can in-clude dry mouth (xerostomia), dysphagia, constipation, vomiting, and thirst. GU effects may include urinary retention or hesitancy. Cardiovascular effects include sinus tachycardia (at higher doses), bradycardia (initially or at very low doses), hypertension, hypoten-sion, arrhythmias (ectopic complexes), and circulatory failure. Reproductive/Nursing Safety Benzodiazepines have been implicated in causing congenital ab-normalities in humans if adminis tered during the first trimester of pregnancy. Infants born of mothers receiving large doses of benzo-diazepines shortly before delivery have been reported to suffer from apnea, impaired metabolic re sponse to cold stress, difficulty in feed-

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182 CHl ORDIAz EPOx IDE ± Cl IDINIUm ing, hyperbilirubinemia, hypotonia, etc. Withdrawal symp toms have occurred in infants whose mothers chronically took benzodiazepines during pregnancy. The veterinary significance of these effects is un-clear, but the use of these agents during the first trimester of preg-nancy should only occur when the benefits clearly outweigh the risks associated with their use. In humans, the FDA categorizes chlordiaz-epoxide 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. ) Benzodiazepines and their metabolites are distributed into milk and may cause CNS effects in nursing neonates. Overdosage/Acute Toxicity When administered alone, chlordiazepoxide overdoses are generally limited to significant CNS depression (confusion, coma, decreased reflexes, etc. ). Hypotension, respi ratory depression, and cardiac arrest have been reported in human patients but apparently are quite rare. Treatment of acute toxicity consists of standard protocols for re-moving and/or binding the drug in the gut if taken orally, and sup-portive systemic measures. The use of analeptic agents (CNS stimu-lants such as caffeine) are generally not recommended. Flumazenil may be considered for adjunctive treatment of overdoses of benzo-diazepines. Drug Interactions The following drug interactions have either been reported or are the-oretical in humans or animals receiving chlordiazepoxide or other benzodiazepines and may be of significance in veterinary patients: DIg Ox INT! : The pharmacologic effects of digoxin may be increased; monitor serum digoxin levels or signs of toxicity OTHER CNS DEPRESSANT DRUg ST! (e. g., barbiturates, opiates, anesthet­ ics): Additive effects may occur PROb ENECIDT! : May interfere with benzodiazepine metabolism in the liver, causing increased or pro longed effects RIFAm PINT! : May induce hepatic microsomal enzymes and decrease the pharmacologic effects of ben zodiazepines The following drugs may decrease the metabolism of chlordiazepox-ide and excessive sedation may occur: CIm ETIDINE!! ERy THROmy CIN !! Fl UOx ETINE !! ISONIAz ID !! KETO CONAz Ol E !! m ETOPROl Ol T! PROPRANOl Ol T! When using the product containing clidinium the following potential in-teractions noted with atropine may apply and the following drugs may enhance the activity or toxicity of clidinium: Am ANTADINE!! ANTICHOl INERg IC Ag ENTS !! (OTHER ) ANTICHOl INERg IC m USCl E REl Ax ANTS!! ANTIHISTAm INES !! (e. g., diphenhydramine ) DISOPy RAm IDE!! m EPERIDINE!! PHENOTHIAz INES!! PROCAINAm IDE!! PRIm IDONE T! TRICy Cl IC ANTIDEPRESSANTST! (e. g., amitriptyline, clomipramine )Am ITRAz T! : Atropine may aggravate some signs seen with amitraz toxicity; leading to hypertension and further inhibition of peri-stalsis ANTACIDST! : May decrease PO atropine absorption; give oral atro-pine at least 1 hour prior to oral antacids CORTICOSTEROIDST! (long­term use ): may increase intraocular pressure DIg Ox INT! (slow­dissolving ): Atropine may increase serum digoxin levels; use regular digoxin tablets or oral liquid KETOCONAz Ol ET! : Increased gastric p H may decrease GI absorption; administer atropine 2 hours after ketoconazole m ETOCl OPRAm IDET! : Atropine and its derivatives may antagonize the actions of metoclopramide laboratory Considerations Chlordiazepoxide can cause interference with the Zimmerman T! reac tion for 17­ketosteroids, resulting in false results. It can also cause a false-positive result in the T! Gravindex® pregnancy test. Doses DOg S:T! Chlordiazepoxide alone: For behavior indications (thunderstorm/noise phobias): a) 2. 2-6. 6 mg/kg PO as needed (start low) (Overall 2000) Chlordiazepoxide with clidinium:For symptomatic treatment of irritable bowel syndrome: a) Using the combination product (e. g., Librax®), give 0. 1-0. 25 mg/kg of clidinium or 1-2 cap sules PO two times to three times a day. Owner may give when abdominal pain or diar-rhea first noticed or if stressful conditions are encountered. Drug can usually be discon tinued in a few days. (Leib 2004a) b) Using the combination product (e. g., Librax®), give 0. 44-1. 1 mg/kg of clidinium PO two to three times a day. Use at first signs of cramping or abdominal pain. Most dogs only require for a day to 2 weeks. Some require long-term treatment at 1-2 doses per day. (Tams 2000) CATS:T! As an anxiolytic: a) Chlordiazepoxide: 0. 5-1 mg/kg PO q12-24h (Virga 2002) monitoring Clinical efficacy T! Adverse effects T! Client Information Keep out of reach of children and in tightly closed containers T! Notify veteri narian if animal's behavior worsens T! Chemistry/Synonyms A benzodiazepine, chlordiazepoxide HCl occurs as an odorless, white crystalline pow der. It is soluble in water and alcohol, but is unstable in aqueous solutions. A synthetic quaternary antimuscarinic agent similar to glycopyr-rolate, clidinium bromide occurs as a white to nearly white, crystal-line powder. It is soluble in alcohol and water. Chlordiazepoxide HCl may also be known as: chlordiazep-oxidi hydrochloridum, methamino-diazepoxide hydrochloride, NSC-115748, or Ro-5-0690; many trade names are available.

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CHl OROTHIAz IDE 183 Storage/Stability Chlordiazepoxide HCl capsules or tablets should be stored pro-tected from light. The chlordiazepoxide HCl injection should be prepared immediately prior to use and any unused portions dis-carded. The diluent should be stored in the refrigerator before use. Clidinium bromide and chlordiazepoxide capsules should be stored at room temperature in tight, light-resistant containers. Dosage Forms/Regulatory Status VETERINAR y­l Ab El ED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more informa-tion. HUm AN­l Ab El ED PRODUCTS: Chlordiazepoxide HCl Capsules: 5 mg, 10 mg & 25 mg; Librium® (ICN Pharmaceuticals); generic; (Rx, C-IV) Chlordiazepoxide HCl Powder for Injection: 100 mg in 5 m L amp with 2 m L amp of IM diluent;, Librium® (ICN Pharmaceuticals); (Rx, C-IV) Chlordiazepoxide HCl 5 mg and Clidinium Br 2. 5 mg Capsules; Librax® Capsules (Valeant); generic; (Rx, C-IV) Also available in fixed dose combinations: tablets containing chlordiazepoxide: 5 mg and 12. 5 mg amitriptyline or chlordiazep-oxide 10 mg and amitriptyline 25 mg; Limbi trol® & Limbitrol DS® (Valeant); generic; (Rx, C-IV) chlorothi Azide chlorothi Azide sodium (klor-oh-thye-a-zide) Diuril® thiazide diuretic Prescriber Highlights Thiazide diuretic used for nephrogenic diabetes insipidus T T & hypertension in dogs; ud der edema in dairy cattle (cattle product now discontinued in USA) Contraindications: Hypersensitivity; pregnancy (relative T T contraindication)Extreme caution/avoid: Severe renal disease, preexisting T T electrolyte/water balance ab normalities, impaired he-patic function, hyperuricemia, SLE, diabetes mellitus Adverse Effects: Hypokalemia, hypochloremic alkalosis, T T other electrolyte imbalances, hyperuricemia, GI effects Many drug-drug & laboratory test interactions T T Uses/Indications In veterinary medicine, furosemide has largely supplanted the use of thiazides as a general diuretic (edema treatment). Thiazides are still used for the treatment of systemic hyperten sion, nephrogenic diabetes insipidus, and to help prevent the recurrence of calcium oxalate uroliths in dogs. Chlorothiazide is approved for use in dairy cattle for the treat-ment of post parturient udder edema, but the veterinary labeled product has been discontinued in the USA. Pharmacology/Actions Thiazide diuretics act by interfering with the transport of sodi-um ions across renal tubular epithelium possibly by altering the metabolism of tubular cells. The principle site of action is at the cortical diluting segment of the nephron; enhanced excretion of sodium, chloride, and water results. Thiazides also increase the ex-cretion of potassium, magnesium, phosphate, iodide, and bro mide and decrease the glomerular filtration rate (GFR). Plasma renin and resulting aldosterone levels are increased which contributes to the hypokalemic effects of the thiazides. Bicarbonate excretion is increased, but effects on urine p H are usually minimal. Thiazides initially have a hypercalciuric ef fect but with continued therapy, calcium excretion is significantly decreased. Uric acid excretion is also decreased by the thiazides. Thiazides can cause, or exacerbate, hyperglycemia in diabetic pa tients, or induce diabetes mellitus in prediabetic patients. The antihypertensive effects of thiazides are well known, and these agents are used extensively in human medicine for treating essential hypertension. The exact mechanism of this effect has not been established. Thiazides paradoxically reduce urine output in patients with diabetes insipidus (DI). They have been used as adjunctive therapy in patients with neurogenic DI and are the only drug therapy for nephrogenic DI. Pharmacokinetics The pharmacokinetics of the thiazides have apparently not been studied in do mestic animals. In humans, chlorothiazide is only 10-21% absorbed after oral administration. The onset of diuretic activity occurs in 1-2 hours and peaks at about 4 hours. The serum half-life is ap proximately 1-2 hours and the duration of activity is from 6-12 hours. Like all thiazides, the antihy pertensive effects of chlorothiazide can take several days to transpire. Thiazides are found in the milk of lactating humans. Because of the chance of idiosyncratic or hy persensitive reactions, it is recom-mended that these drugs not be used in lactating females or nursing mothers. Contraindications/Precautions/Warnings Thiazides are contraindicated in patients hypersensitive to any one of these agents or to sulfonamides, and those with anuria. They are also contraindicated in pregnant females who are otherwise healthy and have only mild edema; newborn human infants have developed thrombocytopenia when their mothers received thiazides. Thiazides should be used with extreme caution, if at all, in patients with severe renal disease or with preexisting electrolyte or water balance abnormalities, impaired hepatic function (may precipi tate hepatic coma), hyperuricemia, lupus (SLE); or diabetes mellitus. Patients with conditions that may lead to electrolyte or water balance abnormalities (e. g., vomiting, diarrhea, etc. ) should be moni tored carefully. Adverse Effects Hypokalemia is one of the most common adverse effects associ-ated with the thiazides but rarely causes clinical signs or progresses further; however, monitoring of potassium is recommended with chronic therapy. Hypochloremic alkalosis (with hypokalemia) may develop, es-pecially if there are other causes of potassium and chloride loss (e. g., vomiting, diarrhea, potassium-losing nephropathies, etc. ) or if the patient has cirrhotic liver disease. Dilutional hyponatremia and hypomagnesemia may also occur. Hyperparathyroid-like ef-fects of hypercalcemia and hypophosphatemia have been reported in hu mans, but have not led to effects such as nephrolithiasis, bone resorption, or peptic ulceration.

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184 CHl OROTHIAz IDE Hyperuricemia can occur but is usually asymptomatic. Other possible adverse effects include GI reactions (vomiting, di-arrhea, etc. ), hypersensitiv ity/dermatologic reactions, GU reactions (polyuria), hematologic toxicity, hyperglycemia, hyperlipi demias, and orthostatic hypotension. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the 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. ) Chlorothiazide enters maternal milk and can reduce milk vol-ume and suppress lactation. Generally, discontinuation of the drug or nursing is recommended in humans. Overdosage Acute overdosage may cause electrolyte and water balance prob-lems, CNS effects (lethargy to coma and seizures), and GI effects (hypermotility, GI distress). Transient increases in BUN have also been reported. Treatment consists of emptying the gut after recent oral ingestion using standard protocols. Avoid giving concomitant cathartics as they may exacerbate the fluid and electrolyte imbalances that may ensue. Monitor and treat electrolyte and water balance abnormalities sup-portively. Additionally, monitor respiratory, CNS and cardiovascular status; treat supportively and symptomatically, if re quired. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving chlorothiazide and may be of significance in veterinary patients: Am PHO TERICIN b T! : Use with thiazides can lead to an increased risk for severe hypokalemia CORTICOSTEROIDS, CORTICOTROPINT! : Use with thiazides can lead to an increased risk for severe hypokalemia DIAz Ox IDET! : Increased risk for hyperglycemia, hyperuricemia, and hypotension may occur DIg ITAl IS, DIg Ox INT! : Thiazide-induced hypokalemia, hypo-mag-nesemia, and/or hypercalcemia may increase the likelihood of digitalis toxicity INSUl INT! : Thiazides may increase insulin requirements l ITHIUm T! : Thiazides can increase serum lithium concentrations m ETHENAm INET! : Thiazides can alkalinize urine and reduce meth-enamine effectiveness NSAIDST! : Thiazides may increase risk for renal toxicity and NSAIDs may reduce diuretic actions of thiazides NEUROm USCUl AR bl OCKINg Ag ENTS T! : Tubocurarine or other nonde-polarizing neuromuscular blocking agents response or duration may be increased in pa tients taking thiazide diuretics PROb ENECIDT! : Blocks thiazide-induced uric acid retention (used to therapeutic advantage) QUINIDINET! : Half-life may be prolonged by thiazides (thiazides can alkalinize the urine) VITAm IN DT! or CAl CIUm SAl TS: Hypercalcemia may be exacerbated if thiazides are concurrently administered with Vitamin D or cal-cium salts laboratory Considerations Amyl ASET! : Thiazides can increase serum amylase values in asymp-tomatic patients and those in the developmental stages of acute pancreatitis (humans)CORTISOl T! : Thiazides can decrease the renal excretion of cortisol ESTROg EN, URINAR y T! : Hydrochlorothiazide may falsely decrease to-tal urinary estrogen when using a spectrophotometric assay HISTAm INET! : Thiazides may cause false-negative results when testing for pheochromocytoma PARATHy ROID­FUNCTION TESTS T! : Thiazides may elevate serum cal-cium; recommend discontinuing thiazides prior to testing PHENOl SUl FONPHTHAl EINT! (PSP): Thiazides can compete for secre-tion at proximal renal tubules PHENTOl Am INE TESTT! : Thiazides may give false-negative results PROTEIN­b OUND IODINET! : Thiazides may decrease values TRIIODOTHy RONINE RESIN UPTAKE TEST T! : Thiazides may slightly re-duce uptake Ty RAm INET! : Thaizides can cause false-negative results. Doses DOg S:T! For treatment of nephrogenic diabetes insipidus: a) 20-40 mg/kg PO q12h (Polzin and Osborne 1985), (Nichols 1989), (Behrend 2003b) For treatment of systemic hypertension: a) 20-40 mg/kg PO q12-24h with dietary salt restriction (Cowgill and Kallet 1986) As a diuretic: a) 10- 40 mg/kg PO twice daily (Morgan 1988) CATS:T! For treatment of diabetes insipidus: a) 20-40 mg/kg PO q12h may be tried (Behrend 2003b) CATTl E:T! a) 4-8 mg/kg once or twice daily PO for adult cattle (Howard 1986) b) 2 grams PO once to twice daily (Swinyard 1975) monitoring Serum electrolytes, BUN, creatinine, glucose T! Hydration status T! Blood pressure, if indicated T! Hemograms, if indicated T! Client Information Clients should contact veterinarian if signs of water or electrolyte T! imbal ance occur (e. g., excessive thirst, lethargy, lassitude, restless-ness, reduced urination, GI distress, or rapid heart rate) Chemistry/Synonyms Chlorothiazide is a thiazide diuretic and occurs as a white to practi-cally white, odorless, crystalline powder having a slightly bitter taste. It is very slightly soluble in water and slightly soluble in alcohol. Chlorothiazide may also be known as: chlorothiazidum, cloroti-azida, Azide®, Chlorzide®, Chlotride®, Diachlor®, Diuril®, Diurigen®, Pahtlisan®, or Saluric®. Storage/Stability/Compatibility Tablets should be stored at room temperature. The oral suspension should be protected from freezing. The in jectable preparation is stable for 24 hours after reconstitution. If the p H of the reconsti-tuted solution is less than 7. 4, precipitation will occur in less than 24 hours. Chlorothiazide sodium for injection is reportedly compatible with the following IV solutions: dex trose and/or saline products for IV infusion (with the exception of many Ionosol and Normosol prod-ucts), Ringer's injection and Lactated Ringer's, 1/6 M sodium lactate, Dextran 6% with dextrose or sodium chloride, and fructose 10%. It is

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