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ISOSORBIDE 501 Uses/Indications Isosorbide mononitrate (ISMN) and dinitrate (ISDN) are organic nitrates potentially useful as preload reducing agents in treating heart failure in small animals, however, research and clinical expe-rience demonstrating clinical efﬁcacy are lacking in dogs or cats. Limited research indicates that dogs may require much higher dos-ages of isosorbide dinitrate to achieve therapeutic effects than do humans. In humans, isosorbide nitrates are used for treating or prevent-ing angina, treating esophageal spasm, and as an adjunctive treat-ment in CHF. Pharmacology/Actions Organic nitrates (e. g., isosorbide nitrates, nitroglycerin) share a similar pharmacologic proﬁle. They relax vascular smooth muscle causing vasodilation, predominantly on the venous side, but some-what on arteries/arterioles as well. The mechanism of action is re-lated to their conversion to free radical nitric oxide. Nitric acid is thought to activate guanylate cyclase, thus increasing cyclic GMP and eventually leading to dephosphorylating light chain myosin, causing vasodilation. In humans, nitrates reduce myocardial oxy-gen demand, but the exact mechanism for this effect is not well un-derstood. Nitrates functionally antagonize the effects of acetylcho-line, norepinephrine and histamine. Additionally, nitrates relax all smooth muscle including biliary (including biliary ducts, sphincter of Oddi), bronchial, GI (including the esophagus), ureteral and uterine. Serum concentrations of isosorbide mononitrate above 100 ng/ m L minimum concentration of the drug are believed required for hemodynamic effects in dogs and humans. However, a study (Adin, Kittleson et al. 2001) in both normal dogs and those with CHF, demonstrated no hemodynamic effects (blood pressure, heart rate, PCV, thoracic blood volume percentage, abdominal blood volume percentage) at doses that yielded peak levels as high as 2,352 ± 701 ng/m L. In a study (Nagasawa, Takashima et al. 2003) performed in dogs with experimentally induced mitral regurgitation, oral dosages of a sustained-release isosorbide dinitrate product at 8 mg/kg and above resulted in signiﬁcant decreases in preload and afterload with in-creased cardiac output. Effects were sustained for at least 10 hours after dosing. Pharmacokinetics In dogs, isosorbide mononitrate oral bioavailability is approximate-ly 70% after oral administration. Oral doses with standard tablets above 2 mg/kg yield peak plasma levels above 100 ng/m L, which is believed to be the minimum concentration of the drug required for hemodynamic effects in dogs and humans. Elimination half-life in dogs with standard tablets is about 1. 5 hours. Dogs (24-31kg BW) given 60 mg sustained-release tablets (Imdur®) had peak plasma levels of approximately 550 ng/m L 3 hours after dosing. No phar-macokinetic information was located for cats. Limited information on isosorbide dinitrate pharmacokinetics in small animals is available; it is reported that pharmacokinetics are similar in dogs and humans. In humans, both isosorbide dinitrate and mononitrate are well absorbed after oral administration. Food may delay the rate, but not the extent, of absorption. Isosorbide dinitrate undergoes extensive ﬁrst-pass metabolism primarily to isosorbide mononitrate. Isosorbide mononitrate is metabolized primarily in the liver, but does not undergo ﬁrst pass metabolism. Metabolites do not appear to have pharmacologic activity and are principally excreted in the urine. Contraindications/Precautions/Warnings Isosorbide nitrates should not be used in patients in shock or used alone in treating heart failure. Use with extreme caution in patients with low blood pressure or hypovolemia. Adverse Effects As there is limited experience in using these drugs in animals an adverse effect proﬁle is not well known. In humans, the most common adverse effects are headache and postural hypotension. Tachycardia, restlessness or gastrointestinal effects are not uncommon. There have been rare cases of patients who are hypersensitive to organic nitrates. Reproductive/Nursing Safety Isosorbide nitrates are probably safe to use at therapeutic dosages during pregnancy. Dose-related increases in embryotoxicity oc-curred in rabbits given isosorbide dinitrate at 35-150X human dosages and there were some effects noted in rats (litter size, pup survival, prolonged gestation/parturition) given 125X doses of iso-sorbide mononitrate. Isosorbide mononitrate administered to rats and rabbits at 250 mg/kg/day (75X human dose) demonstrated no untoward effects. In humans, the FDA categorizes isosorbide ni-trates 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. ) It is unknown if isosorbide nitrates enter milk. Safe use during lactation cannot be guaranteed, but it is unlikely these drugs would pose signiﬁcant risk to nursing offspring. Overdosage/Acute Toxicity Isosorbide mononitrate caused signiﬁcant lethality in rats and mice at dosages of 2000 mg/kg and 3000 mg/kg, respectively. The pri-mary concerns with an overdosage of isosorbide nitrates would be venous pooling, decreased cardiac output, and hypotension. Treatment is basically supportive; drug therapies with agents such as epinephrine are not recommended. Increasing central ﬂuid vol-ume may be useful but in patients with CHF, must be used with extreme caution. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving isosorbide and may be of signiﬁcance in veterinary patients: !!ANTIHYPERTENSIVE DRUGS : Possible additive hypotensive effects !!PHENOTHIAZINES : Possible additive hypotensive effects !TSELECTIVE PHOSPHODIESTERASE INHIBITORS (e. g., sildenaﬁl ): Pro-found hypotension (use is contraindicated) Laboratory Considerations !TSerum cholesterol levels may be falsely decreased by nitrates when using the Zlatkis-Zak color reaction method Doses !TDOGS/CAT S: a) Cats: For adjunctive treatment of heart failure associated with thyroid storm: Isosorbide dinitrate at 0. 5-2 mg/kg PO q8-12h. Start at lowest level and titrate upward. (Ward 2006) b) Dogs/Cats: Efﬁcacy is unknown, but isosorbide dinitrate at 0. 5-2 mg/kg PO twice daily or isosorbide mononitrate at 0. 25-2 mg/kg PO twice daily are occasionally used for re-fractory heart failure or in combination with hydralazine or amlodipine in patients unable to tolerate ACE inhibitors. It	pppbs.pdf
502 ISOTRETINOIN is unknown if nitrate-free periods are required to prevent ni-trate tolerance. (Bulmer and Sisson 2005) Monitoring T ! Clinical efﬁcacy Client Information T ! Inform clients of the limited experience in veterinary medicine with this medication T ! May be given with or without meals Chemistry/Synonyms T o minimize the risk for explosion, dry isosorbide dinitrate is mixed with lactose, mannitol or other inert excipients. T o further stabilize the mixture, up to 1% ammonium phosphate or other suitable sta-bilizer can be used. The resultant dry mixture contains approxi-mately 25% isosorbide dinitrate and is called diluted isosorbide dinitrate. It is an ivory-white, odorless powder that is very slightly soluble in water and sparingly soluble in alcohol. Undiluted isosorbide mononitrate occurs as a white, crystalline powder that is freely soluble in water or alcohol. It is diluted with lactose or another suitable excipient to stabilize the powder and permit safe handling. Isosorbide dinitrate may also be known as: ISD, ISDN, EV-151, or sorbide nitrate, Dilatrate-SR®, Isochron®, Isordil and Titradose®; many international trade name products are available. Isosorbide mononitrate may also be known as: AHR-4698, BM-22145, IS-5-MN, or isosorbide-5-mononitrate, Imdur®, Ismo®, and Monoket®; many international trade name products are available. Storage/Stability Isosorbide dinitrate oral tablets, chewable tablets, extended-release tablets, and sublingual tablets should be stored in well-closed con-tainers, below 40°C and preferably between 15°-30°C. Heat and moisture accelerates loss of potency. Isosorbide mononitrate tablets should be stored in tight con-tainers, below 40°C and preferably between 15°-30°C. Isosorbide mononitrate extended-release tablets should be stored in tight containers, between 2°-30°C. Heat and moisture accelerates loss of potency. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. HUMAN-LABELED PRODUCTS: Isosorbide Dinitrate Tablets: 5 mg, 10 mg, 20 mg, 30 mg, & 40 mg; generic, Isordil Titradose® (Wyeth); (Rx) Isosorbide Dinitrate Sublingual Tablets: 2. 5 mg, & 5 mg; generic; (Rx) Isosorbide Dinitrate Extended-Release Tablets: 40 mg; Isochron® (Forest); (Rx) Isosorbide Dinitrate Sustained-Release Capsules: 40 mg; Dilatrate-SR® (Schwarz); (Rx) Isosorbide Mononitrate Tablets: 10 mg, & 20 mg; generic, Monoket® (Schwarz), Ismo® (Wyeth; (Rx) Isosorbide Mononitrate Extended-Release Tablets: 30 mg, 60 mg, & 120 mg; generic, Imdur® (Key); (Rx) ISOTRETINOIN (eye-so-tret-i-noyn) Accutane® RETINOID Prescriber Highlights TT Synthetic retinoid that may be useful in treatment a va-riety of dermatology diseases associated with epithelial cell proliferation & differentiation TT Cautions (risk vs. beneﬁt): Serum hypertriglyceridemia, hypersensitivity to drug; known teratogen TT Adverse Effects: Most common adverse effect seen in dogs is keratoconjunctivitis sicca (KCS); apparently not a problem in cats. Other potential adverse effects in small animals include: GI effects (anorexia, vomiting, ab-dominal distention), CNS effects (lassitude, hyperactivity, collapse), pruritus, erythema of feet & mucocutaneous junctions, polydipsia, swollen tongue TT Obtaining the medication for veterinary patients may be difﬁcult TT Pregnant women should avoid contact with medication Uses/Indications Isotretinoin may be useful in treating a variety of dermatologic-related conditions, including canine lamellar ichthyosis, cutaneus T-cell lymphoma, intracutaneous cornifying epitheliomas, mul-tiple epidermal inclusion cysts, comedo syndrome in Schnauzers, and sebaceous adenitis seen in standard poodles. Because of the concerns of teratogenic effects in humans, avail-ability to veterinarians may be restricted by the manufacturers and drug distributors; obtaining the medication for veterinary patients may be difﬁcult. Pharmacology/Actions A retinoid, isotretinoin's major pharmacologic effects appear to be regulation of epithelial cell proliferation and differentiation. It af-fects monocyte and lymphocyte function, which can cause changes in cellular immune responses. The effects on skin include reduction of sebaceous gland size and activity, thereby reducing sebum pro-duction. It also has anti-keratinization and antiinﬂammatory activ-ity and may indirectly reduce bacterial populations in sebaceous pores. Pharmacokinetics Isotretinoin is rapidly absorbed from the gut once the capsule dis-integrates and the drug is dispersed in the GI contents. This may require up to 2 hours after dosing. Animal studies have shown that only about 25% of a dose reaches the systemic circulation, but food or milk in the gut may increase this amount. Isotretinoin is distrib-uted into many tissues, but is not stored in the liver (unlike vitamin A). It crosses the placenta and is highly bound to plasma proteins. It is unknown if it enters milk. Isotretinoin is metabolized in the liver and is excreted in the urine and feces. In humans, terminal half-life is about 10-20 hours. Contraindications/Precautions/Warnings Isotretinoin should only be used when the potential beneﬁts out-weigh the risks when the following conditions exist: hypertriglyc-eridemia or sensitivity to isotretinoin.	pppbs.pdf
ISOTRETINOIN 503 Isotretinoin is a known teratogen. Major anomalies have been reported in children of women taking the medication and it is not advised to use the medication in households were pregnant women are present. Adverse Effects There appears to be a low incidence of adverse effects, particularly in dogs. The most common adverse effect seen in dogs is kerato-conjunctivitis sicca (KCS). This apparently is not a problem in cats. Other potential adverse effects include: GI effects (anorexia, vomit-ing, diarrhea, abdominal distention), CNS effects (lassitude, hyper-activity, behavioral changes, collapse), stiffness of limbs, pruritus, exfolliative dermatitis, erythema of feet and mucocutaneous junc-tions/cheilitis, polydipsia, and swollen tongue. Incidence of adverse effects may be higher in cats. Effects report-ed include: blepharospasm, periocular crusting, erythema, diarrhea and, especially, weight loss secondary to anorexia. If cats develop adverse effects, the time between doses may be prolonged (e. g., ev-ery other week give every other day) to reduce the total dose given. Reproductive/Nursing Safety Isotretinoin is a known teratogen. Major anomalies have been re-ported in children of women taking the medication. It is absolutely contraindicated in pregnant veterinary patients as well. Isotretinoin also appears to inhibit spermatogenesis. In humans, the FDA cate-gorizes this drug as category X for use during pregnancy (Studies in animals or humans demonstrate fetal abnormalities or adverse reac-tion; reports indicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible beneﬁt. ) It is not known whether this drug is excreted in breast milk. At this time, it is not recommended for use in nursing mothers. Overdosage/Acute Toxicity There were 129 exposures to isotretinoin reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org ) dur-ing 2005-2006. In these cases 126 were dogs with 5 showing clinical signs and the remaining 4 reported cases were cats with no clinical signs. Common ﬁndings in dogs recorded in decreasing frequency included vomiting, diarrhea, and lethargy. Because of the drug's potential adverse effects, gut emptying should be considered with acute overdoses when warranted. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving isotretinoin and may be of signiﬁcance in veterinary patients: !TVITAMIN A or OTHER RETINOIDS : Isotretinoin used with other retin-oids ( etretinate, tretinoin, or vitamin A ) may cause additive toxic effects. !TTETRACYCLINES : Use with tetracyclines may increase the potential for the occurrence of pseudotumor cerebri (cerebral edema and increased CSF pressure). Laboratory Considerations !TIncreases in serum triglyceride and cholesterol levels may be noted which can be associated with corneal lipid deposits !!Platelets may be increased !!ALT (SGOT), AST (SGPT), and LDH levels may be increased Doses !TDOGS: a) For sebaceous adenitis when more conservative treatments have failed: 1 mg/kg PO q12h for one month; if improvement is noted reduce dose to 1 mg/kg PO once daily; long-term goal is to treat with either 1 mg/kg PO every other day or 0. 5 mg/kg once daily (Rosser 1992) b) For sebaceous adenitis: 1-3 mg/kg PO once a day to twice daily (Bloom 2006c) c) For treatment of Schnauzer comedo syndrome: 1 mg/kg once daily or divided q12h PO; For sebaceous adenitis in poodles; granulomatous sebaceous adenitis in viszlas: 1-2 mg/kg once daily or divided q12h PO; For epitheliotrophic lymphoma, cutaneus lymphoma: 2 mg/ kg once daily or divided q12h PO (Power and Ihrke 1995) d) For schnauzer comedo syndrome, sebaceous adenitis in poo-dles, ichthyosis, keratocanthoma, epitheliotropic lymphoma, and sebaceous gland hyperplasia and adenoma: 1-3 mg/kg q12-24h PO (Kwochka 2003b) e) For cutaneous lymphosarcoma: Isotretinoin at 3-4 mg/kg PO daily. Prednisone (1 mg/kg/day) may be useful to allevi-ate pruritus. Lomustine at 50 mg/m2 q21-30 days may be effective (see lomustine monograph for more information) (White 2005c) !TCATS: For feline acne: a) 5 mg/kg PO once daily (Hall and Campbell 1994) b) 10 mg per cat once daily PO (Power and Ihrke 1995) c) 1-3 mg/kg q12-24h PO (Kwochka 2003b) For epitheliotrophic lymphoma, cutaneus lymphoma: a) 10 mg/cat once daily PO (Power and Ihrke 1995) Monitoring See Lab Considerations and Adverse Effects. !TEfﬁcacy !TLiver function tests (baseline and if signs appear) !TDogs: Schirmer T ear tests (monthly—especially in older dogs) !TCats: Weight Client Information !TIsotretinoin should not be handled by pregnant females and use in households with pregnant women present is ill advised. Veteri-narians must take the personal responsibility to educate clients of the potential risk of ingestion by pregnant females. !TMilk or high fat foods will increase the absorption of isotretin-oin. T o reduce variability of absorption, either have clients con-sistently give with meals or not. !TLong-term therapy can be quite expensive. Chemistry/Synonyms A synthetic retinoid, isotretinoin occurs as a yellow-orange to or-ange, crystalline powder. It is insoluble in both water and alcohol. Commercially, it is available in soft gelatin capsules as a suspension in soybean oil. Isotretinoin may also be known as: isotretinoinum, 13-cis-retin-oic acid, Ro-4-3780, Accure®, Accutane®, Accutin®, Amnesteem®, Claravis®, Curatane®, Isoacne®, Isohexal®, Isotrex ®, Liderma®, Nimegen®, Oratane®, Procuta®, Roaccutan®, Roaccutane®, Roacutan®, Sotret®, Stiefotrex®, and Tretin®. Storage/Stability/Compatibility Capsules should be stored at room temperature in tight, light re-sistant containers. The drug is photosensitive and will degrade with light exposure. Expiration dates of 2 years are assigned after manufacture.	pppbs.pdf
504 ISOXSUPRINE HCL T TDosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Isotretinoin Capsules: 10 mg, 20 mg, 30 mg & 40 mg (regular & soft gel); Accutane® (Roche); Claravis® (Barr Laboratories); Amnesteem® (Bertek); Sotret® (Ranbaxy); (Rx) Note : Because of the concerns of teratogenic effects in humans, avail-ability to veterinarians may be restricted by the manufacturers and drug distributors; obtaining the medication for veterinary patients may be difﬁcult. ISOXSUPRINE HCL (eye-sox-suh-preen) Vasodilan® Prescriber Highlights TT Peripheral vasodilator that may have some efﬁcacy in treatment of navicular disease in horses; efﬁcacy in doubt when used orally TT May be beneﬁcial for Raynaud's-like syndrome in dogs TT Contraindications: Immediately post-partum or in the presence of arterial bleeding TT Adverse Effects: After injection, CNS stimulation (uneasi-ness, hyperexcitability, nose-rubbing) or sweating. Ad-verse effects are unlikely after oral administration. Uses/Indications Isoxsuprine is used in veterinary medicine principally for the treat-ment of navicular disease in horses; however, recent studies have shown disappointing efﬁcacy when used orally. It has been used in humans for the treatment of cerebral vascular insufﬁciency, dys-menorrhea, and premature labor, but efﬁcacies are unproven for these indications. There has been an anecdotal report of isoxsuprine being helpful for treating dogs with a Raynaud's-like syndrome (periodic digital cyanosis, onychogryphosis) (Carlotti 2002). Pharmacology/Actions Isoxsuprine causes direct vascular smooth muscle relaxation pri-marily in skeletal muscle. While it stimulates beta-adrenergic recep-tors it is believed that this action is not required for vasodilatation to occur. In horses with navicular disease, isoxsuprine will raise dis-tal limb temperatures signiﬁcantly. Isoxsuprine will relax uterine smooth muscle and may have positive inotropic and chronotropic effects on the heart. At high doses, isoxsuprine can decrease blood viscosity and reduce platelet aggregation. Pharmacokinetics In humans, isoxsuprine is almost completely absorbed from the GI tract, but in one study that looked at the cardiovascular and phar-macokinetic effects of isoxsuprine in horses (Mathews and et 1986), bioavailability was low after oral administration, probably due to a high ﬁrst-pass effect. After oral dosing of 0. 6 mg/kg, the drug was non-detectable in plasma and no cardiac changes were detected. This study did not evaluate cardiovascular effects in horses with navicular disease, nor did it attempt to measure changes in distal limb blood ﬂow. After IV administration in horses, the elimination half-life is between 2. 5-3 hours. Contraindications/Precautions/Warnings Isoxsuprine should not be administered to animals immediately post-partum or in the presence of arterial bleeding. Adverse Effects After parenteral administration, horses may show signs of CNS stimulation (uneasiness, hyperexcitability, nose-rubbing) or sweat-ing. Adverse effects are unlikely after oral administration, but hy-potension, tachycardia, and GI effects are possible. 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. ) No speciﬁc lactation safety information was found. Overdosage/Acute Toxicity Serious toxicity is unlikely in horses after an inadvertent oral over-dose, but signs listed in the Adverse Effects section could be seen. Treat signs if necessary. CNS hyperexcitability could be treated with diazepam, and hypotension with ﬂuids. Drug Interactions No clinically signiﬁcant drug interactions have been reported for this agent. Laboratory Considerations None were noted Doses T ! HORSES: (Note : ARCI UCGFS Class 4 Drug) For treatment of orthopedic conditions, such as navicular disease: a) For long break-over if therapeutic shoeing does not correct: Initially, 1. 2 mg/kg PO q8h for 3 weeks. The dose is decreased as soundness improves, to 1. 2 mg/kg PO once daily for 6 weeks, then every other day until heel ﬁrst landing occurs. Phenylbutazone is added if lameness is greater than grade II on a scale of I-V, or until recheck occurs. T o increase the circulation to the podotrochlea: 0. 6-1. 2 mg/kg twice daily until sound, then decreased to once daily for 2 weeks then further decreased to every other day. The drug is classiﬁed as a “blocking” agent by the AHSA. (Turner 1999) b) 0. 6-2 mg/kg PO q12h (Brumbaugh, Lopez et al. 1999) As a tocolytic agent: a) 0. 4-0. 6 mg/kg IM or PO twice daily. Efﬁcacy is unproven and oral bioavailability appears highly variable. (Wilkins 2004b) T ! DOGS: For treatment of “Raynaud-like” disease: a) 1 mg/kg/day PO (Carlotti 2002), Monitoring T ! Clinical efﬁcacy T ! Adverse effects (tachycardia, GI disturbances, CNS stimulation) Client Information T ! o be maximally effective, doses must be given routinely as directed. T ! ablets may be crushed and made into a slurry, suspension, or paste by adding corn syrup, cherry syrup, etc., just before admin-istration.	pppbs.pdf
ITRACONAZOLE 505 Chemistry/Synonyms A peripheral vasodilating agent, isoxsuprine occurs as an odorless, bitter-tasting, white, crystalline powder with a melting point of about 200°C. It is slightly soluble in water and sparingly soluble in alcohol. Isoxsuprine HCl may also be known as: Caa-40, isoxsuprini hy-drochloridum,phenoxyisopropylnorsuprifen, Dilum®, Duvadilan®, Fadaespasmol®, Fenam®, Inibina®, Isodilan®, Isotenk ®, Uterine®, Vadosilan®, Vasodilan®, Vasolan ®, Vasosuprina Ilﬁ®, Voxsuprine®, and Xuprin®. Storage/Stability Tablets should be stored in tight containers at room temperature (15-30°C). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Isoxsuprine HCl Tablets: 10 mg & 20 mg; Vasodilan® (Mead John-son); Voxsuprine® (Major); generic; (Rx) ITRACONAZOLE (ey-tra-kon-a-zole) Sporanox® ANTIFUNGAL Prescriber Highlights TT Synthetic oral triazole antifungal used for systemic my-coses, including aspergillosis, cryptococcal meningitis, blastomycosis, & histoplasmosis TT Not amenable to compounding; be wary of compounded itraconazole dosage forms as bulk powder itraconazole may not be absorbed TT Contraindications (relative: risk vs. beneﬁt): Hypersensi-tivity to it or other azole antifungal agents, hepatic im-pairment, or achlorhydria (or hypochlorhydria) TT Adverse Effects: DOGS : anorexia is the most common, but hepatic toxicity most signiﬁcant adverse effect. At the higher dosage rate, some develop ulcerative skin le-sions/vasculitis & limb edema. Rare, serious erythema multiforme or toxic epidermal necrolysis TT Adverse Effects: CATS: Dose related; GI effects (anorexia, weight loss, vomiting), hepatotoxicity (increased ALT, jaundice), & depression TT May be more efﬁcacious than ketoconazole, but is also more expensive; long-term treatment may be required TT Maternotoxicity, fetotoxicity, & teratogenicity in lab ani-mals at high dosages (5-20 times labeled) TT Drug interactions Uses/Indications Itraconazole may have use in veterinary medicine in the treatment of systemic mycoses, including aspergillosis, cryptococcal menin-gitis, blastomycosis, and histoplasmosis. Itraconazole is probably more effective than ketoconazole, but is signiﬁcantly more expen-sive. It may also be useful for superﬁcial candidiasis or dermato-phytosis. Itraconazole does not have appreciable effects (unlike ke-toconazole) on hormone synthesis and may have fewer side effects than ketoconazole in small animals. It is considered by many to be the drug of choice for treating blastomycosis, unless moderate or severe hypoxemia is present (than amphotericin B). In horses, itraconazole may be useful in the treatment of sporo-trichosis and Coccidioides immitis osteomyelitis. Pharmacology/Actions Itraconazole is a fungistatic triazole compound. Triazole-derivative agents, like the imidazoles (clotrimazole, ketoconazole, etc. ), pre-sumably act by altering the cellular membranes of susceptible fungi, thereby increasing membrane permeability and allowing leakage of cellular contents and impaired uptake of purine and pyrimidine precursors. Itraconazole has efﬁcacy against a variety of pathogenic fungi, including yeasts and dermatophytes. In vivo studies using laboratory models have shown that itraconazole has fungistatic ac-tivity against many strains of Candida, Aspergillus, Crypto coccus, Histoplasma, Blastomyces, and Trypanosoma cruzi. Itraconazole has immune-suppressing activity, probably via suppressing T-lymphocyte proliferation. Pharmacokinetics Itraconazole absorption is highly dependent on gastric p H and presence of food. When given on an empty stomach, bioavailabil-ity may only be 50% or less; with food, it may approach 100%. In cats, the oral solution is more bioavailable and probably has fewer GI effects. The commercially available capsules are specially formu-lated to increase oral bioavailability. Compounding capsules from bulk powders may not yield a dosage form that is absorbed. The commercially available liquid preparation possesses adequate oral bioavailability. Itraconazole has very high protein binding and is widely dis-tributed throughout the body, particularly to tissues high in lip-ids (drug is highly lipophilic). Skin, sebum, female reproductive tract, and pus all have concentrations greater than those found in the serum. Only minimal concentrations are found in CSF, urine, aqueous humor, and saliva. However, many fungal infections in the CNS, eye, or prostate can be effectively treated with itraconazole. Itraconazole is metabolized by the liver to many different me-tabolites, including to hydroxyitraconazole, which is active. In humans, itraconazole's serum half-life ranges from 21-64 hours. Elimination may be a saturable process. Because of its long half-life, itraconazole does not reach steady state plasma levels for at least 6 days after starting therapy. If loading doses are given, levels will ap-proach those of steady-state sooner. Contraindications/Precautions/Warnings Itraconazole should not be used in patients hypersensitive to it or other azole antifungal agents. Use itraconazole in patients with hepatic impairment or achlo-rhydria (or hypochlorhydria) only when the potential beneﬁts out-weigh the risks. Compounding capsules from bulk powders may not yield a dos-age form that is absorbed. Adverse Effects In dogs, anorexia is the most common adverse effect seen, especially at higher dosages, but hepatic toxicity appears to be the most signif-icant adverse effect. Approximately 10% of dogs receiving 10 mg/ kg/day and 5% of dogs receiving 5 mg/kg/day developed hepatic toxicosis serious enough to discontinue treatment (at least tempo-rarily). Hepatic injury is determined by an increased ALT activity. Anorexia is often the symptomatic marker for toxicity and usually	pppbs.pdf
506 ITRACONAZOLE occurs in the second month of treatment. Some dogs (7%) given itraconazole at the higher dosage rate (10 mg/kg/day) may develop ulcerative skin lesions/vasculitis and limb edema that may require dosage reduction. These generally resolve following drug discon-tinuation. Rarely, serious erythema multiforme or toxic epidermal necrolysis reactions have been noted. In cats, adverse effects appear to be dose related. GI effects (an-orexia, weight loss, vomiting), hepatotoxicity (increased ALT, jaun-dice) and depression have been noted. Should adverse effects occur and ALT is elevated, the drug should be discontinued. Increased liv-er enzymes in the absence of other signs do not necessarily mandate dosage reduction or drug discontinuation. Once ALT levels return to normal and other adverse effects have diminished, if necessary, the drug may be restarted at a lower dosage or use longer dosing intervals with intense monitoring. Reproductive/Nursing Safety In laboratory animals, itraconazole has caused dose-related mater-notoxicity, fetotoxicity and teratogenicity at high dosages (5-20 times labeled). As safety has not been established, use only when the beneﬁts outweigh the potential risks. In humans, the FDA cat-egorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Itraconazole does enter maternal milk; signiﬁcance is unknown. Overdosage/Acute Toxicity There is very limited information on the acute toxicity of itracona-zole. Giving oral antacids may help reduce absorption. If a large overdose occurs, consider gut emptying and give supportive thera-py as required. Itraconazole is not removed by dialysis. In chronic toxicity studies, dogs receiving 40 mg/kg PO daily for 3 months demonstrated no overt toxicity. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving itraconazole and may be of signiﬁcance in veterinary patients: !TAMPHOTERICIN B : Lab animal studies have shown that itraconazole used concomitantly with amphotericin B may be antagonistic against Aspergillus or Candida; the clinical importance of these ﬁndings is not yet clear !TANTACIDS : May reduce oral absorption of itraconazole; administer itraconazole at least 1 hour before or 2 hours after antacids !TBENZODIAZEPINES (alprazolam, diazepam, midazolam, triazolam ): Itraconazole may increase levels !TBUSPIRONE : Plasma concentrations may be elevated !TBUSULFAN : Itraconazole may increase levels !TCALCIUM-CHANNEL BLOCKING AGENTS (amlodipine, verapamil ): Itra-conazole may increase levels !TCISAPRIDE : Itraconazole may increased cisapride levels and pos-sibility for toxicity; use together contraindicated in humans !TCORTICOSTEROIDS : Itraconazole may inhibit the metabolism of corticosteroids; potential for increased adverse effects !TCYCLOPHOSPHAMIDE : Itraconazole may inhibit the metabolism of cyclophosphamide and its metabolites; potential for increased toxicity !TCYCLOSPORINE : Increased cyclosporine levels !TDIGOXIN : Itraconazole may increase digoxin levels; use together considered contraindicated in humans !TFENTANYL/ALFENTANIL : Itraconazole may increase fentanyl or al-fentanil levels !TH2-BLOCKERS (ranitidine, famotidine, etc. ): Increased gastric p H may reduce itraconazole absorption !TIVERMECTIN : Itraconazole may increase risk for neurotoxicity !TMACROLIDE ANTIBIOTICS (erythromycin, clarithromycin ): May increase itraconazole concentrations !TPHENOBARBITAL/PHENYTOIN : May decrease itraconazole levels !TPROTON-PUMP INHIBITORS (omeprazole, etc. ): Increased gastric p H may reduce itraconazole absorption !TQUINIDINE : Itraconazole may increase digoxin levels; use together considered contraindicated in humans !TRIFAMPIN : May decrease itraconazole levels; itraconazole may in-crease rifampin levels !TSULFONYLUREA ANTIDIABETIC AGENTS (e. g., glipizide, glyburide ): Itra-conazole may increase levels; hypoglycemia possible !TVINCRISTINE/VINBLASTINE : Itraconazole may inhibit vinca alkaloid metabolism and increase levels !TWARFARIN : Itraconazole may cause increased prothrombin times in patients receiving warfarin or other coumarin anticoagulants Laboratory Considerations !TItraconazole may cause hypokalemia or increases in liver function tests in a small percentage of patients. Doses !TDOGS: For systemic mycoses: a) For Malassezia dermatitis: 5-10 mg/kg PO once daily (Muse 2000) b) Pulse therapy for Malassezia dermatitis: 5 mg/kg for 2 con-secutive days per week for 3 weeks (Foil 2003a) c) For dermatophytosis: 5 mg/kg PO once daily. Prolonged course of therapy required. Begin taking cultures after 4 weeks of treatment. Continue therapy for 2 weeks beyond clinical cure and when 2-3 negative cultures are obtained at weekly intervals. (Frank 2000) d) For dermatophytosis: 5 mg/kg PO once daily on an every other week schedule. Treatment is generally continued for three “pulses” of one week on, one week off. T oxicity prob-lems are rare with this protocol. (De Boer 2006) e) For Blastomycosis: 5 mg/kg PO once daily for at least 30 days after all signs of disease have resolved (treatment must persist for at least 60-90 days). Give with food. For Nasal Aspergillosis: 5 mg/kg p O twice daily for at least 90 days. Because of expense, larger dogs may require a more cost effective treatment such as 1% topical clotrimazole in nasal passages and sinuses. (Davidson and Mathews 2000) f) For Histoplasmosis: 10 mg/kg daily PO; given with food; if dog has intestinal histoplasmosis, treat with amphotericin B (0. 5 mg/kg IV over 3-4 hours in D5W every other day) ini-tially. Usually after six doses of amphotericin B, may switch to itraconazole. T otal treatment times (amphotericin B and itraconazole) should be for at least 30 days after all signs of disease have resolved (treatment must persist for at least 90 days). (Legendre and T oal 2000) g) For Blastomycosis: 5 mg/kg PO once a day or divided twice a day. Continue for 2-3 months or until active disease is not apparent. A loading dose of 10 mg/kg once a day (or divided twice a day) for the ﬁrst three days may reduce the “lag” phase of effectiveness. For coccidiomycosis: 5-10 mg/kg PO once daily; may need to treat for 6-12 months (Taboada 2000)	pppbs.pdf
ITRACONAZOLE 507 h) For sporotrichosis: 5-10 mg/kg once daily for 30 days be-yond complete resolution of detectable lesions. For pythiosis or lagendiosis (after lesion resection): 10 mg/kg PO once daily (with terbinaﬁne at 5-10 mg/kg PO q24h) for at least 2 months after surgery. For zygomycosis (after aggressive surgical resection: 5-10 mg/kg PO q24h. For non-resectable lesions, either itracon-azole for 3-6 months or amphotericin B lipid complex. Re-currence is possible with either surgical or medical therapy. (Grooters 2005) !TCATS: For susceptible systemic mycoses: a) For Histoplasmosis: 10 mg/kg daily PO; given with food For Cryptococcosis: 50-100 mg per cat per day PO for many months. Mean treatment time is 8. 5 months. If response in-adequate, may add ﬂucytosine (at 100-125 mg/kg divided into three doses per day). (Legendre and T oal 2000) b) For Blastomycosis: 10 mg/kg PO once a day or divided twice a day. Continue for 2-3 months or until active disease is not apparent ( Note : cats usually require longer treatment than dogs) For Histoplasmosis: 10 mg/kg once daily or divided twice daily PO; at least 2-4 months of treatment required For coccidiomycosis: 5-10 mg/kg PO once daily; may need to treat for 6-12 months (Taboada 2000) c) For sporotrichosis: 5-10 mg/kg once daily for 30 days be-yond complete resolution of detectable lesions. (Grooters 2005) d) For Cryptococcosis: For mild to moderate disease where cats are eating and do not have CNS involvement: Cats weighing 3. 5 kg or less receive 50 mg PO once daily or 100 mg PO every other day; medium to large cats get 100 mg PO once daily. Give with food; may be mixed with tasty food treat. Monitor ALT; itraconazole hepatotoxicity is reversible upon discontinuation of the drug and it can usually be restarted safely at 50% of the original dose. Continue treatment until cat appears completely normal; generally takes 3-12 months. Then obtain serum sample to determine decline in antigen titer. A 4-5 fold reduction suggests successful therapy. Then restart therapy (possibly at a reduced dose) or change to ke-toconazole (50 mg/day) until antigen level declines to zero. (Malik 2006b) For generalized dermatophytosis: a) 10 mg/kg PO once daily; prolonged course of therapy re-quired. Begin taking cultures after 4 weeks of treatment. Continue therapy for 2 weeks beyond clinical cure and when 2-3 negative cultures are obtained at weekly intervals. (Frank 2000) b) 5 mg/kg PO twice daily or 10 mg/kg with food. Give until culture is negative 2 times at two week intervals; generally 3-5 weeks. Open capsule and measure out calculated por-tion; give in butter or a/d®. Can be stored in the freezer. Pulse therapy: 5 mg/kg PO for 2 consecutive days per week, increasing interval gradually is useful in the management of dermatophytosis in longhaired cats and in cats in a heavily contaminated environment. For dermatophyte granuloma (TOC): 10 mg/kg PO once daily for weeks to months, at least one month beyond clini-cal resolution and until brush culture is negative x 2. (Foil 2003b) c) For dermatophytosis: 5 mg/kg PO once daily on an every other week schedule. Treatment is generally continued for three “pulses” of one week on, one week off. T oxicity prob-lems are rare with this protocol. (De Boer 2006) !TRABBITS, RODENTS, SMALL MAMMALS: a) Mice: For blastomycosis: 50-150 mg/kg q24h; Rats: For vagi-nal candidiasis: 2. 5-10 mg/kg q24h; Guinea pigs: 5 mg/kg q24h for systemic candidiasis (Adamcak and Otten 2000) !THORSES: For aspergillosis: a) 3 mg/kg twice a day (Legendre 1993) !TBIRDS: a) Ratites: 6-10 mg/kg PO once daily; if neuro signs develop reduce dose or discontinue (Jenson 1998) b) 10-20 mg/kg PO q12-24h (based upon extrapolation from mammalian kinetics). Use with caution in African grey par-rots. (Flammer 2003a) Monitoring !TClinical Efﬁcacy !TWith long-term therapy, routine liver function tests are recom-mended (monthly ALT) !TAppetite !TPhysical assessment for ulcerative skin lesions in dogs Client Information !TCompliance with treatment recommendations must be stressed !THave clients report any potential adverse effects !TGive with food !TDo not give with any other medications without veterinarian's approval Chemistry/Synonyms A synthetic triazole antifungal, itraconazole is structurally related to ﬂuconazole. It has a molecular weight of 706 and a p Ka of 3. 7. Itraconazole may also be known as: itraconazolum, oriconazole, R-51211, or Sporanox®; many other trade names are available. Storage/Stability/Compatibility Itraconazole capsules should be stored between 15-25°C and pro-tected from light an moisture. Itraconazole oral solution should be stored at temperatures less than 26°C, and protected from freezing. Itraconazole for injection should be stored at temperatures less than 26°C, and protected from light and freezing. After diluting with the 0. 9% sodium chloride injection supplied, the resulting so-lution may stored at 2-8°C or 15-25°C for up to 48 hours. Protect solution from light during storage. It may be exposed to normal room light during administration. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Itraconazole Capsules: 100 mg; Sporanox® (Janssen-Ortho); generic; (Rx) Itraconazole Oral Solution: 10 mg/m L in 150 m L; Sporanox® (Ortho Biotech); (Rx) Itraconazole Injectable Solution: 10 mg/m L in Kits of 25 m L amps, & 50 m L bags of 0. 9% Na Cl Injection and 1 ﬁltered infusion set; Spora-nox® (Ortho Biotech); (Rx)	pppbs.pdf
508 IVERMECTIN IVERMECTIN (eye-ver-mek-tin) Heartgard®, Ivomec® ANTIPARASITIC Prescriber Highlights TT Prototype avermectin drug used in variety of species as an antiparasiticide TT Contraindications: Label speciﬁc due to lack of safety data (foals, puppies, etc. ) or public health safety (lactat-ing dairy animals) TT Caution in breeds susceptible to MDR1-allele mutation (Collies, Australian Shepherds, Shelties, Long-haired Whippet, “white feet”); at higher risk for CNS toxicity TT Adverse Effects: HORSES: Swelling & pruritus at the ven-tral mid-line can be seen approximately 24 hours after ivermectin administration due to a hypersensitivity reac-tion to dead Onchocerca spp. microﬁlaria. DOGS: May exhibit a shock-like reaction when ivermectin is used as a microﬁlaricide, presumably due to a reaction associ-ated with the dying microﬁlaria. CATTLE: Ivermectin can induce serious adverse effects by killing the larva when they are in vital areas; may also cause discomfort or transient swelling at the injection site. MICE & RAT S: May cause neurologic toxicity at doses slightly more than usu-ally prescribed. BIRDS: Death, lethargy, or anorexia may be seen. Orange-cheeked Waxbill Finches & budgerigars may be more sensitive to ivermectin than other species Uses/Indications Ivermectin is approved in horses for the control of: large strongyles (adult) (Strongylus vulgaris, S. edentatus, S. equinus, Triodontophorus spp. ), small strongyles, pinworms (adults and 4th stage larva), as-carids (adults), hairworms (adults), large-mouth stomach worms (adults), neck threadworms (microﬁlaria), bots (oral and gastric stages), lungworms (adults and 4th stage larva), intestinal thread-worms (adults), and summer sores (cutaneous 3rd stage larva) sec-ondary to Hebronema or Draschia Spp. In cattle, ivermectin is approved for use in the control of gas-trointestinal roundworms (adults and 4th stage larva), lungworms (adults and 4th stage larva), cattle grubs (parasitic stages), sucking lice, and mites (scabies). For a listing of individual species covered, refer to the product information. In swine, ivermectin is approved for use to treat GI roundworms, lungworms, lice, and mange mites. For a listing of individual spe-cies covered, refer to the product information. In reindeer, ivermectin is approved for use in the control of warbles. In American Bison, ivermectin is approved for use in the control of grubs. In dogs and cats, ivermectin is approved only for use as a pre-ventative for heartworm. It has also been used as a microﬁlaricide, slow-kill adulticide, ectoparasiticide, and endoparasiticide. Pharmacology/Actions Ivermectin enhances the release of gamma amino butyric acid (GABA) at presynaptic neurons. GABA acts as an inhibitory neu-rotransmitter and blocks the post-synaptic stimulation of the ad-jacent neuron in nematodes or the muscle ﬁber in arthropods. By stimulating the release of GABA, ivermectin causes paralysis of the parasite and eventual death. As liver ﬂukes and tapeworms do not use GABA as a peripheral nerve transmitter, ivermectin is ineffec-tive against these parasites. Pharmacokinetics In simple-stomached animals, ivermectin is up to 95% absorbed after oral administration. Ruminants only absorb G-N of a dose due to inactivation of the drug in the rumen. While there is greater bioavailability after SC administration, absorption after oral dos-ing is more rapid than SC. It has been reported that ivermectin's bioavailability is lower in cats than in dogs, necessitating a higher dosage for prophylaxis of heartworm in this species. Ivermectin is well distributed to most tissues, but does not read-ily penetrate into the CSF, thereby minimizing its toxicity. Collie-breed dogs with a speciﬁc gene defect allow more ivermectin into the CNS than other breeds/species. Ivermectin has a long terminal half-life in most species (see be-low). It is metabolized in the liver via oxidative pathways and is primarily excreted in the feces. Less than 5% of the drug (as parent compound or metabolites) is excreted in the urine. Pharmacokinetic parameters of ivermectin have been reported for various species: Cattle: Volume of distribution = 0. 45-2. 4 L/kg; elimination half-life = 2-3 days; total body clearance = 0. 79 L/kg/day. Dogs: Bioavailability = 0. 95; volume of distribution = 2. 4 L/kg; elimination half-life = 2 days. Swine: Volume of distribution = 4 L/kg; elimination half-life = 0. 5 days. Sheep: Bioavailability = 1 (intra-abomasal), 0. 25 (intra-rumi-nal); volume of distribution = 4. 6 L/kg; elimination half-life = 2-7 days. Contraindications/Precautions/Warnings The manufacturer recommends that ivermectin not be used in foals less than 4 months old, as safety of the drug in animals this young has not been ﬁrmly established. However, foals less than 30 days of age have tolerated doses as high as 1 mg/kg without signs of toxicity. Ivermectin is not recommended for use in puppies less than 6 weeks old. After receiving heartworm prophylaxis doses, the manufacturer recommends observing Collie-type breeds for at least 8 hours after administration. Most clinicians feel that iver-mectin should not be used in breeds susceptible (Collies, Shelties, Australian shepherds, etc. ) to the mdr1 gene mutation at the doses speciﬁed for treating microﬁlaria or other parasites unless the pa-tient has been tested and found not to have the gene defect. A spe-ciﬁc test for identifying dogs that have the gene defect (deletion mutation of the mdr1 gene) is now available. Contact the veterinary clinical pharmacology lab at www. vetmed. wsu. edu. Ivermectin is reportedly contraindicated in chelonian species. Because milk withdrawal times have not been established, the drug is not approved for use in lactating dairy animals or females of breeding age. The injectable products for use in cattle and swine should be given subcutaneously only; do not give IM or IV. If using a product in a species not labeled for that product (ex-tra-label), be certain of the dosage and/or dilutions. There are many reports of overdoses in small animals when large animal products have been used. Adverse Effects In horses, swelling and pruritus at the ventral mid-line can be seen approximately 24 hours after ivermectin administration due to a hypersensitivity reaction to dead Onchocerca spp. microﬁlaria. The reaction is preventable by administering a glucocorticoid just prior	pppbs.pdf
IVERMECTIN 509 to, and for 1-2 days after ivermectin. If untreated, swelling usu-ally subsides within 7-10 days and pruritus will resolve within 3 weeks. Dogs may exhibit a shock-like reaction when ivermectin is used as a microﬁlaricide, presumably due to a reaction associated with the dying microﬁlaria. Other adverse effects when used as a microﬁlari-cide include depression, hypothermia, and vomiting. Pretreatment with diphenhydramine (2 mg/kg IM) and dexamethasone (0. 25 mg/kg IV) can help prevent adverse reactions (Atkins 2005). When used to treat Hypoderma bovis larva (Cattle grubs) in cat-tle, ivermectin can induce serious adverse effects by killing the larva when they are in vital areas. Larva killed in the vertebral canal can cause paralysis and staggering. Larva killed around the gullet can induce salivation and bloat. These effects can be avoided by treating for grubs immediately after the Heal ﬂy (Warble ﬂy) season or after the stages of grub development where these areas would be affected. Cattle may experience discomfort or transient swelling at the injec-tion site. Using a maximum of 10 m L at any one-injection site can help minimize these effects. Neurotoxicity is possible in dogs, particularly in those with the gene defect (deletion mutation of the mdr1 gene) that has been seen in certain genetic lines of Collie-type breeds. In mice and rats, ivermectin may cause neurologic toxicity at doses slightly more than usually prescribed (less than 0. 5 mg/kg). In birds, death, lethargy or anorexia may be seen. Orange-cheeked Waxbill Finches and budgerigars may be more sensitive to ivermectin than other species. For additional information refer to the Overdosage/Acute T oxicity section below. Reproductive/Nursing Safety Ivermectin is considered safe to use during pregnancy. Reproductive studies performed in dogs, horses, cattle and swine have not dem-onstrated adverse effects to fetuses. Reproductive performance in male animals is apparently unaltered. In humans, the FDA cat-egorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although spe-ciﬁc 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. ) Ivermectin is excreted in milk in low concentrations; it is un-likely to pose signiﬁcant risk to nursing offspring. Overdosage/Acute Toxicity There were 660 exposures to ivermectin reported to the ASPCA Animal Poison Control Center (APCC) during 2005-2006. In these cases 575 were dogs with 104 showing clinical signs, 47 cats with 8 showing clinical signs, 9 wild felines with 3 showing clini-cal signs, 5 reported bird cases with 2 showing clinical signs, and 2 reported turtle cases with 1 showing clinical signs. The remain-ing 22 cases consisted of 12 rodents, 3 lagomorphs, 2 caprine, 2 equine, 1 ovine, and 2 unknown species none of which showed clinical signs. Common ﬁndings in dogs recorded in decreasing frequency included ataxia, blindness, mydriasis, tremors and vom-iting. Common ﬁndings in cats recorded in decreasing frequency included ataxia, mydriasis, tremors, hyperesthesia and hypo-thermia. Common ﬁndings in wild felines recorded in decreasing frequency included ataxia, blindness and disorientation. Common ﬁndings in birds recorded in decreasing frequency included aba-sia, ataxia, head held low, lethargy and paresis. Common ﬁndings in turtles in decreasing frequency included ﬂaccid paralysis and unresponsiveness. In dogs (non-sensitive breeds), signs of acute toxicity rarely oc-cur at single dosages of 1 mg/kg (1000 microgram/kg) or less. At 2. 5 mg/kg, mydriasis occurs, and at 5 mg/kg, tremors occur. At doses of 10 mg/kg, severe tremors and ataxia are seen. Deaths occurred when dosages exceeded 40 mg/kg, but the LD 50 is 80 mg/kg. Dogs (Beagles) receiving 0. 5 mg/kg PO for 14 weeks developed no signs of toxicity, but at 1-2 mg/kg for the same time period, developed mydriasis and had some weight decreases. Half of the dogs receiv-ing 2 mg/kg/day for 14 weeks developed signs of depression, trem-ors, ataxia, anorexia, and dehydration. Ivermectin is actively transported by the p-glycoprotein pump and certain breeds susceptible to MDR1-allele mutation (Collies, Australian Shepherds, Shelties, Long-haired Whippets, etc. ) are at higher risk for CNS toxicity. At the dosage recommended for heart-worm prophylaxis, it is generally believed that the drug is safe to use in these animals. Dogs who receive an overdosage of ivermectin or develop signs of acute toxicity (CNS effects, GI, cardiovascular) should receive supportive and symptomatic therapy. Emptying the gut should be considered for recent massive oral ingestions in dogs or cats. For both oral and injected ivermectin overdoses, the use of repeated activated charcoal doses is advised to interrupt enterohepatic re-circulation. Ivermectin has a large safety margin in cats. Kittens receiving doses of at least 110 mcg/kg and adult cats receiving at least 750 mcg/kg showed no untoward effects. Acute toxic signs associated with massive overdoses in cats will appear within 10 hours of inges-tion. Signs may include agitation, vocalization, anorexia, mydria-sis, rear limb paresis, tremors, and disorientation. Blindness, head pressing, wall climbing, absence of oculomotor menace reﬂex, and a slow and incomplete response to pupillary light may also be seen. Neurologic signs usually diminish over several days and most ani-mals completely recover within 2-4 weeks. Symptomatic and sup-portive care is recommended. In horses, doses of 1. 8 mg/kg (9x recommended dose) PO did not produce signs of toxicity, but doses of 2 mg/kg caused signs of visual impairment, depression and ataxia. In cattle, toxic effects generally do not appear until dosages of 30x those recommended are injected. At 8 mg/kg, cattle showed signs of ataxia, listlessness, and occasionally, death. Sheep showed signs of ataxia and depression at ivermectin doses of 4 mg/kg. Swine showed signs of toxicosis (lethargy, ataxia, tremors, lat-eral recumbency, and mydriasis) at doses of 30 mg/kg. Neonatal pigs may be more susceptible to ivermectin overdosages, presum-ably due to a more permeable blood-brain barrier. Accurate dosing practices are recommended. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ivermectin and may be of signiﬁcance in veterinary patients: !TBENZODIAZEPINES : Effects may be potentiated by ivermectin; use together not advised in humans Caution is advised if using other drugs that can inhibit p-glycoprotein. Those dogs at risk for MDR1-allele mutation (Collies, Australian Shepherds, Shelties, Long-haired Whippet, etc.,“white feet”) should probably not receive ivermectin with the following drugs, unless tested “normal”; drugs and drug classes involved include: !!AMIODARONE !!CARV EDILOL	pppbs.pdf
510 IVERMECTIN !!CLARITHROMYCIN !!CYCLOSPORINE !!DILTIAZEM !!ERYTHROMYCIN !!ITRACONAZOLE !!KETOCONAZOLE !!QUINIDINE !!SPIRONOLACTONE !!TAMOXIFEN !!VERAPAMIL Laboratory Considerations !TWhen used at microﬁlaricide dosages, ivermectin may yield false-negative results in animals with occult heartworm infection. Doses !TDOGS: Note : When used for prophylaxis or treatment of diroﬁlariasis it is suggested to review the guidelines published by the American Heart-worm Society at www. heartwormsociety. org for more information. As a preventative for heartworm: a) 6-12 mcg/kg PO once monthly (Knight 2000) b) Minimum dosage of 6 micrograms/kg (0. 006 mg/kg) PO per month. (Package insert; Heartgard 30®—MSD) As a microﬁlaricide: a) When used to kill third, fourth, and young ﬁfth stage larvae for prophylaxis or to kill these larval stages prior to adulticide therapy along with microﬁlariae, ivermectin is dosed at 6-12 mcg/kg PO once a month. When only used to kill circulat-ing microﬁlariae, ivermectin can be administered at 6 mcg/ kg (the approved prophylactic dose) or at a dose of 50 mcg/ kg (approximately 10 times the prophylactic dose). Microﬁ-lariae numbers decrease gradually to, or close to, zero within several months at the lower dose. The chance of adverse reac-tions with this approach is minimal. The higher dose results in a rapid kill that is associated with more adverse effects. (Kittleson 2006b) As an ectoparasiticide (miticide): a) For generalized demodicosis: Note : Do not consider use in MDR1 mutation susceptible breeds unless tested “normal/ normal” for mutation www. vetmed. wsu. edu. If normal/nor-mal, drug reaction is very unlikely. Start at low dosage and increase: Day 1: 100 mcg/kg PO q24h, Day 4: 200 mcg/kg PO q24h, Day 7: 300 mcg/kg; continue to increase by 100 mcg/kg every 3rd day until reach target dose of 600 mcg/kg PO daily and continue treatment 1-2 months after 2 negative skin scrapes. Treatment usually requires 10-33 weeks. (Hillier 2006g) b) For demodicosis: 400-600 mcg/kg PO daily. Consider using the test dose method: Start at 100 mcg/kg PO and increase by 100 mcg/day until target dose is reached. Treatment typically required for 2-4 months. If toxicity is noted, discontinue. Do not use in collies, Shelties, Old English Sheepdogs and other herding dogs. (De Manuelle 2000) c) As scabicide: 300-400 mcg/kg PO or SC once weekly for weeks. If using the 1% injection, 1 m L = 10,000 mcg. Beware in sensitive breeds (e. g., Collies, etc. ; “white feet, don't treat”). Check heartworm status prior to treatment. Adverse effects are rare outside of sensitive breeds. (Foil 2003c) As an endoparasiticide: a) For treatment of parasitic lung disease (Capillaria spp. ): 0. 2 mg/kg PO once (Bauer 1988) b) For Oslerus osleri: 0. 4 mg/kg SC once (Reinemeyer 1995) c) For Eucoleus boehmi: 0. 2 mg/kg PO once (Reinemeyer 1995) d) For Pneumonyssoides caninum: 0. 2 mg/kg SC once (Rein-emeyer 1995) !TCATS: Note : When used for prophylaxis or treatment of diroﬁlariasis it is suggested to review the guidelines published by the Ameri-can Heartworm Society at www. heartwormsociety. org for more information As a preventative for heartworm: a) Minimum effective dosage: 0. 024 mg/kg (24 micrograms/kg) PO every 30-45 days ( Note : also controls hookworms at this dosage) (Knight 1995) For Aelurostrongylus abstrusus: a) 0. 4 mg/kg SC once (Reinemeyer 1995); (Hawkins 2000) !TFERRETS: For prevention of heartworm disease: a) 0. 02 mg/kg PO monthly (Hoeffer 2000) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: For Sarcoptes scabiei, Notoedres cati: 0. 3-0. 4 mg/kg SC, repeat in 14 days. For ear mites (Psoroptes) 0. 2-0. 44 mg/kg PO, SC repeat in 8-18 days (Ivey and Morrisey 2000) b) Rabbits: For treatment of ear mites: 200 mcg/kg SC and re-peated in two weeks. All rabbits in colony should be treated and cages cleaned and disinfected. (Burke 1999) c) Rodents and lagomorphs: For treatment of sarcoptoid and some fur mites: 200-250 mcg/kg SC. Cages should be thor-oughly cleaned and disinfected. (Burke 1999) d) Mice, Rats, Gerbils, Guinea pigs, Chinchillas: 200 mcg/kg SC or PO every 7 days for 3 weeks Hamsters: 200-500 mcg/kg SC or PO every 14 days for 3 weeks (Adamcak and Otten 2000) e) Guinea pigs for Trixacarus caviae mites: 500 mcg/kg SC, re-peated at 14 and 28 days. (Johnson 2006d) !TCATTLE: For susceptible parasites: a) 200 micrograms/kg SC. Doses greater than 10 m L should be given at two separate sites. (Paul 1986) b) For psoroptic mange: 200 mg/kg IM ( Note : Reference was written before approval of the SC labeled bovine product); isolate from other cattle for at least 5 days after treatment. (Mullowney 1986) c) 200 micrograms/kg (0. 2 mg/kg) SC under the loose skin in front of or behind the shoulder (Product Information; Ivo-mec® Inj. for Cattle 1%—MSD) !THORSES: For susceptible parasites: a) 200 micrograms/kg (0. 2 mg/kg) PO using oral paste or oral liquid (Product Information; Eqvalan®—MSD) b) 0. 2 mg/kg PO; 0. 2 mg/kg PO at 4 day intervals for lice and mange (Robinson 1987) c) As a larvicidal for arterial stages of S. vulgaris: 0. 2 mg/kg once (Herd 1987) !TSWINE: For susceptible parasites: a) 300 micrograms/kg (0. 3 mg/kg) SC in the neck immediately behind the ear (Product Information; Ivomec® Inj. for Swine 1%—MSD)	pppbs.pdf
IVERMECTIN 511 b) For general control of endo-and ectoparasites in potbellied pigs: 300 micrograms/kg SC or IM once for internal para-sites and repeated in 10-14 days for external parasites (only partially effective against whipworms—see fenbendazole) (Braun 1995) !TSHEEP: For susceptible parasites: a) 200 micrograms/kg for nasal bot infection (Bennett 1986) b) 200 micrograms/kg SC for one dose (goats also) (Upson 1988) !TLLAMAS: For susceptible parasites: a) 0. 2 mg/kg PO or SC for one dose (Cheney and Allen 1989), (Fowler 1989) !TBIRDS: For susceptible parasites: a) For ascarids, Capillaria and other intestinal worms, Knemi-docoptes pilae (scaly face and leg mites): Dilute to a 2 mg/m L concentration. After diluting product, use immediately. Most birds: Inject 220 mcg/kg IM; Parakeets: 0. 02 mg/30 g (2000 mcg/30 gram) IM; Amazons: 0. 1 mg IM; Macaws: 0. 2 mg IM; Finches: 0. 02 mg (Stunkard 1984) b) For ascarids, coccidia and other intestinal nematodes, Oxy-sipura, gapeworms, Knemidocoptes pilae (scaly face and leg mites): Dilute bovine preparation (10 mg/m L) 1:4 with pro-pylene glycol. For most species: 200 mcg/kg IM or orally; repeat in 10-14 days. Budgerigars: 0. 01 m L of diluted product (see above) IM or PO (Clubb 1986) c) 200 mcg/kg (0. 2 mg/kg) SC; dilute using propylene glycol. (Sikarskie 1986) d) Ratites: 200 mcg/kg PO, IM or SC. Has efﬁcacy against Chandlerella quiscali in emus. (Jenson 1998) !TREPTILES: For most nematodes, ectoparasites: a) For lizards, snakes, and alligators: 0. 2 mg/kg (200 mcg/kg) IM, SC, or PO once; repeat in 2 weeks Note : Ivermectin is toxic to chelonians (Gauvin 1993) Monitoring !TClinical efﬁcacy !TAdverse effects/toxicity (see Adverse Effects and Overdosage Sections) Client Information !TWhen using large animal products the manufacturer recom-mends not eating or smoking and to wash hands after use. Avoid contact with eyes. !TDispose of unused products and containers by incineration or in approved-landﬁlls. Ivermectin may adversely affect ﬁsh or other water-borne organisms if disposed in water. !TContact veterinarian if any treated animal exhibits signs of toxic-ity (see Adverse effects and Overdosage sections above). Chemistry/Synonyms An avermectin anthelmintic, ivermectin occurs as an off-white to yellowish powder. It is very poorly soluble in water (4 micrograms/ m L), but is soluble in propylene glycol, polyethylene glycol, and vegetable oils. Ivermectin may also be known as MK 933, Ivermectine, Ivermectinum or Ivermectina; many trade names are available. Storage/Stability/Compatibility Ivermectin is photolabile in solution; protect from light. Unless otherwise speciﬁed by the manufacturer, store ivermectin products at room temperature (15-30°C). Ivermectin 1% oral solution (equine tube wormer product) is stable at 1:20 and 1:40 dilutions with water for 72 hours when stored in a tight container, at room temperature, and protected from light. Dosage Forms/Regulatory Status VETERINARY APPROVED PRODUCTS: Note : As ivermectin is no longer patent protected in the USA, there are a variety of “generic” products available with many trade names. The following may not be a complete listing. Ivermectin for Injection: 10 mg/m L (1%) in 50 m L, 200 m L and 500 m L packs; Ivomec® (Merial); (OTC); Approved for use in swine. Slaughter withdrawal (at labeled doses) = 18 days. Ivermectin for Injection: 10 mg/m L (1%) and Clorsulon 100 mg/m L; Ivomec® Plus Injection for Cattle (Merial); (OTC). Approved for use in cattle (not female dairy cattle of breeding age). Slaughter with-drawal (at labeled doses) = 40 days. No milk withdrawal has been established. Ivermectin for Injection: 10 mg/m L (1%) in 50 m L, 200 m L, 500 m L bottles; Ivomec® 1% Injection for Cattle and Swine (Merial), Double Impact® (Agri Labs); Ultramectrin® Injection (RXV); (OTC). Ap-proved for use in cattle (not female dairy cattle of breeding age) and swine. Slaughter (when used as labeled): cattle = 35 days, swine = 18 days, reindeer = 56 days, bison = 56 days. No milk withdrawal time has been established. Ivermectin for Injection: 2. 7 mg/m L (0. 27%) in 200 m L bottles; Ivo-mec® 0. 27% Injection for Feeder and Grower Pigs (Merial); (OTC). Ap-proved for use in swine. Slaughter (when used as labeled) = 18 days Ivermectin Oral Paste: 1. 87% (18. 7 mg/gram) in 6. 08 g syringes; Equimectrin® Paste 1. 87% (Farnam), Eqvalan® Paste 1. 87% (Merial), Rotectin® 1 Paste 1. 87% (Farnam), Zimectrin® Paste (Farnam); (OTC). Approved for use in horses (not intended for food purposes). Oral Paste: containing 1. 87% ivermectin and 14. 03% of praziquan-tel in oral syringes (sufﬁcient to treat one 1320 lb horse); Equimax® (Pﬁzer); (OTC). Approved for use in horse or ponies not intended for food purposes. Oral Paste: containing 1. 55% ivermectin and 7. 75% of praziquantel in oral syringes; Zimecterin Gold®(Merial); (OTC). Approved for use in horse or ponies not intended for food purposes. Ivermectin Liquid: 1% (10 mg/m L) in 50 m L and 100 m L btls (for tube administration; NOT for injection); Amtech Phoenectin® Liquid for Horses (Phoenix Scientiﬁc), Eqvalan® Liquid (Merial), Ivercide® Liquid for Horses (Phoenix Pharmaceutical); (Rx). Approved for use in horses (not intended for food purposes). Ivermectin Oral Tablets: 68 mcg, 136 mcg, 272 mcg (Plain or Chew-able) in 6 chewables in carton in 10 carton trays, Heartgard® Tablets (Merial), Heartgard® Chewables (Merial); (Rx). Approved for use in dogs. Ivermectin Oral Chewable Tablets: 55 mcg or 165 mcg in cartons of 6 in 10 cartons per tray. Heartgard® for Cats (Merial); (Rx) Approved for use in cats. Ivermectin/Pyrantel Oral Tablets: 68 mcg/57 mg, 136 mcg/114mg, 272 mcg/228 mg); Heartgard® Plus Chewables (Merial); Tri-Heart® Plus Chewable Tablets (Schering); (Rx). Approved for use in dogs.	pppbs.pdf
512 KAOLIN/PECTIN Ivermectin Oral Solution: 0. 08% in 960 m L and 4,800 m L containers; Ivomec® Sheep Drench (Merial); (OTC); Approved for use in sheep. Slaughter withdrawal time = 11 days. Ivermectin Bolus: 1. 72 g; Ivomec® SR Bolus (Merial); (OTC). Ap-proved for use in cattle (not female dairy cattle of breeding age). Slaughter withdrawal time = 180 days. No milk withdrawal time has been established. Ivermectin Medicated feeds: Ivomec® Premix for Swine Type A Medi-cated Article (Merial) 0. 6% in 50 lb. Ivomec® Premix for Swine Type C Medicated Feed 0. 02% (Merial) in 20 lb one-ton bag and 40 lb two-ton bag, Ivomec® Premix for Swine Type C medicated feed 0. 1% (Merial) in 20 lb one-ton bag. Approved for use in swine. Slaughter withdrawal = 5 days Ivermectin T opical Parasiticide Pour-on for Cattle: 5 mg/m L 250 m L, 500 m L, 1 liter and 1 gallon bottles. Approved for use in cattle (not female dairy cattle of breeding age). Slaughter withdrawal time = 48 days, milk withdrawal has not been established. Amtech Phoenectin® Pour-on for Cattle (Phoenix Scientiﬁc), Bimectin® Pour-On (Bimeda), Ivercide® Pour-On for Cattle (Phoenix Pharmaceutical), Ivermectin® Pour-On (Aspen, Durvet), Ivomec® Eprinex® Pour-on for Beef and Dairy Cattle and Ivomec® Pour-on for Cattle (Merial), Prozap® Iver-mectin Pour-on (Loveland), Top Line® (Agri Labs), Ultramectrin® Pour-On (RXV); (OTC) An otic product Acarexx® is also available. HUMAN-LABELED PRODUCTS: Ivermectin Tablets: 3 mg and 6 mg; Stromectol® (Merck); (Rx) KAOLIN/PECTIN (kay-oh-lin/pek-tin) Kaopectolin GI ADSORBENT/PROT ECTANT Prescriber Highlights TT Adsorbent for treatment of diarrhea & GI toxins; questionable efﬁcacy TT Contraindications: Should not be relied on to control severe diarrheas or to replace adequate ﬂuid/electro-lyte monitoring or as replacement therapy in severe or chronic diarrheas TT Adverse Effects: Transient constipation TT Drug Interactions Uses/Indications Although its efﬁcacy is in question, kaolin/pectin is used primarily in veterinary medicine as an oral anti-diarrheal agent. It has also been used as an adsorbent agent following the ingestion of certain toxins. Administration may be difﬁcult due to the large volumes that may be necessary to give orally. Pharmacology/Actions Kaolin/pectin is thought to possess adsorbent and protective quali-ties. Presumably, bacteria and toxins are adsorbed in the gut and the coating action of the suspension may protect inﬂamed GI mucosa. The pectin component, by forming galacturonic acid, has been demonstrated to decrease p H in the intestinal lumen. In one study in children with acute nonspeciﬁc diarrhea, stool ﬂuidity was decreased, but stool frequency, water content, and weight remained unchanged. No studies documenting the clinical efﬁcacy of this combination in either human or veterinary species were located. Pharmacokinetics Neither kaolin nor pectin are absorbed after oral administration. Up to 90% of the pectin administered may be decomposed in the gut. Contraindications/Precautions/Warnings There are no absolute contraindications to kaolin/pectin therapy, but it should not be relied on to control severe diarrheas. Kaolin/ pectin should not replace adequate ﬂuid/electrolyte monitoring or replacement therapy in severe or chronic diarrheas. Adverse Effects At usual doses, kaolin/pectin generally has no adverse effects. Constipation may occur, but is usually transient and associated with high dosages. High doses in debilitated, or in very old or young patients may rarely cause fecal impaction. In rats, kaolin/pectin has been demonstrated to increase fecal sodium loss in diarrhea. In humans, kaolin/pectin is recommended for use only under the direct supervision of a physician, in patients less than 3 years of age or for longer than 48 hours. Reproductive/Nursing Safety Adsorbent (only) anti-diarrheal products should be safe to use dur-ing pregnancy and lactation. The addition of other active ingredi-ents (e. g., as opiates) may alter this recommendation. Overdosage/Acute Toxicity Overdosage is unlikely to cause any serious effects, but constipation requiring treatment may occur. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving kaolin/pectin and may be of signiﬁcance in veterinary patients: T ! DIGOXIN : Some evidence exists that kaolin/pectin may impair the oral absorption of digoxin. Separate doses by at least two hours. T ! LINCOMYCIN : Kaolin/pectin may inhibit the oral absorption of lin-comycin. If both drugs are to be used, administer kaolin/pectin at least 2 hours before or 3-4 hours after the lincomycin dose. Doses T ! DOGS: For diarrhea: a) 1-2 m L/kg PO q4-6h (Davis 1985a) b) 1-2 m L/kg PO four times daily (Johnson 1984) c) 1-2 m L/kg PO q2-6h (Kirk 1986) For enterotoxins secondary to garbage ingestion: a) 2-5 m L/kg PO q1-6 hours (Coppock and Mostrom 1986) b) 10-15 grams of kaolin/kg PO four times daily (Grauer and Hjelle 1988a) T ! CATS: For diarrhea: a) 1-2 m L/kg PO q4-6h (Davis 1985a) b) 1-2 m L/kg PO four times daily (Johnson 1984) c) 1-2 m L/kg PO q2-6h (Kirk 1986) T ! FERRETS: a) 1-2 m L/kg PO 3-4 times daily (Williams 2000) T ! RABBITS/RODENTS/SMALL MAMMALS: a) Guinea pigs: 0. 2 m L PO 3-4 times a day (Adamcak and Ot-ten 2000)	pppbs.pdf
KETAMINE HCL 513 T ! CATTLE: a) Adult: 4-10 ﬂ. oz. PO; Calves: 2-3 ﬂ. oz PO; repeat every 2-4 hours or as indicated until condition improves. If no improvement in 48 hours additional treatment is indicated. (Label Directions; Kao-Forte®—Vet-A-Mix) T ! HORSES: For diarrhea: a) 2-4 quarts PO per 450 kg body weight twice daily (Robinson 1987) b) 1 oz. per 8 kg body weight PO 3-4 times a day (Clark and Becht 1987) c) Foals: 3-4 oz PO q6-8h (authors believe that bismuth sub-salicylate is superior) (Martens and Scrutchﬁeld 1982) T ! SWINE: a) H-2 ﬂ. oz PO; repeat every 2-4 hours or as indicated un-til condition improves. If no improvement in 48 hours additional treatment is indicated. (Label Directions; Kao-Forte®—Vet-A-Mix) T ! SHEEP: a) 3-4 oz PO q2-3h (Mc Connell and Hughey 1987) T ! BIRDS: a) Canary or parakeet: 1 drop PO twice daily; or 1 and H drop-perful placed in 2/3 oz. drinking water. Medium-sized birds: 0. 5 m L PO Large birds: 1 m L PO 1 to 4 times a day (Stunkard 1984) b) 2 m L/kg PO two to four times a day (Clubb 1986) Monitoring T ! Clinical efﬁcacy T ! Fluid and electrolyte status in severe diarrhea Client Information T ! Shake well before using T ! If diarrhea persists, or if animal appears listless or develops a high fever, contact veterinarian Chemistry/Synonyms Kaolin is a naturally occurring hydrated aluminum silicate that is powdered and reﬁned for pharmaceutical use. Kaolin is a white/ light, odorless, almost tasteless powder that is practically insoluble in water. Pectin is a carbohydrate polymer consisting primarily of partial-ly methoxylated polygalacturonic acids. Pectin is a course or ﬁne, yellowish-white, almost odorless with a mucilaginous ﬂavor. It is obtained from the inner rind of citrus fruits or from apple pomace. One gram of pectin is soluble in 20 m L of water and forms a vis-cous, colloidal solution. In the United States, the two compounds generally are used together in an oral suspension formulation in most proprietary products. Kaolin may also be known as: bolus alba, E559, weisser ton, Childrens Diarrhoea Mixture®, Entrocalm®, Kao-Pec®, Kao-Pect®, Kao-Pront®, Kaogel®; many multi-ingredient trade names are available. Storage/Stability/Compatibility Kaolin/pectin should be stored in airtight containers; protect from freezing. It is physically incompatible when mixed with alkalis, heavy metals, salicylic acid, tannic acid, or strong alcohol. Dosage Forms/Regulatory Status There are variety of kaolin/pectin products available without pre-scription. Several products are labeled for veterinary use; their ap-proval status is not known. Many products that formerly contained kaolin (e. g., Kaopectate®) no longer contain any kaolin, but use at-tapulgite as the adsorbent. VETERINARY-LABELED PRODUCTS: Kaolin Pectin 90 gr kaolin/2 g pectin per ﬂuid oz. in 1 quart and 1 gallon containers. generic, (Bimeda, Durvet), Kaolin Pectin Plus® (Agri Pharm), Kao-Pec® (Agri Labs), Kao-Pect® (Phoenix Pharmaceu-tical), Kaopectolin (Aspen, Butler); (OTC). Products may be labeled for use in horses, cattle, dogs and cats. Kaolin Pectin 90 gr kaolin/4 g pectin per ﬂ oz. in 1 gallon containers. Kaolin Pectin Suspension (Vedco); (OTC) HUMAN-LABELED PRODUCTS: Kaolin, Pectin Antidiarrheal Suspension: 90 g kaolin, 2 g pectin/30 m L in 180 m L and 360 m L, pt and UD 30 m L; Kaopectolin (various); generic; (OTC) KETAMINE HCL (kee-ta-meen) Ketaset®, Ketaﬂo®, Vetalar® DISSOCIATIVE GENERAL A NESTHETIC; NMDA-RECEPTOR ANTAGONIST Prescriber Highlights TT Dissociative general anesthetic; also inhibits NMDA-receptors so may be adjunctively useful to control pain TT Contraindications: Prior hypersensitivity reactions; ani-mals to be used for human consumption, alone for gen-eral anesthesia, increased CSF pressure/head trauma TT Relative contraindications: Signiﬁcant blood loss, ma-lignant hyperthermia, increased intra-ocular pressure or open globe injuries; procedures involving the pharynx, larynx, or trachea TT Caution: Signiﬁcant hypertension, heart failure, & arte-rial aneurysms, hepatic or renal insufﬁciency, seizure disorders TT Adverse Effects: Hypertension, hypersalivation, respirato-ry depression, hyperthermia, emesis, vocalization, erratic & prolonged recovery, dyspnea, spastic jerking move-ments, seizures, muscular tremors, hypertonicity, opistho-tonos, & cardiac arrest; pain after IM injection may occur TT Cats' eyes remain open after ketamine; protect TT Minimize exposure to handling or loud noises during the recovery period, but monitor adequately TT Drug interactions Uses/Indications Ketamine has been approved for use in humans, sub-human pri-mates, and cats, although it has been used in many other species (see Dosage section). The approved indications for cats include, “for restraint, or as the sole anesthetic agent for diagnostic, or mi-nor, brief, surgical procedures that do not require skeletal muscle relaxation... and in subhuman primates for restraint. ” (Package Insert; Ketaset®—Bristol).	pppbs.pdf
514 KETAMINE HCL Ketamine can inhibit NMDA receptors in the CNS and can decrease “wind-up” effect. There is increasing interest in using it to prevent exaggerated pain associated with surgery or chronic pain states in animals. Pharmacology/Actions Ketamine is a rapid acting general anesthetic that has signiﬁcant analgesic activity and a lack of cardiopulmonary depressant effects. It is thought to induce both anesthesia and amnesia by functionally disrupting the CNS through over stimulating the CNS or inducing a cataleptic state. Ketamine inhibits GABA, and may block sero-tonin, norepinephrine, and dopamine in the CNS. The thalamo-neocortical system is depressed while the limbic system is activated. It induces anesthetic stages I and II, but not stage III. In cats, it causes a slight hypothermic effect as body temperatures decrease on average by 1. 6°C after therapeutic doses. Effects on muscle tone are described as being variable, but ket-amine generally either causes no changes in muscle tone or increased tone. Ketamine does not abrogate the pinnal and pedal reﬂexes, nor the photic, corneal, laryngeal or pharyngeal reﬂexes. Ketamine's effects on the cardiovascular system include increased cardiac output, heart rate, mean aortic pressure, pulmonary artery pressure, and central venous pressure. Its effects on total peripheral resistance are described as being variable. Cardiovascular effects are secondary to increased sympathetic tone; ketamine has negative inotropic effects if the sympathetic system is blocked. Ketamine does not cause signiﬁcant respiratory depression at usual doses, but at higher doses it can cause respiratory rates to de-crease. In humans with asthma, ketamine causes decreased airway resistance. Pharmacokinetics After IM injection in the cat, peak levels occur in approximately 10 minutes. Ketamine is distributed into all body tissues rapidly, with highest levels found in the brain, liver, lung, and fat. Plasma protein binding is approximately 50% in the horse, 53% in the dogs, and 37-53% in the cat. The drug is metabolized in the liver principally by demethylation and hydroxylation and these metabolites, along with unchanged ketamine, are eliminated in the urine. Ketamine will induce hepatic microsomal enzymes, but there appears to be little clinical signiﬁ-cance associated with this effect. The elimination half-life in the cat, calf, and horse is approximately 1 hour, in humans it is 2-3 hours. Like the thiobarbiturates, the redistribution of ketamine out of the CNS is more of a factor in determining duration of anesthesia than is the elimination half-life. By increasing the dose, the duration of anesthesia will increase, but not the intensity. Contraindications/Precautions/Warnings Ketamine is contraindicated in patients who have exhibited prior hypersensitivity reactions to it and animals to be used for human consumption. Use in patients with signiﬁcant hypertension, heart failure, and arterial aneurysms could be hazardous. The manufac-turer warns against its use in patients with hepatic or renal insuf-ﬁciency but in humans with renal insufﬁciency, the duration of action is not prolonged. Because ketamine does not provide good muscle relaxation, it is contraindicated when used alone for major surgery. Ketamine can cause increases in CSF pressure and it should not be used in cases with elevated pres sures or when head trauma has occurred. Because of its supposed epileptogenic potential, it should generally not be used (unless very cautiously) in animals with preexisting seizure disorders. As myel ography can induce sei-zures, ketamine should be used cautiously in animals undergoing this proce dure. Ketamine is considered to be relatively contraindicated when in-creased intra-ocular pressure or open globe injuries exist, and for procedures involving the pharynx, larynx, or trachea. Animals that have lost signiﬁcant amounts of blood, may require signiﬁcantly reduced ketamine dosages. While ketamine has been used safely in humans with malignant hyperthermia, its use in animals susceptible to this condition is controversial. Hyperthyroid human patients (and those receiving exogenous thyroid replacement) may be susceptible to developing severe hypertension and tachycardia when given ketamine. The vet-erinary signiﬁcance of this potential problem is unknown. Cats' eyes remain open after receiving ketamine, and should be protected from injury plus an ophthalmic lubricant (e. g., Lacri-Lube®) should be applied to prevent excessive drying of the cornea. T o minimize the incidences of emergence reactions, it is recom-mended to minimize exposure to handling or loud noises during the recovery period. The monitoring of vital signs should still be performed during the recovery phase, however. Because ketamine can increase blood pressure, careful control of post-surgical hemorrhage (e. g., declawing) should be managed. It is not essential to withhold food or water prior to surgery, but in elective procedures, it is recommended to withhold food for 6 hours prior to surgery. Adverse Effects In approved species the following adverse reactions are listed by the manufacturer: “respiratory depression... following high doses, em-esis, vocalization, erratic and prolonged recovery, dyspnea, spastic jerking movements, convulsions, muscular tremors, hypertonicity, opisthotonos and cardiac arrest. In the cat, myoclonic jerking and/ or tonic/clonic convulsions can be controlled by ultrashort-acting barbiturates or acepromazine. These latter drugs must be given intravenously, cautiously, and slowly, to effect (approximately 1/6 to G the normal dose may be required). ” (Package Insert; Ketaset®— Fort Dodge) Seizures have been reported to occur in up to 20% of cats that receive ketamine at therapeutic dosages. Diazepam is suggested if treatment is necessary. It has been reported to rarely cause a vari-ety of other CNS effects (mild CNS effects to blindness and death). Ketamine has been documented to cause hyperthermia in cats; low doses of acepromazine (0. 01-0. 02 mg/kg IV) may alleviate. Anecdotal reports of ketamine causing acute, CHF in cats with mild to moderate heart disease have been reported. Pain after IM injection may occur. T o reduce the incidence of hypersalivation and other autonomic signs, atropine or glycopyrrolate is often administered. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as class: B (Safe for use if used cautiously. Studies in laboratory animals may have un-covered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term. ) No speciﬁc lactation information was found.	pppbs.pdf
KETAMINE HCL 515 Overdosage/Acute Toxicity Ketamine is considered to have a wide therapeutic index (approxi-mately 5 times greater when compared to pentobarbital). When given too rapidly or in excessive doses, signiﬁcant respiratory de-pression may occur. Treatment using mechanically assisted respira-tory support is recommended versus the use of analeptic agents. In cats, yohimbine with 4-aminopyridine has been suggested for use as a partial antagonist. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ketamine and may be of signiﬁcance in veterinary patients: !TCHLORAMPHENICOL (parenteral ): May prolong the anesthetic ac-tions of ketamine !TCNS DEPRESSANTS : Narcotics, barbiturates, or diazepam may pro-long the recovery time after ketamine anesthesia !THALOTHANE : When used with halothane, ketamine recovery rates may be prolonged and the cardiac stimulatory effects of ketamine may be inhibited; close monitoring of cardiac status is recom-mended when using ketamine with halothane !TNEUROMUSCULAR BLOCKERS (e. g., succinylcholine and tubocurarine ): May cause enhanced or prolonged respiratory depression !TTHYROID HORMONES : When given concomitantly with ketamine, thyroid hormones have induced hypertension and tachycardia in humans; beta-blockers (e. g., propranolol) may be of beneﬁt in treating these effects Doses Note : Ketamine is used in many different combinations with other agents. The following are representative, but not necessarily inclu-sive; it is suggested to refer to a recent veterinary anesthesia refer-ence for more information. !TDOGS: Note : Ketamine/xylazine has induced cardiac arrhythmias, pul-monary edema, and respiratory depression in dogs. This combi-nation should be used with caution. As an adjunct to anesthesia: a) Diazepam 0. 5 mg/kg IV, then ketamine 10 mg/kg IV to in-duce general anesthesia (Booth 1988a) b) Midazolam 0. 066-0. 22 mg/kg IM or IV, then ketamine 6. 6-11 mg/kg IM (Mandsager 1988) c) Xylazine 2. 2 mg/kg IM, in 10 minutes give ketamine 11 mg/ kg IM. Dogs weighing more than 22. 7 kg (50 lbs. ) reduce dose (per kg) of both drugs by approx. 25% (Booth 1988a) d) Atropine (0. 044 mg/kg) IM, in 15 minutes give xylazine (1. 1 mg/kg) IM, 5 minutes later give ketamine (22 mg/kg) IM (Booth 1988a) As an NMDA antagonist for adjunctive pain control: a) 0. 1-1 mg/kg PO, IM or SC q4-6h for mild to moderate pain in conjunction with opioids. (Nieves 2002) b) For intraoperative use: If anesthesia was induced with a drug other than ketamine, give a loading dose of 0. 5 mg/kg IV, then an infusion of 10-20 mcg/kg/minute. A CRI of 2-10 mcg/kg/minute can be used post-op. (Hellyer 2006) !TCATS: Most clinicians recommend giving atropine or glycopyrrolate before use to decrease hypersalivation. a) 11 mg/kg IM for restraint; 22-33 mg/kg for diagnostic or minor surgical procedures not requiring skeletal muscle re-laxation (Package Insert; Ketaset®—Bristol) b) 2-4 mg/kg IV or 11-33 mg/kg IM (Davis 1985b) c) Restraint: 0. 1 m L (10 mg) IV Anesthesia: 22-33 mg/kg IM or 2. 2-4. 4 mg/kg IV (with at-ropine) (Morgan 1988) d) Sedation, restraint: 6. 6-11 mg/kg IM Anesthetic: 17. 6-26. 4 mg/kg IM Induction (following sedation): 4. 4-11 mg/kg IV (Mand-sager 1988) As an NMDA antagonist for adjunctive pain control: a) 0. 1-1 mg/kg IM or SC q4-6h for mild to moderate pain in conjunction with opioids. (Nieves 2002) b) For intraoperative use: If anesthesia was induced with a drug other than ketamine, give a loading dose of 0. 5 mg/kg IV, then an infusion of 10-20 mcg/kg/minute. A CRI of 2-10 mcg/kg/minute can be used post-op. (Hellyer 2006) !TRABBITS/RODENTS/SMALL MAMMALS: For chemical restraint: a) Mice: Alone: 50-100 mg/kg IM or IP, 50 mg/kg IV; In combination with diazepam: Ketamine 200 mg/kg with Diazepam 5 mg/kg IM or IP; In combination with xylazine: Ketamine 100 mg/kg with Xy-lazine 5-15 mg/kg IM or IP (Burke 1999) b) Rats: Alone: 50-100 mg/kg IM or IP, 40-50 mg/kg IV; In combination with diazepam: Ketamine 40-60 mg/kg/Di-azepam 5-10 mg/kg IP; In combination with xylazine: Ketamine 40-75 mg/kg with Xylazine 5-12 mg/kg IM or IP (Burke 1999) c) Hamsters/Gerbils: 100 mg/kg IM; In combination with diazepam: Ketamine 50 mg/kg with Di-azepam 5 mg/kg IM; In combination with xylazine: Not recommended (Burke 1999) d) Guinea pig: Alone: 10-30 mg/kg IM; In combination with diazepam: Ketamine 60-100 mg/kg with Diazepam 5-8 mg/kg IM; In combination with xylazine: Ketamine 85 mg/kg with Xyla-zine 12-13 mg/kg IM (Burke 1999) e) Rabbits: Alone: 20-60 mg/kg IM or IV; In combination with diazepam: Ketamine 60-80 mg/kg with Diazepam 5-10 mg/kg IM; In combination with xylazine: Ketamine 10 mg/kg with Xyla-zine 3 mg/kg IV (Burke 1999) f) Rabbits: Alone: 20-50 mg/kg IM or 15-20 mg/kg IV In combination with diazepam for induction: Diazepam 5-10 mg/kg IM give ketamine 30 minutes after diazepam at 20-40 mg/kg IM or Diazepam 0. 2-0. 5 mg/kg and Ketamine 10-15 mg/kg (to effect) IV; In combination with diazepam for anesthesia without inhal-ants: Diazepam 5-10 mg/kg IM plus ketamine 60-80 mg/kg IM 30 minutes later; In combination with xylazine: Not recommended for pet rabbits (Ivey and Morrisey 2000) !TFERRETS: a) For injectable anesthesia: Butorphanol 0. 1 mg/kg, Ketamine 5 mg/kg, medetomidine 80 mcg/kg. Combine in one sy-ringe and give IM. May need to supplement with isoﬂurane (0. 5-1. 5%) for abdominal surgery. (Finkler 1999) !TCATTLE: a) Premedicate with atropine and xylazine, then ketamine 2 mg/kg IV bolus (Thurmon and Benson 1986) b) After sedation, 2. 2 mg/kg IV (Mandsager 1988)	pppbs.pdf
516 KETAMINE HCL !THORSES: (Note : ARCI UCGFS Class 2 Drug) a) 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, or 2) Add butorphanol (0. 02-0. 04 mg/kg IV). Butorphanol can be given with the original xylazine if you suspect that the horse will be difﬁcult to tranquilize (e. g., high-strung Thoroughbreds) or added before the ketamine. This combination will improve induc-tion, increase analgesia and increase recumbency time by about 5-10 minutes, or 3) Diazepam (0. 03 mg/kg IV). Mix the diazepam with the ketamine. This combination will im-prove induction when sedation is marginal, improve muscle relaxation during anesthesia and prolong anesthesia by about 5-10 minutes, or 4) Guaifenesin (5% solution administered IV to effect) can also be used to increase sedation and muscle relaxation. (Mathews 1999) b) Initially give xylazine 1. 1 mg/kg IV and wait for full sedative effect (4-8 minutes); then give ketamine 2. 2-2. 75 mg/kg IV only (the higher dose may be necessary for ponies, young “high-strung” Arabians, Hackneys, and Thoroughbreds) as a bolus. Do not administer to an “excited” horse. If surgery time requires additional anesthesia, N-H of the original xylazine/ketamine doses may be given IV. For procedures where better muscle relaxation is required, use guaifenesin-thiobarbiturate. Do not disturb horse until fully recovered. (Thurmon and Benson 1987) c) For foals and ponies: Add 500 mg ketamine and 250 mg xy-lazine to 500 m L of 5% guaifenesin solution. For induction, give 1. 1 m L/kg IV rapidly. Anesthesia may be maintained by constant IV infusion of 2-3 m L/kg/hr. Lower doses for foals, higher doses for ponies. (Thurmon and Benson 1987) d) For induction of surgical colic patients: Use guaifenesin to effect, than 1. 6-2. 2 mg/kg ketamine (Mandsager 1988) e) 200 mg bolus (in a 454 kg horse) intra-operatively to reduce movement with light general anesthesia (Mandsager 1988) !TSWINE: a) Give atropine, then ketamine at 11 mg/kg IM. T o prolong anesthesia and increase analgesia give additional ketamine 2-4 mg/kg IV. Local anesthetics injected at the surgical site (e. g., 2% lidocaine) may enhance analgesia. (Thurmon and Benson 1986) b) Ketamine (22 mg/kg) combined with acepromazine (1. 1 mg/ kg) IM (Swindle 1985) c) 4. 4 mg/kg IM or IV after sedation (Mandsager 1988) !TSHEEP: a) Premedicate with atropine (0. 22 mg/kg) and acepromazine (0. 55 mg/kg; then ketamine 22 mg/kg IM. T o extend anes-thetic time, may give ketamine intermittently IV at 2-4 mg/ kg. (Thurmon and Benson 1986) b) 2 mg/kg IV for induction, then 4 m L/minute constant in-fusion of ketamine in a concentration of 2 mg/m L in D 5W (Thurmon and Benson 1986) !TGOATS: a) Give atropine 0. 4 mg/kg, followed by xylazine 0. 22 mg/kg IM 20-25 minutes later. Approximately 10 minutes after xyla-zine give ketamine 11 mg/kg IM. T o extend anesthesia give ketamine 2-4 mg/kg IV (shorter extension) or 6 mg/kg (lon-ger extension). (Thurmon and Benson 1986) !TREPTILES: a) Medium to small land T ortoises: Medetomidine 100-150 mcg/kg with ketamine 5-10 mg/kg IV or IM; Freshwater Turtles: Medetomidine 150-300 mcg/kg with ketamine 10-20 mg/kg IV or IM; Giant Land T ortoises: 200 kg Aldabra tortoise: Medetomi-dine 40 mcg/kg with ketamine 4 mg/kg IV or IM Smaller Aldabra tortoises: Medetomidine 40-80 mcg/kg with ketamine 4-8 mg/kg IV or IM. Wait 30-40 minutes for peak effect; Iguanas: Medetomidine 100-150 mcg/kg with ketamine 5-10 mg/kg IV or IM; Reversal of all dosages with atipamezole is 4-5 times the me-detomidine dose (Heard 1999) b) 20-60 mg/kg IM (Mc Connell and Hughey 1987) !TSUB-HUMAN PRIMATES: a) Doses vary with regard to individual species; refer to package insert for Ketaset®. !TBIRDS: a) Birds weighing: <100 grams (canaries, ﬁnches, budgies): 0. 1-0. 2 mg/gm IM; 250-500 grams (parrots, pigeons): 0. 05-0. 1 mg/gm IM; 500 grams-3 kg (chickens, owls, hawks): 0. 02-0. 1 mg/gm IM; >3 kg (ducks, geese, swans): 0. 02-0. 05 mg/gm IM (Booth 1988a) b) In combination with xylazine: Ketamine 10-30 mg/kg IM; Xylazine 2-6 mg/kg IM; birds less than 250 g require a high-er dosage (per kg) than birds weighing greater than 250 g. Xylazine is not recommended to be used in debilitated birds because of its cardiodepressant effects. In combination with diazepam: Ketamine 10-50 mg/kg IM; Diazepam 0. 5-2 mg/kg IM or IV; doses can be halved for IV use In combination with acepromazine: Ketamine 25-50 mg/kg IM; Acepromazine 0. 5-1 mg/kg IM (Wheler 1993) Monitoring !TLevel of anesthesia/analgesia !TRespiratory function; cardiovascular status (rate, rhythm, BP if possible) !TMonitor eyes to prevent drying or injury; !TBody temperature Client Information !TShould only be administered by individuals familiar with its use. Chemistry/Synonyms A congener of phencyclidine, ketamine HCl occurs as white, crys-talline powder. It has a melting point of 258-261°C, a characteristic odor, and will precipitate as the free base at high p H. One gram is soluble in 5 m L of water, and 14 m L of alcohol. The p H of the commercially-available injections are between 3. 5-5. 5. Ketamine HCl may also be known as: CI-581, CL-369, CN-52372-2, ketamini hydrochloridum, Amtech®, Brevinaze®, Calypsol®, Cost®, Inducmina®, Keta ®, Keta-Hameln®, Ketaject®, Ketalin®, Ketanest®, Ketaset®, Ketasthesia®, Keta-sthetic®, Ketava®, Ketina®, Ketmin®, Ketolar®, Velonarcon®, Veta Ket®, and Vetalar®. Storage/Stability/Compatibility Ketamine injection should be stored between 15-30°C (59-86°C) and protected from light.	pppbs.pdf
KETOCONAZOLE 517 Solution may darken upon prolonged exposure to light which does not affect the drug's potency. Do not use if precipitates appear. Ketamine may be mixed with sterile water for injection, D 5W, and normal saline for diluent purposes. Ketamine is physically com-patible with xylazine in the same syringe. Do not mix ketamine with barbiturates or diazepam in the same syringe or IV bag as precipita-tion may occur. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Ketamine HCl for Injection: 100 mg/m L in 10 m L vials; Amtech® Ket-amine Hydrochloride Injection, USP (IVX), Ketaject® (Phoenix Phar-maceutical), Ketaset® (Fort Dodge), Keta-sthetic® (RXV), Vetalar® (Fort Dodge); Veta Ket® (Lloyd), Ketasthesia® (Butler); (Rx, C-III). Approved for use in cats and sub-human primates. The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Ketamine HCl Injection: 10 mg/m L in 20 m L vials; 50 mg/m L in 10 m L vials; 100 mg/m L in 5 m L vials; Ketalar® (Monarch); generic; (Rx, C-III) KETOCONAZOLE (kee-toe-kah-na-zole) Nizoral® AZOLE ANTIFUNGAL Prescriber Highlights TT Original imidazole oral antifungal used for systemic my-coses, including aspergillosis, cryptococcal meningitis, blastomycosis, & histoplasmosis; also used as an alter-native treatment of hyperadrenocorticism in dogs. TT Contraindications: Known hypersensitivity; some believe ketoconazole is contraindicated in cats TT Caution: Hepatic disease or thrombocytopenia TT Potentially teratogenic & embryotoxic; weigh risks vs. beneﬁts TT May cause infertility in male dogs by decreasing testos-terone synthesis. TT Adverse Effects: GI (anorexia, vomiting, &/or diarrhea) most common & more prevalent in cats; hepatic toxic-ity, thrombocytopenia, reversible lightening of haircoat, transient dose-related suppressant effect on gonadal & adrenal steroid synthesis TT Long-term treatment may be required; relatively expensive TT Drug interactions Uses/Indications Because of its comparative lack of toxicity when compared to am-photericin B, oral administration, and relatively good efﬁcacy, ke-toconazole has been used to treat several fungal infections in dogs, cats, and other small species. Ketoconazole is often employed with amphotericin B to enhance the efﬁcacy of ketoconazole, and by reducing the dose of amphotericin B, decreasing its risk of toxic-ity. See the Dosage section or Pharmacology section for speciﬁcs. Newer antifungal agents (ﬂuconazole, itraconazole) have advan-tages over ketoconazole, primarily less toxicity and/or enhanced efﬁcacy; however, ketoconazole can be signiﬁcantly less expensive than the newer agents. Ketoconazole is considered by some to still be the drug of choice for treating histoplasmosis in dogs. Use of ketoconazole in cats is controversial and some say it should never be used that species. Ketoconazole is also used clinically for the medical treatment of hyperadrenocorticism in dogs. Ketoconazole appears to be a viable option (although relatively expensive) to mitotane, particularly for palliative therapy in dogs with large, malignant, or invasive tumors where surgery is not an option. Ketoconazole is also used frequently in dogs for stabilization prior to surgery. It is a reversible inhibitor of steroidogenesis, so it is usually not a viable option for long-term treatment. Because it interferes with the metabolism of cyclosporine, it has been used to reduce the dosage necessary for cyclosporine in dogs. Pharmacology/Actions At usual doses and serum concentrations, ketoconazole is fungistat-ic against susceptible fungi. At higher concentrations for prolonged periods of time or against very susceptible organisms, ketoconazole may be fungicidal. It is believed that ketoconazole increases cellu-lar membrane permeability and causes secondary metabolic effects and growth inhibition. The exact mechanism for these effects has not been determined, but may be due to ketoconazole interfering with ergosterol synthesis. The fungicidal action of ketoconazole may be due to a direct effect on cell membranes. Ketoconazole has activity against most pathogenic fungi, in-cluding Blastomyces, Coccidioides, Cryptococcus, Histoplasma, Microsporum, and Trichophyton. Higher levels are necessary to treat most strains of Aspergillus and Sporothrix. Resistance to ketoconazole has been documented for some strains of Candida albicans. Ketoconazole has in vitro activity against Staphylococcus aureas and epidermidis, Nocardia, enterococci, and herpes simplex virus types 1 and 2. The clinical implications of this activity are un-known. Via inhibition of 5-lipooxygenase, ketoconazole possesses some antiinﬂammatory activity. The drug can suppress the immune sys-tem, probably by suppressing T-lymphocytes proliferation. Ketoconazole also has endocrine effects as steroid synthesis is directly inhibited by blocking several P-450 enzyme systems. Measurable reductions in testosterone or cortisol synthesis can occur at dosages used for antifungal therapy, but higher dosages are gener-ally required to reduce levels of testosterone or cortisol to be clini-cally useful in the treatment of prostatic carcinoma or hyperadreno-corticism. Effects on mineralocorticoids are negligible. Pharmacokinetics Although it is reported that ketoconazole is well absorbed after oral administration, oral bioavailability of ketoconazole tablets in dogs is highly variable. One study (Baxter et al. 1986) in six normal dogs, found bioavailabilities ranging from 0. 04-0. 89 (4-89%) after 400 mg (19. 5-25. 2 mg/kg) was administered to fasted dogs. Peak se-rum concentrations occur between 1 and 4. 25 hours after dosing and peak serum levels ranged from 1. 1-45. 6 micrograms/m L. This wide interpatient variation may have signiﬁcant clinical implica-tions from both a toxicity and efﬁcacy standpoint, particularly since ketoconazole is often used in life-threatening infections, and assays for measuring serum levels are not readily available. Administration with food may increase absorption. Oral absorption in horses is poor. Single doses of 30 mg/kg yielded nondetectable blood levels. Ketoconazole absorption is enhanced in an acidic environment and should not be administered (at the same time) with H 2 block-	pppbs.pdf
518 KETOCONAZOLE ers or antacids (see Drug Interactions below). Whether to admin-ister ketoconazole with meals or during a fasted state to maximize absorption is controversial. The manufacturer recommends giving with food in human patients. Dogs or cats that develop anorexia/ vomiting during therapy may beneﬁt from administration with meals. After absorption, ketoconazole is distributed into the bile, ceru-men, saliva, urine, synovial ﬂuid, and CSF. CSF levels are generally less than 10% of those found in the serum, but may be increased if the meninges are inﬂamed. High levels of the drug are found in the liver, adrenals, and pituitary gland, while more moderate levels are found in the kidneys, lungs, bladder, bone marrow, and myo-cardium. At usual doses (10 mg/kg), attained levels are probably inadequate in the brain, testis, and eyes to treat most infections; higher dosages are required. Ketoconazole is 84-99% bound to plasma proteins and crosses the placenta (at least in rats). The drug is found in bitch's milk. Ketoconazole is metabolized extensively by the liver into several inactive metabolites. These metabolites are excreted primarily into the feces via the bile. About 13% of a given dose is excreted into the urine and only 2-4% of the drug is excreted unchanged in the urine. Half-life in dogs is about 1-6 hours (avg. 2. 7 hours). Contraindications/Precautions/Warnings Ketoconazole is contraindicated in patients with known hypersen-sitivity to it. It should be used with caution in patients with hepatic disease or thrombocytopenia. Adverse Effects Gastrointestinal signs of anorexia, vomiting, and/or diarrhea are the most common adverse effects seen with ketoconazole therapy and are more prevalent in cats. Anorexia may be minimized by dividing the dose and/or giving it with meals. Appetite stimulants such as oxazepam or cyproheptadine may also be of beneﬁt in cats. Hepatic toxicity consisting of cholangiohepatitis and increased liver enzymes has been reported with ketoconazole, and may be ei-ther idiosyncratic in nature or a dose-related phenomenon. Cats may be more prone to developing hepatotoxicity than dogs. While liver enzymes should be monitored during therapy, an increase does not necessarily mandate dosage reduction or discontinuation un-less concomitant anorexia, vomiting, diarrhea, or abdominal pain is present. Thrombocytopenia has also been reported with ketocon-azole therapy, but is rarely encountered. A reversible lightening of haircoat may also occur in patients treated with ketoconazole. Ketoconazole has a transient dose-related suppressant effect on gonadal and adrenal steroid synthesis. Doses as low as 10 mg/kg depressed serum testosterone levels in dogs within 3-4 hours after dosing, but levels returned to normal within 10 hours. Doses of 30 mg/kg/day have been demonstrated to suppress serum cortisol lev-els in dogs with hyperadrenocorticism (see Dosages section). Dogs undergoing high dose antifungal therapy may need additional glu-cocorticoid support during periods of acute stress. Reproductive/Nursing Safety Ketoconazole is a known teratogen and embryotoxin in rats. There have been reports of mummiﬁed fetuses and stillbirths in dogs who have been treated. Ketoconazole should not be considered abso-lutely contraindicated in pregnant animals, however, as it is often used in potentially life-threatening infections. The beneﬁts of thera-py should be weighed against the potential risks. Ketoconazole may cause infertility in male dogs by decreasing testosterone synthesis. T estosterone production rebounds once the drug is discontinued. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In 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. ) Ketoconazole is excreted in milk; use with caution in nursing dams. Overdosage/Acute Toxicity No reports of acute toxicity associated with overdosage were lo-cated. The oral LD 50 in dogs after oral administration is >500 mg/ kg. Should an acute overdose occur, the manufacturer recommends employing supportive measures, including gastric lavage with so-dium bicarbonate. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ketoconazole and may be of signiﬁcance in veterinary patients: !TALCOHOL : Ethanol may interact with ketoconazole and produce a disulﬁram-like reaction (vomiting) !TANTACIDS : May reduce oral absorption of ketoconazole; adminis-ter ketoconazole at least 1 hour before or 2 hours after !TANTIDEPRESSANTS, TRICYCLIC (amitriptyline, clomipramine ): Keto-conazole may reduce metabolism and increase adverse effects !TBENZODIAZEPINES (midazolam, triazolam ): Ketoconazole may in-crease levels !TBUSPIRONE : Plasma concentrations may be elevated !TBUSULFAN : Ketoconazole may increase levels !TCALCIUM-CHANNEL BLOCKING AGENTS (amlodipine, verapamil ): Keto-conazole may increase levels !TCISAPRIDE : Ketoconazole may increase cisapride levels and pos-sibility for toxicity; use together contraindicated in humans !TCORTICOSTEROIDS : Ketoconazole may inhibit the metabolism of corticosteroids; potential for increased adverse effects !TCYCLOPHOSPHAMIDE : Ketoconazole may inhibit the metabolism of cyclophosphamide and its metabolites; potential for increased toxicity !TCYCLOSPORINE : Increased cyclosporine levels !TDIGOXIN : Ketoconazole may increase digoxin levels !TFENTANYL/ALFENTANIL : Ketoconazole may increase fentanyl or al-fentanil levels !TH2-BLOCKERS (ranitidine, famotidine, etc. ): Increased gastric p H may reduce ketoconazole absorption !THEPATOTOXIC DRUGS, OTHER : Because ketoconazole can cause he-patotoxicity, it should be used cautiously with other hepatotoxic agents !TISONIAZID : May affect ketoconazole levels and concomitant use not recommended in humans !TIVERMECTIN : Ketoconazole may increase risk for neurotoxicity !TMACROLIDE ANTIBIOTICS (erythromycin, clarithromycin ): May increase ketoconazole concentrations !TMITOTANE : Mitotane and ketoconazole are not recommended for use together to treat hyperadrenocorticism as the adrenolytic ef-fects of mitotane may be inhibited by ketoconazole's inhibition of cytochrome P450 enzymes !TPHENYTOIN : May decrease ketoconazole levels !TPROTON-PUMP INHIBITORS (omeprazole, etc. ): Increased gastric p H may reduce ketoconazole absorption	pppbs.pdf
KETOCONAZOLE 519 !TQUINIDINE : Ketoconazole may increase quinidine levels !TRIFAMPIN : May decrease ketoconazole levels; ketoconazole may increase rifampin levels !TSUCRALFATE : May reduce absorption of ketoconazole !TSULFONYLUREA ANTIDIABETIC AGENTS (e. g., glipizide, glyburide ): Ke-toconazole may increase levels; hypoglycemia possible !TTHEOPHYLLINE : Ketoconazole may decrease serum theophylline concentrations in some patients; theophylline levels should be monitored !TVINCRISTINE/VINBLASTINE : Ketoconazole may inhibit vinca alka-loid metabolism and increase levels !TWARFARIN : Ketoconazole may cause increased prothrombin times in patients receiving warfarin or other coumarin anticoagulants Doses Note : Clinical antifungal effects may require 10-14 days of therapy !TDOGS: For coccidioidomycosis: a) For the systemic form of the disease: 5-10 mg/kg PO twice daily; For the CNS form: 15-20 mg/kg PO twice daily. Treat-ment should persist for a minimum of 3-6 months. Animals with bony lesions or relapses after discontinuing therapy, give lifelong therapy at 5 mg/kg PO every other day. (Macy 1988) b) 10-30 mg/kg PO divided twice a day, most animals need to be treated for 6-12 months (Taboada 2000) For blastomycosis: a) 10 mg/kg PO twice daily (15-20 mg/kg PO twice daily if CNS involvement) for at least 3 months with amphotericin B: initially at 0. 25-0. 5 mg/kg every other day IV. If toler-ated, increase dose to 1 mg/kg until 4-5 mg/kg total dose is administered. See amphotericin B monograph for more information. (Macy 1988) b) Ketoconazole 20 mg/kg/day PO once daily or divided twice daily; 40 mg/kg divided twice daily for ocular or CNS in-volvement (for at least 2-3 months or until remission then start maintenance) with amphotericin B 0. 15-0. 5 mg/kg IV 3 times a week. When a total dose of amphotericin B reaches 4-6 mg/kg, start maintenance dosage of amphotericin B at 0. 15-0. 25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or keto-conazole at 2. 5-5 mg/kg PO once daily. If CNS/ocular in-volvement, use ketoconazole at 20-40 mg/kg PO divided twice daily (Greene, O'Neal, and Barsanti 1984) For histoplasmosis: a) 10 mg/kg PO once a day or twice a day for at least 3 months. Treat at least 30 days after complete resolution of clinical dis-ease. If patient relapses, retreat as above then put on main-tenance 5 mg/kg PO every other day indeﬁnitely. For acute cases: use with amphotericin B (see blastomycosis recom-mendation by same author above) (Macy 1988) b) Ketoconazole 10-20 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance) with amphotericin B at 0. 15-0. 5 mg/kg IV 3 times a week. When a total dose of amphotericin B reaches 2-4 mg/kg start maintenance dosage of amphotericin B at 0. 15-0. 25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2. 5-5 mg/kg PO once daily (Greene, O'Neal, and Barsanti 1984) For aspergillosis: a) 20 mg/kg PO for at least 6 weeks; may require long-term/ maintenance therapy (Macy 1988) b) For nasal aspergillosis: 10 mg/kg PO once daily (q24h) or 5 mg/kg PO q12h. Treatment requires many weeks and should continue for 1 month beyond last detection of infection. Itraconazole somewhat more effective. (Greene, Hartmannn et al. 2006) For cryptococcosis: a) Amphotericin B 0. 15-0. 4 mg/kg IV 3 times a week with ﬂu-cytosine 150-175 mg/kg PO divided three to four times a day. When a total dose of amphotericin B reaches 4-6 mg/ kg start maintenance dosage of amphotericin B at 0. 15-0. 25 mg/kg IV once a month with ﬂucytosine at dosage above or with ketoconazole at 10 mg/kg PO once daily or divided twice daily (Greene, O'Neal, and Barsanti 1984) For fungal myocarditis: a) 10 mg/kg PO three times daily (Ogburn 1988) For Candidiasis: a) 10 mg/kg PO once daily (q24h) or 5 mg/kg PO q12h. Treat-ment requires many weeks and should continue for 1 month beyond last detection of infection. Itraconazole somewhat more effective. (Greene, Hartmannn et al. 2006) For Sporotrichosis: a) 15 mg/kg PO q12h. Treatment requires many weeks and should continue for 1 month beyond last detection of infec-tion. (Greene, Hartmannn et al. 2006) For Malassezia dermatitis: a) 5-10 mg/kg PO twice a day for 30 days. Often used with therapeutic shampoos containing selenium disulﬁde, micon-azole, ketoconazole or chlorhexidine. Underlying conditions must be identiﬁed and remedied or condition will recur. (Noxon 1997) b) 5-10 mg/kg PO daily for 10 days, then every other day for an additional 10 days. This regimen resolves the majority of cases, but some may need higher dosages. (Muse 2000) c) Initial dose is 5 mg/kg twice daily for 21-30 days, may in-crease to 10 mg/kg PO twice daily if poor response. Absorp-tion is enhanced when administered with food and is ideal in an acid environment. (Mc Donald 1999) d) 2. 5-10 mg/kg PO once daily (q24h) for 7-14 days; once a good response is seen taper to every other day (q48h) and continue until a complete remission occurs. In the rare case when ketoconazole is ineffective or intolerance or toxicity is seen, itraconazole or ﬂuconazole can be used. (Rosenkrantz 2006a) For treatment of hyperadrenocorticism: a) 5 mg/kg PO twice a day for 7 days. If no problems with appe-tite or icterus, increase dose to 10 mg/kg PO twice a day. Re-peat ACTH response test in 14 days (animal stays on drug). If not satisfactorily controlled, increase to 15 mg/kg twice a day. Goal is pre-and post-ACTH plasma cortisol levels of less than 5 mcg/kg. (Feldman 2000) b) Begin with a dose of 5 mg/kg q12h for 5-7 days and if there are no side effects (usually GI-related), increase dose to 10 mg/kg q12h for 10-14 days and perform ACTH stimulation test. Plasma cortisol levels should be between 0. 7-1. 8 mcg/ dl if ketoconazole is to be effective. Over 25% of cases do not respond to ketoconazole and many cases that do respond, require doses of between 15-20 mg/kg q12h. Because of un-predictable efﬁcacy, high occurrence of adverse effects, twice daily dosing, and expense, ketoconazole usage for PDH has been limited. (Church 2004) c) For palliative treatment of canine Cushing's syndrome: 15 mg/kg PO q12h (Lorenz and Melendez 2002b)	pppbs.pdf
520 KETOCONAZOLE T o reduce the dosage requirements of cyclosporine: a) Ketoconazole at 5-10 mg/kg PO per day can be adminis-tered concurrently with cyclosporine; in these patients the cyclosporine dose can be reduced (approximately half) or possibly tapered sooner than in patients not receiving the combination. Addition of ketoconazole is particularly useful in allergic patients with concurrent Malassezia dermatitis or otitis. (Hnilica 2006) b) T o treat perianal ﬁstula: ketoconazole 7. 5 mg/kg PO twice daily; cyclosporine 0. 5-0. 75 mg PO twice daily. (O'Neill, Ed-wards et al. 2001) c) For atopic dermatitis: Cyclosporine at 5-7 mg/kg/day or less. Ideally should be given on an empty stomach, but if causes GI upset administration with food may help. In large dogs, administration of cyclosporine at 2. 5 mg/kg/day with keto-conazole (5 mg/kg/day) may give good results and reduce expenses. (White 2007) d) As an alternative immunosuppressive agent for refrac-tory IMHA, especially those that are non-regenerative: Cy-closporine at 5-10 mg/kg PO divided twice daily to achieve plasma trough levels of >200 ng/m L ( Note: reference states >200 mg/m L, but it is believed this is a typo). Large breed dogs can be dosed concurrently with ketoconazole (10 mg/ kg/day) to allow reduction of cyclosporine dose. (Macintire 2006d) !TCATS: Note : Use of ketoconazole in cats is somewhat controversial and some clinicians recommend that it not be used in this species because of its toxic potential. Consider using itraconazole in its place. a) For coccidioidomycosis: 10-30 mg/kg PO divided twice a day, most animals need to be treated for 6-12 months (Ta-boada 2000) b) For coccidioidomycosis: 50 mg per cat PO once daily; or 25-75 mg per cat q12-48h. Treatment requires many months (9-12 on average) and should continue for 1 month beyond last detection of infection. (Greene, Hartmannn et al. 2006) c) For blastomycosis: 10 mg/kg q12h PO (for at least 60 days) with amphotericin B: 0. 25 mg/kg in 30 m L D 5W IV over 15 minutes q48h. Continue amphotericin B therapy until a cu-mulative dose of 4 mg/kg is given or until BUN >50 mg/dl. If renal toxicity does not develop, may increase dose to 0. 5 mg/ kg of amphotericin B. (Legendre 1989) d) For cryptococcosis: 10 mg/kg twice daily. Very useful for this condition in cats, but at this dosage can produce anorexia and debility. (Legendre 1995) e) For aspergillosis: 10 mg/kg PO q12h (Legendre 1989) f) For dermatophytosis: Usually reserved for when griseofulvin ineffective or not tolerated. 10 mg/kg PO once daily with an acidic meal. Prolonged course of therapy required. Begin tak-ing cultures after 4 weeks of treatment. Continue therapy for 2 weeks beyond clinical cure andwhen 2-3 negative cultures are obtained at weekly intervals. (Frank 2000) g) For Sporotrichosis: 5-10 mg/kg PO q12-24h. Treatment requires many weeks (2-4 months on average) and should continue for 1 month beyond last detection of infection. (Greene, Hartmannn et al. 2006) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: 10-40 mg/kg per day PO for 14 days (Ivey and Mor-risey 2000) b) Hamsters, Gerbils, Mice, Rats, Guinea pigs, Chinchillas: For systemic mycoses/candidiasis: 10-40 mg/kg per day PO for 14 days (Adamcak and Otten 2000) !TBIRDS: For susceptible fungal infections: a) For severe refractory candidiasis in Psittacines: 5-10 mg/kg as a gavage twice daily for 14 days. For local effect in crop dissolve G tablet (50 mg) in 0. 2 m L of 1 N hydrochloric acid and add 0. 8 m L of water. Solution turns pale pink when dis-solved. Add mixture to food for gavage. T o add to water for most species: 200 mg/L for 7-14 days. As drug is not water soluble at neutral p H, dissolve in acid prior to adding to water (see above). T o add to feed for most species: 10-20 mg/kg for 7-14 days. Add to favorite food or add to mash. (Clubb 1986) b) 20-30 mg/kg PO twice daily (based on the kinetics deter-mined in a single trial of Moluccan Cockatoos) (Flammer 2003a) c) Ratites: 5-10 mg/kg PO once daily (Jenson 1998) !TREPTILES: a) For susceptible infections: For most species: 15-30 mg/kg PO once daily for 2-4 weeks (Gauvin 1993) b) For fungal shell diseases in turtles/tortoises: 25 mg/kg PO once a day for 2-4 weeks (Rosskopf 1986) Monitoring !TLiver enzymes with chronic therapy (at least every 2 months; some clinicians say monthly) !TCBC with platelets !TEfﬁcacy and other adverse effects Client Information !TIf animal develops gastrointestinal signs divide dose and admin-ister with meals. !TLong-term therapy with adequate dosing compliance is usually necessary for successful results !TClients must be committed for both the ﬁnancial and dosing burdens associated with therapy. Chemistry/Synonyms An imidazole antifungal agent, ketoconazole occurs as a white to slightly beige powder with p K as of 2. 9 and 6. 5. It is practically in-soluble in water. Ketoconazole may also be known as ketoconazolum, and R-41400; many trade names are available. Storage/Stability Ketoconazole tablets should be stored at room temperature in well-closed containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Ketoconazole Tablets: 200 mg (scored); Nizoral® (Janssen); generic; (Rx) T opical forms are also available.	pppbs.pdf
KETOPROFEN 521 KETOPROFEN (kee-toe-proe-fen) Ketofen® NON-STEROIDAL A NTIINFLA MMATORY AGENT Prescriber Highlights TT Nonsteroidal antiinﬂammatory agent used in horses, cats (short-term) & dogs TT Contraindications: Hypersensitivity to ketoprofen TT Cautions: GI ulceration or bleeding, hypoproteinemia, breeding animals (especially late in pregnancy), signiﬁ-cant renal or hepatic impairment; may mask the signs of infection (inﬂammation, hyperpyrexia) TT Adverse Effects: Horses: Potentially, gastric mucosal damage & GI ulceration, renal crest necrosis, & mild hep-atitis may occur. Dogs: Vomiting, anorexia, & GI ulcers TT Do not administer intra-arterially & avoid SC injections TT Drug-drug; drug-lab interactions Uses/Indications Ketoprofen is labeled for use in horses for the alleviation of inﬂam-mation and pain associated with musculoskeletal disorders. Like ﬂunixin (and other NSAIDs), ketoprofen potentially has many oth-er uses in a variety of species and conditions. There are approved dosage forms for dogs and cats in Europe and Canada. Some con-sider ketoprofen to be the NSAID of choice for use short-term for analgesia in cats. Pharmacology/Actions Ketoprofen exhibits actions similar to that of other nonsteroidal antiinﬂammatory agents in that it possesses antipyretic, analgesic and antiinﬂammatory activity. Its purported mechanism of action is the inhibition of cyclooxygenase catalysis of arachidonic acid to prostaglandin precursors (endoperoxides), thereby inhibiting the synthesis of prostaglandins in tissues. Ketoprofen purportedly has inhibitory activity on lipoxygenase, whereas ﬂunixin reportedly does not at therapeutic doses. In vitro studies have not conﬁrmed lipoxygenase activity in studied species. The S (+) enantiomer is associated with anti-prostaglandin activity and toxicity and the R (-) form analgesia without the GI effects. Pharmacokinetics In species studied (rats, dog, man), ketoprofen is rapidly and nearly completely absorbed after oral administration. The presence of food or milk decreases oral absorption. Oral absorption character-istics in horses were not located. It has been reported that when comparing IV vs. IM injections in horses, the areas under the curve are relatively equivalent. While distribution characteristics are not well described, the drug does enter synovial ﬂuid and is highly bound to plasma pro-teins (99% in humans, and approximately 93% in horses). In hors-es, the manufacturer reports that the onset of activity is within 2 hours and peak effects 12 hours post dose. Ketoprofen is eliminated via the kidneys both as a conjugated metabolite and unchanged drug. The elimination half-life in horses is approximately 1. 5 hours. Contraindications/Precautions/Warnings While the manufacturer states that there are no contraindications to the drug's use (other than previous hypersensitivity to ketopro-fen), it should be used only when the potential beneﬁts outweigh the risks in cases where GI ulceration or bleeding is evident or in patients with signiﬁcant renal or hepatic impairment. Ketoprofen may mask the clinical signs of infection (inﬂammation, hyperpy-rexia). Because ketoprofen is highly protein bound, patients with hypoproteinemia may have increased levels of free drug, thereby increasing the risks for toxicity. Adverse Effects Because ketoprofen is a relatively new agent, its adverse effect pro-ﬁle in horses has not been clearly elucidated. Preliminary studies and reports indicate that ketoprofen appears relatively safe to use in horses and may have a lower incidence of adverse effects than ei-ther phenylbutazone or ﬂunixin. Potentially, gastric mucosal dam-age and GI ulceration, renal crest necrosis, and mild hepatitis may occur. Do not administer intra-arterially and avoid SC injections. While not labeled for IM use in horses, it reportedly is effective and may only cause occasional inﬂammation at the injection site. In dogs or cats, ketoprofen may cause vomiting, anorexia, and GI ulcers. Reproductive/Nursing Safety The manufacturer cautions against ketoprofen's use in breeding an-imals because effects on fertility, pregnancy, or fetal health have not been established in horses. However, rat and mice studies have not demonstrated increased teratogenicity or embryotoxicity. Rabbits receiving twice the human dose exhibited increased embryotoxic-ity, but not teratogenicity. Because non-steroidal antiinﬂammatory agents inhibit prostaglandin synthesis, adversely affecting neonatal cardiovascular systems (premature closure of patent ductus), keto-profen should not be used late in pregnancy. Studies in male rats demonstrated no changes in fertility. In humans, the FDA catego-rizes this drug as category B for use during the ﬁrst two trimesters of pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) It is presently unknown whether ketoprofen enters equine milk. Ketoprofen does enter canine milk; use with caution. Overdosage/Acute Toxicity Horses given ketoprofen at doses up to 11 mg/kg administered IV once daily for 15 days exhibited no signs of toxicity. Severe laminitis was observed in a horse given 33 mg/kg/day (15X over labeled dos-age) for 5 days. Anorexia, depression, icterus, and abdominal swell-ing were noted in horses given 55 mg/kg/day (25X labeled dose) for 5 days. Upon necropsy, gastritis, nephritis, and hepatitis were diagnosed in this group. There were 24 exposures to ketoprofen reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org ) dur-ing 2005-2006. In these cases 9 were dogs with 1 showing clinical signs and the remaining 15 cases were cats that showed no clinical signs. Common ﬁndings in dogs include vomiting. Humans have survived oral ingestions of up to 5 grams. The LD50 in dogs after oral ingestion has been reported to be 2000 mg/ kg. 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	pppbs.pdf
522 KETOPROFEN is warranted. If renal effects are also expected, ﬂuid diuresis is warranted. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ketoprofen and may be of signiﬁcance in veterinary patients: !TAMINOGLYCOSIDES (gentamicin, amikacin, etc. ): Increased risk for nephrotoxicity !TANTICOAGULANTS (heparin, LMWH, warfarin ): Increased risk for bleeding possible !TASPIRIN : When aspirin is used concurrently with ketoprofen, plasma levels of ketoprofen could decrease and an increased likelihood of GI adverse effects (blood loss) could occur. Con-comitant administration of aspirin with ketoprofen cannot be recommended. !TBISPHOSPHONATES (alendronate, etc. ): May increase risk for GI ulceration !TCORTICOSTEROIDS : Concomitant administration with NSAIDs may signiﬁcantly increase the risks for GI adverse effects !TCYCLOSPORINE : May increase risk for nephrotoxicity !TFLUCONAZOLE : May increase NSAID levels !TFUROSEMIDE : Ketoprofen may reduce the saluretic and diuretic ef-fects of furosemide !THIGHLY PROTEIN BOUND D RUGS (e. g., phenytoin, valproic acid, oral anti-coagulants, other antiinﬂammatory agents, salicylates, sulfonamides, and the sulfonylurea antidiabetic agents ): Because ketoprofen is highly bound to plasma proteins (99%), it potentially could dis-place other highly bound drugs; increased serum levels and dura-tion of actions may occur. Although these interactions are usually of little concern clinically, use together with caution. !TMETHOTREXATE : Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate; use together with extreme caution. !TPROBENECID : May cause a signiﬁcant increase in serum levels and half-life of ketoprofen Laboratory Considerations Ketoprofen may cause: !TFalsely elevated blood glucose values when using the glucose oxi-dase and peroxidase method using ABTS as a chromogen; !TFalsely elevated serum bilirubin values when using DMSO as a re-agent; !TFalsely elevated serum iron concentrations using the Ramsey method, or falsely decreased serum iron concentrations when using bathophenanthroline disulfonate as a reagent Doses !TDOGS: As an antiinﬂammatory/analgesic: a) 2 mg/kg IV one time (Hardie 2000) b) For osteoarthritis unresponsive to aspirin: 0. 5-1 mg/kg PO twice daily with food; decrease the dose by 50% when giving to geriatric patients (Trepanier 1999) c) For post-operative pain control: 1-2 mg/kg IV, IM once dai-ly for 2-3 days duration (Tranquilli 2003) d) For post-operative pain control: 1-2 mg/kg IV, SC once daily for 3 days duration after surgery; or 1 mg/kg PO once daily for 5 days, after surgery (Hansen 2003b) e) For acute indications: 2 mg/kg SC, IM, IV once daily for up to 3 consecutive day. If preferred after one injection treat-ment may be followed on the next day with tablets at 1 mg/ kg PO per day and continued on successive days for up to 4 days (i. e., up to 5 days in total). For chronic pain: 0. 25 mg/kg PO once daily for up to 30 days. (Label Information Ketofen 1%; Ketofen ® Tablets—Merial U. K. ) !TCATS: As an antiinﬂammatory/analgesic: a) 2 mg/kg IV one time (Hardie 2000) b) For mild to moderate pain: 1-2 mg/kg SC, IM initially, then 0. 5-1 mg PO, SC once daily; not recommended to treat more than 5 days (Nieves 2002) c) For post-operative pain control: 1-2 mg/kg IV, SC once daily for 3 days duration after surgery; or 1 mg/kg PO once daily for 3 days, after surgery (Hansen 2003b) d) 2 mg/kg SC once daily for up to 3 consecutive days. If pre-ferred after one injection treatment may be followed on the next day with tablets at 1 mg/kg and continued on successive days for up to 4 days (i. e., up to 5 days in total). (Label Infor-mation Ketofen 1%; Ketofen ® Tablets—Merial U. K. ) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: For chronic pain/antiinﬂammatory: 1 mg/kg IM q12-24h (Ivey and Morrisey 2000) b) Rats: 5 mg/kg SC (Adamcak and Otten 2000) !THORSES: (Note : ARCI UCGFS Class 4 Drug) a) For labeled indications: 2. 2 mg/kg (1 m L/100 lbs) IV once daily for up to 5 days (Package insert; Ketofen ®) b) As an adjunctive treatment for laminitis: 2. 2 mg/kg IV once daily (Brumbaugh, Lopez et al. 1999) !TCATTLE: a) 3 mg/kg IV or deep IM once daily for up to 3 days; withdraw-al times (U. K. ) are meat: 4 days; milk: 0 days (Label informa-tion Comforion Vet®—Merial U. K. ) b) 3. 3 mg/kg; duration of effect 24 hours; appropriate withdraw-al times: 24 hour for milk; 7 days for meat. (Walz 2006b) !TSWINE: a) 3 mg/kg IM once daily for up to 3 days; withdrawal times (U. K. ) for meat: 4 days (Label information Comforion Vet®— Merial U. K. ) !TBIRDS: a) As an antiinﬂammatory analgesic 2 mg/kg IM q8-24 hours (Clyde and Paul-Murphy 2000) Monitoring !TEfﬁcacy !TAdverse Effects (occasional liver or renal function tests are rec-ommended with long-term therapy) Chemistry/Synonyms A propionic acid derivative nonsteroidal antiinﬂammatory agent (NSAID), ketoprofen occurs as an off-white to white, ﬁne to granu-lar powder. It is practically insoluble in water, but freely soluble in alcohol at 20°C. Ketoprofen has a p K a of 5. 9 in a 3:1 methanol:water solution. Ketoprofen has both an S enantiomer and R enantiomer. The commercial product contains a racemic mixture of both. The S (+) enantiomer has greater antiinﬂammatory potency than the R (-) form. Ketoprofen may also be known as ketoprofenum and RP-19583; many trade names are available. Storage/Stability/Compatibility Ketoprofen oral capsules should be stored at room temperature in tight, light resistant containers. The veterinary injection should be stored at room temperature. Compatibility studies with inject-	pppbs.pdf
KETOROLAC TROMETHAMINE 523 able ketoprofen and other compounds have apparently not been published. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Ketoprofen Injection: 100 mg/m L in 50 m L and 100 m L multi-dose vials; Ketofen ® (Fort Dodge), generic (Phoenix Pharmaceutical), (Rx). Approved for use in horses not intended for food. In Canada and the U. K., there are approved oral dosage forms (5, 10, 20 mg tablets) and an injectable form (10 mg/m L) for use in dogs and cats. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Ketoprofen Capsules: 50 mg & 75 mg; generic; (Rx) Ketoprofen Extended-Release Capsules: 100 mg, 150 mg and 200 mg; Keto profen (Andrx); (Rx) KETOROLAC TROMETHAMINE (kee-toe-role-ak) Toradol® NON-STEROIDAL A NTIINFLA MMATORY AGENT Prescriber Highlights TT NSAID used primarily for short-term analgesia TT Contraindications: Active GI ulcers or history of hypersen-sitivity to the drug TT Relatively contraindicated: Hematologic, renal, or hepatic disease TT Caution: History of gastric ulcers, heart failure TT Adverse Effects: GI ulcers & perforation, renal effects possible with chronic use; consider co-dosing with miso-prostol/sucralfate in dogs to reduce chances of ulcers Uses/Indications Ketorolac is used primarily for its analgesic effects for short-term treatment of mild to moderate pain in dogs and rodents. The dura-tion of analgesic effect in dogs is about 8-12 hours, but because of the availability of approved, safer NSAIDs for dogs, its use is ques-tionable. Pharmacology/Actions Like other NSAIDs, ketorolac exhibits analgesic, antiinﬂamma-tory, and antipyretic activity probably through its inhibition of cy-clooxygenase with resultant impediment of prostaglandin synthe-sis. Ketorolac may exhibit a more potent analgesic effect than some other NSAIDs. It inhibits both COX-1 and COX-2 receptors. Pharmacokinetics After oral administration, ketorolac is rapidly absorbed; in dogs peak levels occur in about 50 minutes and oral bioavailability is about 50-75%. Ketorolac is distributed marginally through the body. It does not appear to cross the blood-brain barrier and is highly bound to plasma proteins (99%). The volume of distribution in dogs is reported to be about 0. 33-0. 42 L/kg (similar in humans). The drug does cross the placenta. Ketorolac is primarily metabolized via glucuronidation and hy-droxylation. Both unchanged drug and metabolites are excreted mainly in the urine. Patients with diminished renal function will have longer elimination times than normal. In normal dogs, the elimination half-life is between 4-8 hours. Contraindications/Precautions/Warnings Ketorolac is relatively contraindicated in patients with a history of, or preexisting, hematologic, renal or hepatic disease. It is contrain-dicated in patients with active GI ulcers or with a history of hyper-sensitivity to the drug. It should be used cautiously in patients with a history of GI ulcers, or heart failure (may cause ﬂuid retention), and in geriatric patients. Animals suffering from inﬂammation sec-ondary to concomitant infection, should receive appropriate anti-microbial therapy. Because ketorolac has a tendency to cause gastric erosion and ulcers in dogs, long-term use (>3 days) is not recommended in this species. Adverse Effects Ketorolac use is limited in domestic animals because of its ad-verse effect proﬁle and a lack of veterinary-labeled products. The primary issue in dogs is its GI toxicity. GI ulceration can be com-mon if the drug is used chronically. Most clinicians who have used this medication in dogs limit treatment to less than 3 days and give misoprostol with or without sucralfate concurrently. Like other NSAIDS, platelet inhibition, renal, and hepatic toxicity are also pos-sible with this drug. Reproductive/Nursing Safety Ketorolac does cross the placenta. In humans, the FDA categorizes this drug as category C for use during the ﬁrst two trimesters of preg-nancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal re-production studies and no adequate studies in humans. ) In humans, all NSAIDs are assigned to category D for use during pregnancy during the third trimester or near delivery (There is evidence of hu-man fetal risk, but the potential beneﬁts from the use of the drug in pregnant women may be acceptable despite its potential risks. ) Most NSAIDs are excreted in milk. Ketorolac was detected in human breast milk at a maximum milk:plasma ratio of 0. 037. It is unlikely to pose great risk to nursing offspring. Overdosage/Acute Toxicity Limited information is available. The oral LD 50 is 200 mg/kg in mice. GI effects, including GI ulceration are likely in overdoses in small animals. Metabolic acidosis was reported in one human pa-tient. Consider GI emptying in large overdoses; patients should be monitored for GI bleeding. Treat ulcers with sucralfate; consider giving misoprostol early. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving ketorolac and may be of signiﬁcance in veterinary patients: T ! ACE INHIBITORS : Increased risk for nephrotoxicity T ! ALPRAZOLAM : Hallucinations reported in some human patients taking with ketorolac T ! AMINOGLYCOSIDES (gentamicin, amikacin, etc. ): Increased risk for nephrotoxicity T ! ANTICOAGULANTS (heparin, LMWH, warfarin ): Increased risk for bleeding possible T ! ASPIRIN : Increased likelihood of GI adverse effects (blood loss)	pppbs.pdf
524 LACTULOSE T ! BISPHOSPHONATES (alendronate, etc. ): May increase risk for GI ulceration T ! CORTICOSTEROIDS : Concomitant administration with NSAIDs may signiﬁcantly increase the risks for GI adverse effects T ! CYCLOSPORINE : May increase risk for nephrotoxicity T ! FLUCONAZOLE : May increase NSAID levels T ! FLUOXETINE : Hallucinations reported in some human patients taking with ketorolac T ! FUROSEMIDE : Ketorolac may reduce the saluretic and diuretic ef-fects of furosemide T ! METHOTREXATE : Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate; use together with extreme caution T ! MUSCLE RELAXANTS, NONDEPOLARIZING : Ketorolac may potentiate effects T ! PROBENECID : May cause a signiﬁcant increase in serum levels and half-life of ketorolac Doses T ! DOGS: a) As an analgesic: 0. 5 mg/kg IV three times daily or 0. 3 mg/kg PO twice daily. Repeated doses have considerable potential for causing GI or renal toxicity. Treated dogs should receive misoprostol. (Dowling 2000) b) As an analgesic: 0. 3-0. 5 mg/kg IV, IM q8-12h for one or two doses (Scherk 2003a) T ! CATS: a) As an analgesic: 0. 25 mg/kg IM q8-12h for one or two doses (Scherk 2003a) T ! GOATS: a) As an analgesic: 0. 3-0. 7 mg/kg IV, IM, SC, PO three times daily (Resources 2000) T ! RABBITS/RODENTS/SMALL MAMMALS: a) As an analgesic: Mice: 0. 7-10 mg/kg PO once daily. Rats: 3-5 mg/kg PO once to twice a day; 1 mg/kg IM once to twice a day (Huerkamp 2000) Monitoring T ! Analgesic/antiinﬂammatory efﬁcacy T ! GI: appetite, feces (occult blood, diarrhea) Client Information T ! Notify veterinarian if signs of GI distress (anorexia, vomiting, diarrhea, black feces, or blood in stool) occur, or if the animal becomes depressed. Chemistry/Synonyms A carboxylic acid derivative nonsteroidal antiinﬂammatory agent, ketorolac tromethamine occurs as an off-white crystalline powder with a p Ka of 3. 54 (in water). More than 500 mg are soluble in one m L of water at room temperature. The commercially available injection is a clear, slightly yellow solution with a p H of 6. 9-7. 9. Sodium chloride is added to make the solution isotonic. Ketorolac tromethamine may also be known as RS-37619-00-31-3; many trade names are available. Storage/Stability/Compatibility Both the tablets and injection should be stored at room temperature and protected from light. Protect the tablets from excessive humid-ity. It is recommended not to mix the injection with other drugs in the same syringe. The injection is stable for at least 48 hours in commonly used IV solutions. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Ketorolac Tromethamine Tablets: 10 mg; generic; (Rx) Ketorolac Tromethamine Injection: 15 mg/m L & 30 mg/m L in 1 m L, 2 m L vials, & 10 m L multiple-dose vials; generic; (Rx) A topical ophthalmic preparation is also available; see the ophthal-mology section in the appendix for further information. L-Asparaginase — see Asparaginase L-Thyroxine — see Levothyroxine Sodium Lactated Ringer's — see the appendix section on intrave-nous ﬂuids LACTULOSE (lak-tyoo-lose) Cephulac® DISACCHARIDE LAXATIVE/AMMONIA REDUCER Prescriber Highlights TT Disaccharide laxative & reducer of blood ammonia levels TT Adverse Effects: Flatulence, gastric distention, cramping, etc. ; diarrhea & dehydration are signs of overdosage TT Cats dislike the taste of lactulose & administration may be difﬁcult TT May alter insulin requirements in diabetics Uses/Indications The primary use of lactulose in veterinary medicine is to reduce ammonia blood levels in the prevention and treatment of hepatic encephalopathy (portal-systemic encephalopathy; PSE) in small animals and pet birds. It is also used as a laxative in small animals. Pharmacology/Actions Lactulose is a disaccharide (galactose/fructose) that is not hydro-lyzable by mammalian and, probably, avian gut enzymes. Upon reaching the colon, lactulose is metabolized by the resident bacte-ria resulting in the formation of low molecular weight acids (lac-tic, formic, acetic) and CO2. These acids have a dual effect; they increase osmotic pressure drawing water into the bowel causing a laxative effect and also acidify colonic contents. The acidiﬁcation causes ammonia NH 3 (ammonia) to migrate from the blood into the colon where it is trapped as [NH4]+ (ammonium ion) and ex-pelled with the feces. Pharmacokinetics In humans, less than 3% of an oral dose of lactulose in absorbed (in the small intestine). The absorbed drug is not metabolized and excreted unchanged in the urine within 24 hours. Contraindications/Precautions/Warnings Lactulose syrup contains some free lactose and galactose, and may alter the insulin requirements in diabetic patients. In patients with preexisting ﬂuid and electrolyte imbalances, lactulose may exacer-bate these conditions if it causes diarrhea; use cautiously.	pppbs.pdf
LACTULOSE 525 Adverse Effects Signs of ﬂatulence, gastric distention, cramping, etc. are not uncom-mon early in therapy, but generally abate with time. Diarrhea and dehydration are signs of overdosage; dosage should be reduced. Cats dislike the taste of lactulose and administration may be difﬁcult. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) It is not known whether lactulose is excreted in milk, but it would be unexpected. Overdosage/Acute Toxicity Excessive doses may cause ﬂatulence, diarrhea, cramping, and de-hydration. Replace ﬂuids and electrolytes if necessary. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving lactulose and may be of signiﬁcance in veterinary patients: !TANTACIDS, ORAL : Antacids (non-adsorbable) may reduce the co-lonic acidiﬁcation effects (efﬁcacy) of lactulose !TLAXATIVES, OTHER : Do not use lactulose with other laxatives as the loose stools that are formed can be falsely attributed to the lactulose with resultant inadequate therapy for hepatic enceph-alopathy !TNEOMYCIN : Theoretically, orally administered antibiotics (e. g., neomycin) could eliminate the bacteria responsible for metabo-lizing lactulose, thereby reducing its efﬁcacy. However, some data suggests that synergy may occur when lactulose is used with an oral antibiotic (e. g., neomycin) for the treatment of hepatic en-cephalopathy; enhanced monitoring of lactulose efﬁcacy is prob-ably warranted in cases where an oral antibiotic is added to the therapy Doses !TDOGS: For hepatic encephalopathy: a) 15-30 m L PO four times a day; adjust the dosage to produce 2-3 soft stools per day (Cornelius and Bjorling 1988) b) Give 5 m L per 2. 5 lbs. of body weight divided three times a day, may increase as necessary to achieve 2-3 soft stools per day. If patient is in hepatic encephalopathy crisis, may give 20-60 m L via stomach tube every 4-6 hours or may give as an intermittent enema (diluted with water) to total 200-300 m L (300-450 grams). (Tams 2000) c) 5-15 m L PO three times daily; adjust dose to induce 2-3 soft stools per day; reduce dosage if diarrhea develops. In cer-tain cases, neomycin with lactulose may be superior to either drug alone. (Hardy 1985) d) 1-10 m L PO three times daily; adjust dose to give 3-4 soft stools per day; reduce dose if diarrhea develops. May also give via enema in treating severe hepatic encephalopathy. (Twedt 2005a) For constipation: a) 1 m L per 4. 5 kg of body weight PO q8h initially, then adjust as needed (Kirk 1986) !TCATS: For hepatic encephalopathy: a) 0. 25-1 m L PO; individualize dosage until semi-formed stools are produced (Center, Hornbuckle, and Scavelli 1986) For constipation: a) 1 m L per 4. 5 kg of body weight PO q8h initially, then adjust as needed (Kirk 1986) b) 0. 5 m L/kg q8-12h PO (Sherding 1989); (Washabau and Holt 2000) !TBIRDS: For hepatic encephalopathy; to stimulate appetite, improve in-testinal ﬂora: a) Cockatiel: 0. 03 m L PO two to three times a day; Amazon: 0. 1 m L PO two to three times a day. Reduce dosage if diarrhea develops. May be used for weeks. (Clubb 1986) !TREPTILES: As a laxative : a) Green Iguana: 0. 3 m L/kg PO q12h (Wilson 2002a) Monitoring !TClinical efﬁcacy (2-3 soft stools per day) when used for PSE !TIn long-term use (months) or in patients with preexisting ﬂuid/ electrolyte problems, serum electrolytes should be monitored. Client Information !TContact veterinarian if diarrhea develops. !TWhen lactulose is used for hepatic encephalopathy, contact veter-inarian if signs worsen or less than 2-3 soft stools are produced per day. Chemistry/Synonyms A synthetic derivative of lactose, lactulose is a disaccharide contain-ing one molecule of galactose and one molecule of fructose. It oc-curs as a white powder that is very slightly soluble in alcohol and very soluble in water. The commercially available solutions are vis-cous, sweet liquids with an adjusted p H of 3-7. Lactulose may also be known as lactulosum; many trade names are available. Storage/Stability Lactulose syrup should be stored in tight containers, preferably at room temperature; avoid freezing. If exposed to heat or light, dark-ening or cloudiness of the solution may occur, but apparently this does not affect drug potency. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Lactulose Solution: 10 g lactulose per 15 m L (<1. 6 g galactose, <1. 2 g lactose and < or = to 1. 2 g of other sugars) in 30 m L, 237 m L, 240 m L, 473 m L, 480 m L, 946 m L, 960 m L, 1893 m L, 1920 m L and 3785 m L, 1. 89 L and 1. 9 L, and UD 30 m L; Cephulac® (Hoechst-Marion Roussel); Cholac® (Alra); Constulose® and Enulose® (Alpharma); ge-neric; (Rx) Lactulose Crystals for Reconstitution: Lactulose (<0. 3 g galactose and lactose/10 g) in 10 g and 20 g; Kristalose® (Bertek); (Rx)	pppbs.pdf
526 LEFLUNOMIDE T TLEFLUNOMIDE (le-ﬂoo-noh-myde) Arava IMMUNOMODULATING AGENT Prescriber Highlights TT Immunomodulating drug that may be useful in dogs for treating a variety of immune-mediated conditions such as IMHA, systemic & cutaneous reactive histiocytosis, granulomatous meningoencephalitis, etc. ; can be used as part of transplant rejection protocols in dogs. Has been used with methotrexate to treat rheumatoid arthri-tis in cats. TT Appears well-tolerated in dogs, but number treated is low TT Teratogenic (Category X) TT Active metabolite can persist in body for years TT Treatment can be very expensive Uses/Indications Leﬂunomide is an immunomodulating drug that may be useful in dogs for treating a variety of immune-related conditions such as IMHA, systemic and cutaneous reactive histiocytosis, granuloma-tous meningoencephalitis, etc; it can be used as part of transplant rejection protocols in dogs. Leﬂunomide has been used with methotrexate to treat rheuma-toid arthritis in cats. Pharmacology/Actions Leﬂunomide inhibits autoimmune T-cell proliferation and autoan-tibody production by B cells. Leﬂunomide acts almost exclusively via its active metabolite A77 1726 (M1). This metabolite reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase thereby preventing the formation of ribonucleotide uridine mono-phosphate (r UMP). This causes decreased DNA and RNA synthe-sis, inhibition of cell proliferation, and G1 cell cycle arrest. Pharmacokinetics Information on the pharmacokinetics of leﬂunomide in dogs and cats was not located. In humans, leﬂunomide is rapidly converted to A77 1726 (active metabolite; M1) in the GI mucosa and liver. Peak levels of A77 1726 occur between 6-12 hours after an oral dose. The presence of food in the gut does not appear to affect oral bioavailability. A77 1726 Is highly bound to albumin >99%). A77 1726 is further degraded in the liver as glucuronides and an oxalinic acid compound which are excreted in the urine and bile. Half life is about 15 days, but the drug (A77 1726) can be detectable in patients up to 2 years after it is discontinued. Contraindications/Precautions/Warnings Leﬂunomide is contraindicated during pregnancy and in patients hypersensitive to it. It should be used with extreme caution in pa-tients with immunodeﬁciency. Adverse Effects Leﬂunomide appears to be well tolerated by dogs. Adverse effects reported include vomiting, lymphopenia, and anemia. In humans, gastrointestinal effects (diarrhea, nausea), alopecia and rash are most commonly reported. Serious adverse effects that have been reported include hematologic toxicity, dermatologic ef-fects (TEN, Stevens-Johnson, etc. ), and hepatotoxicity. Reproductive/Nursing Safety Leﬂunomide should not be used during pregnancy. A variety of teratogenic effects in laboratory animals have been detailed at doses used clinically. In humans, the FDA categorizes this drug as cat-egory X for use during pregnancy (Studies in animals or humans demonstrate fetal abnormalities or adverse reaction; reports indicate evidence of fetal risk. The risk of use in pregnant women clearly out-weighs any possible beneﬁt. ) It is not known whether leﬂunomide is excreted in milk; it is suggested to use milk replacer if the dam is receiving the drug. Overdosage/Acute Toxicity Acute toxicologic studies in mice and rats have demonstrated that the minimally toxic dose is 200 mg/kg and 100 mg/kg, respectively. Cholestyramine or activated charcoal are recommended to acceler-ate elimination. 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 leﬂunomide and may be of signiﬁcance in veterinary patients: T ! CHARCOAL, ACTIVATED : Can increase elimination and decrease A77 1726 drug concentrations; may be used when more rapid elimi-nation is desirable T ! CHOLESTYRAMINE : Can increase elimination and decrease A77 1726 drug concentrations; may be used when more rapid elimi-nation is desirable T ! HEPATOTOXIC AGENTS, OTHER : Increased risk for toxicity T ! METHOTREXATE : Increased adverse effects and ALT possible T ! PHENYTOIN : Leﬂunomide can increase phenytoin levels T ! RIFAMPIN : Can increase A77 1726 peak levels T ! VACCINES, LIVE VIRUS : Live virus vaccines should be used with cau-tion, if at all, during leﬂunomide therapy T ! WARFARIN : Leﬂunomide may increase INR Doses T ! DOGS: a) As an immunosuppressive as part of a protocol (with cy-closporine) following organ transplant: Leﬂunomide 4-6 mg/kg PO q24h and then to maintain trough plasma levels of 20 mcg/m L. (Sykes 2007) b) As an adjunctive immunosuppressive for immune-mediated hemolytic anemia: 4 mg/kg PO q24h. (Chabanne 2006) c) For treatment of systemic and cutaneous reactive histiocy-tosis: 2-4 mg/kg PO once daily to attain trough levels of 20 mcg/m L. (Foil 2003a) T ! CATS: a) For rheumatoid arthritis: Initially, leﬂunomide at 10 mg (to-tal dose) PO once daily and methotrexate at 2. 5 mg (total dose) PO three times on one day per week. When signiﬁcant improvement occurs, reduce doses of leﬂunomide to 10 mg PO twice weekly and methotrexate to 2. 5 mg PO once week-ly. (Bennett 2005) Monitoring T ! Adverse effects (CBC, liver enzymes) T ! rough levels (20 mcg/m L is target) Client Information T ! Relatively experimental when used in veterinary patients; contact veterinarian if any unusual effects are noted T ! reatment can be very expensive	pppbs.pdf
LEUCOVORIN CALCIUM 527 Chemistry/Synonyms Leﬂunomide has a molecular weight of 270. 207 g/mol and a melt-ing point of 165-166°C. It is poorly soluble in water (21 mg/L). Leﬂunomide may also be known as HWA 486, RS 34821, or SU 101; a common trade name is Arava ®. Storage/Stability Leﬂunomide tablets should be stored at room temperature (15-30°C) and protected from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Leﬂunomide Tablets: 10 mg & 20 mg: Arava ® (Hoechst Marion Rous-sel); generic; (Rx) LEUCOVORIN CALCIUM (loo-koe-vor-in) Folinic Acid, Citrovorum Factor ORAL OR INJECTA BLE FOLIC ACID DERIV ATIVE Prescriber Highlights TT Primarily used in veterinary medicine to help reverse neurotoxicity or hematologic toxicity associated with dihydrofolate reductase inhibitors (e. g., pyrimethamine, trimethoprim, or ormetoprim) TT Leucovorin does not require conversion by dihydrofolate reductase for it to be active Uses/Indications Leucovorin calcium is the calcium salt of folinic acid and is used as an antidote for toxicity from folic acid antagonists (e. g., metho-trexate, pyrimethamine, trimethoprim, ormetoprim). It is used routinely in human medicine as a rescue agent for high-dose meth-otrexate chemotherapy, but the drug is rarely used for this in vet-erinary medicine. More commonly, it is used in dogs, cats or horses to help reverse or prevent hematologic toxicity associated with py-rimethamine, trimethoprim, or ormetoprim. Pharmacology/Actions Reduced folates act as coenzymes in the synthesis of purine and py-rimidine nucleotides that are necessary for DNA synthesis. Folates are also required for maintenance of normal erythropoiesis. Leucovorin is a reduced form of folic acid that does not require dihydrofolate reductase conversion, as does folic acid, for it to be-come biologically active. It is further converted to active reduced forms, of which 5-methyltetrahdyrofolate (5-methyl THF) is pre-dominantly responsible for its activity. Although, leucovorin is a mixture of diastereoisomers, only the (-)-L-isomer (citrovorum factor) becomes biologically active. Leucovorin inhibits thymidylate synthase by stabilizing the bind-ing of ﬂuorodeoxyuredylic acid to the enzyme. This can potentiate the activity, but also the toxicity of ﬂuorouracil (5-FU). Pharmacokinetics There is limited information available on the pharmacokinetics of leucovorin in animals. In dogs, the elimination half-life of the L-isomer (active) of leucovorin is about 50 minutes. It is extensively metabolized and then excreted into the urine. The D-form (not bi-ologically active) elimination half-life is about 2. 5 hours. Apparent volume of distribution for both forms is about 0. 6 L/kg. In humans, oral bioavailability of leucovorin is reduced as dosage is increased above 25 mg. A 25 mg dose in an adult has a bioavail-ability of 97%, while 50 mg and 100 mg doses have bioavailabilities of 75% and 37%, respectively. IM bioavailability is similar to IV. Oral doses of 25 mg yield peak levels of leucovorin in about an hour and peaks of the active reduced folates occur between 1. 7 and 2. 4 hours after dosing. After intravenous administration, peak total reduced folate levels occur in about 10 minutes. About 50% of oral body stores of reduced folates are found in the liver. Elimination oc-curs in the urine, primarily as 10-formyl-THF or 5,10-methyl-THF. Elimination half-life is approximately 5-6 hours for total reduced folates. Contraindications/Precautions/Warnings Leucovorin is contraindicated only when known intolerance to the drug is documented. In humans, cobalamin (B-12) levels may be reduced with megaloblastic anemias and folinic acid therapy may mask the signs associated with it. Use with extreme caution in patients receiving systemic ﬂuorou-racil (see Drug Interactions). Because of its calcium content, large intravenous doses should be given slowly and not bolused. Reproductive/Nursing Safety Leucovorin reproductive studies have not been performed nor is it known if it enters milk, however, it is likely safe to administer dur-ing pregnancy or nursing. Adverse Effects Adverse effects have not been noted when leucovorin has been used in animals. In humans, gastrointestinal effects can be seen when the drug is given orally and, very rarely, seizures or hypersensitivity reactions may occur. Overdosage/Acute Toxicity Except in situations where drug interactions are possible, an inad-vertent overdose is unlikely to be of concern. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving leucovorin and may be of signiﬁcance in veterinary patients: T ! BARBITURATES, PRIMIDONE, PHENYTOIN : Large doses of leucovorin may reduce the antiseizure efﬁcacy of these agents T ! FLUOROURACIL : Leucovorin may increase both the antineoplastic efﬁcacy and toxicity of 5-FU T ! TRIMETHOPRIM, ORMETOPRIM, PYRIMETHAMINE (drugs that inhibit dihydrofolate reductase): Leucovorin may reduce efﬁcacy some-what, however, protozoa cannot utilize leucovorin Laboratory Considerations No speciﬁc concerns were noted Doses T ! DOGS/CAT S: a) For folate deﬁciency associated with pyrimethamine use: 5-15 mg (total dose) PO or parenterally once daily. (Greene, Hartmannn et al. 2006) b) Cats: For bone marrow suppression associated with py-rimethamine or trimethoprim/sulfa: 5 mg (route not speciﬁed) once daily. (Lindsay 2004) c) Cats: T o prevent bone marrow toxicity associated with pyrimethamine: 1 mg/kg (route not speciﬁed) once daily. (Inzana 2002)	pppbs.pdf
528 LEUPROLIDE d) For methotrexate overdose: Most effective if given within 48 hours of overdose. The dose of leucovorin is dependent on the serum methotrexate concentration. Dogs with se-rum methotrexate levels greater than 10-7 M at 48 hours have toxic reactions. Leucovorin dosage ranges from 25-200 mg/m2 parenterally every 6 hours until metho-trexate levels are less than 1 X 10-8 M. In one study, dogs tolerated methotrexate dosages up to 3 g/m2 when leuco-vorin was given at 15 mg/m2 IV q 3 hours for 8 doses, then IM q6h hours for 8 doses. Higher doses of methotrexate may be tolerated if higher doses of leucovorin are given. (O'Keefe and Harris 1990) T ! HORSES: a) For macrocytic anemia and neutropenia associated with pyrimethamine and/or trimethoprim (especially in preg-nant mares): 0. 1-0. 3 mg/kg PO once daily. A more prac-tical approach would be to ensure that the horse receives green hay or pasture (high tetrahydrofolate levels in green roughage) (Divers 2002) Monitoring T ! CBC T ! Methotrexate serum levels (contact a local human hospital) if used for methotrexate overdoses Client Information T ! If being used for methotrexate toxicity, this medication should only be administered in an inpatient setting T ! Oral leucovorin may be administered with or without meals. T ! Stress adherence to dosage schedule in order to adequately treat or prevent hematologic toxicity Chemistry/Synonyms Leucovorin calcium occurs as a yellowish-white or yellow, odorless powder. It is very soluble in water and practically insoluble in alco-hol. It is a mixture of diasterioisomers of 5-formyl tetrahydrofolic acid. Leucovorin calcium may also be known as: folinic acid, citro-vorum factor, 5-formyl tetrahydrofolate, citrovorin, folidan, folinic, FTHF, NSC-3590, calcium folinate, calcifolin, calfonat, or folinic acid calcium salt; many international trade names are available. Storage/Stability/Compatibility Leucovorin calcium tablets should be stored below 40°C, preferably between 15-30°C in a well-closed container; protect from light. Leucovorin solution for injection should be stored refrigerated be-tween 2°-8°C; protect from light. Leucovorin Powder for reconstitution and injection should be stored below 40°C, preferably between 15-30°C; protect from light. The powder for injection is reconstituted by adding 5 or 10 m L of bacteriostatic water for injection or sterile water for injection. As bacteriostatic water for injection contains benzyl alcohol, it is not recommended in neonates or very small animals. If reconstituting with sterile water for injection, the resulting solution should be ad-ministered immediately; solutions made with bacteriostatic water for injection are stable for up to 7 days. Intravenous solutions containing leucovorin calcium in Ringer's lactate, Ringer's, or 0. 9% sodium chloride are stable for up to 24 hours at room temperature. Leucovorin calcium is not compatible with solutions containing ﬂuorouracil. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Note : Strengths listed are in terms of leucovorin base. Leucovorin Calcium Tablets: 5 mg, 15 mg, & 25 mg; generic; (Rx) Leucovorin Calcium Injection: 3 mg/m L in 1 m L amps, & 5 mg/0. 5 m L single dose vials; generic; (Rx) Leucovorin Calcium Powder for Injection: 50 mg, 100 mg, & 350 mg vials; generic; (Rx) LEUPROLIDE (loo-proe-lide) Lupron® HORMONAL A GONIST Prescriber Highlights TT For medical treatment of adrenal associated endocrinop-athy in ferrets, & to treat inappropriate egg laying in cap-tive birds TT Depot form must not be confused with once a day inject-able, doses below are for depot (IM suspension) TT Teratogenic, contraindicated in pregnancy TT Extremely costly (especially for ferrets); may be obtained in smaller aliquots from compounding pharmacies TT Lab considerations Uses/Indications The primary uses for leuprolide at present are for the medical treat-ment of adrenal associated endocrinopathy in ferrets, and to treat inappropriate egg laying in captive cockatiels. In ferrets, it may be more effective in treating clinical signs associated with adrenal hy-perplasia or adenomas than with adenocarcinomas. Pharmacology/Actions Leuprolide is a luteinizing hormone-releasing hormone agonist. Via negative feedback, leuprolide inhibits the release of luteinizing hormone and follicle stimulating hormone from the pituitary. Both estrogen and androgen levels are decreased in the serum. Pharmacokinetics No veterinary data was located. The depot forms appear to have sustained effects in birds and ferrets. Contraindications/Precautions/Warnings Contraindicated in pregnancy. Adverse Effects In ferrets, adverse effects reported include pain/irritation at injec-tion site, dyspnea, and lethargy. Tachyphylaxis (higher dosages re-quired over time to obtain same effect) has been reported when using leuprolide in ferrets. Little information is available on the adverse effect proﬁle of leuprolide birds. At this point, it appears safe at the recommended doses. Reproductive/Nursing Safety Leuprolide is considered contraindicated in pregnancy. Major fetal abnormalities may result. In humans, the FDA categorizes this drug as category X for use during pregnancy (Studies in animals or hu-mans demonstrate fetal abnormalities or adverse reaction; reports in-	pppbs.pdf
LEVAMISOLE 529 dicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible beneﬁt. ) It is not known whether leuprolide is excreted in milk; use with caution. Overdosage/Acute Toxicity Because of its expense and method of dosing, it is unlikely an acute overdose would occur. Studies in lab animals at dosages of up to 5 gm/kg IM produced no untoward effects. Drug Interactions No documented adverse drug interactions with leuprolide were located. Laboratory Considerations T ! Diagnostic tests measuring pituitary gonadotrophic and gonadal functions may be misleading during, and for several months after discontinuing therapy Doses T ! FERRETS: For treatment of adrenal associated endocrinopathy: a) Using the depot form: 100 mcg IM once a month (Wagner, Bailey et al. 2001) b) Using the 4 month depot form: 2 mg IM for a 3 lb ferret; may last 5-6 months. Not as effective with carcinomas. (Weiss 2002a) c) Using the 30 day depot form: If ferret weighs less than 1 kg: 100 mcg IM q30 days. If weighs >1 kg: 200 mcg IM q30 days. Generally, the drug is diluted from its original concentra-tion to negate the muscle necrosis problem that has been reported. The diluted form appears to remain active after be-ing stored in the freezer for a year. (Murray 2002) ( Note : The manufacturer states that the depot form is not to be frozen and no studies are known that support the stability of the depot activity when frozen and thawed—Plumb) d) Using the one month depot form: 100-250 mcg/kg IM every 4 weeks until signs resolve, then every 4-8 weeks as needed, lifelong. Larger ferrets may require the higher dosage range. (Johnson 2006b) T ! BIRDS: T o inhibit egg laying in pet birds: a) For inappropriate egg laying (to reduce or prevent ovulation) in Cockatiels using Lupron Depot: 0. 375 mg per Cockatiel IM once monthly (Tully 2000) b) 100 mcg/kg per day. Multiply dose by number of days for ef-fect and give once monthly. Example: 100 mcg/kg for 28 days = 2800 mcg/kg dose (Olsen and Orosz 2000) Monitoring T ! Clinical effects (Birds: decreased egg-laying; Ferrets: decreases in vulvar swelling, pruritus, undesirable sexual behaviors, aggres-sion, and increased hair regrowth Client Information T ! Relatively experimental in birds or ferrets. Long-term safety is not known. T ! Can be extremely expensive to treat. Chemistry/Synonyms A synthetic nonapeptide analog of Gn RH (gonadotropin releasing hormone, gonadorelin, luteinizing hormone-releasing hormone), leuprolide acetate occurs as a white to off-white powder. In water more than 250 mg are soluble in one m L. Leuprolide may also be known as: leuproprelin, leuprore-linum, abbott-43818, leuprolide acetate, TAP-144, Carcinil®, Daronda®, Eligard®, Elityran®, Enanton®, Enantone®, Enantone-Gyn®, Ginecrin®, Lectrum®, Leuplin®, Lucrin®, Lupride®, Lupron®, Procren®,Procrin®,Prostap®,Reliser®,Trenantone®,Uno-Enantone®, and Viadur®. Storage/Stability/Compatibility The injection should be stored below room temperature (<78°F); do not freeze and protect from light (store in carton until use). The depot form may be stored at room temperature. After reconstitut-ing the suspension is stable for 24 hours, but as it contains no pre-servative it is recommended for immediate use. The manufacturer states that the depot form is not to be frozen and no studies are known that support the stability of the depot activity when frozen and thawed. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Leuprolide Acetate Injection: 5 mg/m L in 2. 8 m L multi-dose vials; Lupron® & Lupron® for Pediatric Use (TAP Pharm); generic; (Rx) Leuprolide Acetate Injection: 22. 5 mg in single-use kits with a 2-sy-ringe mixing system and needle; 30 mg & 45 mg in single-use kit with 2-syringe mixing system and syringe containing Atrigel; Eligard® (Sanoﬁ-Synthelabo); (Rx) Leuprolide Powder for Injection: lyophilized 7. 5 mg in single-use kits with a 2-syringe mixing system and needle; Eligard® (Sanoﬁ-Synthelabo); (Rx) Leuprolide Acetate Microspheres for Injection, lyophilized and pre-servative free with mannitol: 3. 75 mg, 7. 5 mg, 11. 25 mg, 15 mg single dose kits and pre-ﬁlled dual-chamber syringes; Lupron® Depot and Lupron® Depot-Ped (TAP Pharm); (Rx) Leuprolide Acetate Microspheres for Injection, lyophilized and pre-servative free with mannitol: 11. 25 mg and 22. 5 mg (3 month), 30 mg (4 month) in single pre-ﬁlled dual-chamber syringes; Lupron® Depot-3 or-4 Month, (TAP Pharm); (Rx) Leuprolide Acetate Implants: 72 mg in single-dose kit; Viadur® (ALZA Corporation); (Rx) LEVAMISOLE (leh-vam-i-sole) Levasole®, Tramisol® ANTIPARASITIC, IMMUNE STIMULANT Prescriber Highlights TT Antinematodal parasiticide that also may be useful as an immune stimulant TT Contraindications: Milk-producing animals (not approved) TT Very cautiously, if at all: Severely debilitated, or sig-niﬁcant renal or hepatic impairment; in cattle that are stressed due to vaccination, dehorning, or castration TT Not usually used in horses; infrequently used in small animals today as an antiparasitic agent TT Numerous adverse effects	pppbs.pdf
530 LEVAMISOLE Uses/Indications Depending on the product licensed, levamisole is indicated for the treatment of many nematodes in cattle, sheep and goats, swine, poultry. In sheep and cattle, levamisole has relatively good activ-ity against abomasal nematodes, small intestinal nematodes (not particularly good against Strongyloides spp. ), large intestinal nema-todes (not Trichuris spp. ), and lungworms. Adult forms of species that are usually covered by levamisole, include: Haemonchus spp., Trichostrongylus spp., Osteragia spp., Cooperia spp., Nematodirus spp., Bunostomum spp., Oesophagostomum spp., Chabertia spp., and Dictyocaulus vivapurus. Levamisole is less effective against the im-mature forms of these parasites, and is generally ineffective in cattle (but not sheep) against arrested larval forms. Resistance of parasites to levamisole is a growing concern. In swine, levamisole is indicated for the treatment of Ascaris suum, Oesophagostomum spp., Strongyloides, Stephanurus, and Metastrongylus. Levamisole has been used in dogs as a microﬁlaricide to treat Diroﬁlaria immitis infection in the past, but is rarely used today. It has also garnered some interest as an immunostimulant in the adjunctive therapy of various neoplasms. Because of its narrow margin for safety and limited efﬁcacy against many equine parasites, levamisole is not generally used in horses as an antiparasitic agent. It has been tried as an immune stimulant, however. Pharmacology/Actions Levamisole stimulates the parasympathetic and sympathetic gan-glia in susceptible worms. At higher levels, levamisole interferes with nematode carbohydrate metabolism by blocking fumarate reduction and succinate oxidation. The net effect is a paralyzing ef-fect on the worm that is then expelled alive. Levamisole's effects are considered to be nicotine-like in action. Levamisole's mechanism of action for its immunostimulating effects are not well understood. It is believed it restores cell-medi-ated immune function in peripheral T-lymphocytes and stimulates phagocy tosis by monocytes. Its immune stimulating effects appear to be more pronounced in animals that are immune-compromised. Pharmacokinetics Levamisole is absorbed from the gut after oral dosing and through the skin after dermal application, although bioavailabilities are vari-able. It is reportedly distributed throughout the body. Levamisole is primarily metabolized with less than 6% excreted unchanged in the urine. Plasma elimination half-lives have been determined for sev-eral veterinary species: Cattle, 4-6 hours; Dogs, 1. 8-4 hours; and Swine, 3. 5-6. 8 hours. Metabolites are excreted in both the urine (primarily) and feces. Contraindications/Precautions/Warnings Levamisole is contraindicated in lactating animals (not approved). It should be used cautiously, if at all, in animals that are severely debilitated, or signiﬁcant renal or hepatic impairment. Use cautiously or, preferably, delay use in cattle that are stressed due to vaccination, dehorning, or castration. Levamisole is not indicated for use as a diroﬁlarial adulticide. Avoid, if possible, administering levamisole intramuscularly to birds. Adverse Effects Adverse effects that may be seen in cattle can include muzzle foam-ing or hypersalivation, excitement or trembling, lip-licking and head shaking. These effects are generally noted with higher than recommended doses or if levamisole is used concomitantly with organophosphates. Signs generally subside within 2 hours. When injecting into cattle, swelling may occur at the injection site. This will usually abate in 7-14 days, but may be objectionable in ani-mals that are close to slaughter. In sheep, levamisole may cause a transient excitability in some animals after dosing. In goats, levamisole may cause depression, hy-peresthesia, and salivation. Injecting levamisole SC in goats appar-ently causes a stinging sensation. In swine, levamisole may cause salivation or muzzle foaming. Swine infected with lungworms may develop coughing or vomiting. Adverse effects that may be seen in dogs include GI disturbances (usually vomiting, diarrhea), neurotoxicity (panting, shaking, agi-tation or other behavioral changes), immune-mediated anemia, agranulocytosis, dyspnea, pulmonary edema, immune-mediated skin eruptions (erythroedema, erythema multiforme, toxic epider-mal necrolysis), and lethargy. Adverse effects seen in cats include hypersalivation, excitement, mydriasis, and vomiting. Reproductive/Nursing Safety There is little information available regarding the safety of this drug in pregnant animals. Although levamisole is considered relatively safe to use in large animals that are pregnant, use only if the po-tential beneﬁts outweigh the risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) 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. ) Levamisole is excreted in cows' milk; use with caution in nursing dams. Overdosage/Toxicity Signs of levamisole toxicity often mimic those of organophosphate toxicity. Signs may include hypersalivation, hyperesthesias and ir-ritability, clonic seizures, CNS depression, dyspnea, defecation, uri-nation, and collapse. These effects are best treated by supportive means as animals generally recover within hours of dosing. Acute levamisole overdosage can result in death due to respiratory failure. Should respiratory failure occur, artiﬁcial ventilation with oxygen should be instituted until recovery occurs. Cardiac arrhythmias may also be seen. If the ingestion was oral, emptying the gut and/or administering charcoal with cathartics may be indicated. Levamisole is considered to be more dangerous when ad-ministered parenterally than when given orally or topically. Intravenous administration is particularly hazardous, and is never recommended. In pet birds (cockatoos, budgerigars, Mynah birds, parrots, etc. ), 40 mg/kg has been reported as a toxic dose when administered SC. IM injections may cause more severe toxicity. Depression, ataxia, leg and wing paralysis, mydriasis, regurgitation, and death may be seen after a toxic dose in birds. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving levamisole and may be of signiﬁcance in veterinary patients: !TASPIRIN : Levamisole may increase salicylate levels !TCHLORAMPHENICOL : Fatalities have been reported after concomi-tant levamisole and chloramphenicol administration; avoid us-ing these agents together	pppbs.pdf
LEVAMISOLE 531 !TCHOLINESTERASE-INHIBITING DRUGS (e. g., organophosphates, neostig-mine ): Could theoretically enhance the toxic effects of levamisole; use together with caution !TNICOTINE-LIKE COMPOUNDS (e. g., pyrantel, morantel, diethyl-carbamazine ): Could theoretically enhance the toxic effects of le-vamisole; use together with caution. !TWARFARIN : Increased risk for bleeding Doses !TDOGS: As an immune stimulant: a) For recurrent cutaneous infections: 2. 2 mg/kg PO every oth-er day, with appropriate antimicrobial therapy (Rosenkrantz 1989) b) 0. 5-2 mg/kg PO 3 times a week (Kirk 1989) c) For adjunctive therapy in dogs with chronic pyoderma: 0. 5-1. 5 mg/kg PO 2-3 times a week (efﬁcacy not estab-lished) (Lorenz 1984) d) For adjunctive therapy in dogs with chronic pyoderma: 2. 2 mg/kg PO every other day (may only be efﬁcacious in 10% of cases) (Ihrke 1986) e) For adjunctive therapy in aspergillosis/penicillinosis: 2-5 mg/kg PO every other day (Prueter 1988) As an alternative treatment for SLE: a) 3-7 mg/kg PO every other day for 4 months; alone or in combination with corticosteroids (Marks and Henry 2000) As a microﬁlaricide ( Note : Rarely recommended today): a) 11 mg/kg PO for 6-12 days. Examine blood on 6th day of treatment; discontinue therapy when microﬁlaria negative. May cause neurologic signs, vomiting, behavioral changes, or possibly death. If treatment is prolonged (>15 days), there is increased likelihood of toxicity. (T odd, Paul, Di Pietro 1985) b) 11 mg/kg PO for 6-12 days. Examine for microﬁlaria within 7-10 days and at weekly intervals until eliminated or treat-ment is halted. Retching and vomiting are common. Avoid giving on an empty stomach or immediately after drinking water. A “conditioning” dose of 5 mg/kg PO once a day may be necessary. Stop therapy if abnormal behavior or ataxia de-velops. (Knight 1988) For treatment of Angiostrongylus vasorum: a) 7. 5 mg/kg (route not speciﬁed) for two consecutive days, fol-lowed by 10 mg/kg for 2 days; if the infection is not cleared, the regimen is repeated. (Bowman 2006a) For the treatment of lungworms: a) For Crenosoma vulpis: 8 mg/kg once (T odd, Paul, and Di Pi-etro 1985) b) For Capillaria: 7-12 mg/kg once daily PO for 3-7 days For Filaroides osleri: 7-12 mg/kg once daily PO for 20-45 days (Roudebush 1985) c) 7. 5 mg/kg PO twice daily or 25 mg/kg PO every other day for 10 days (Bauer 1988) d) For Capillaria aerophilia: 10 mg/kg PO once daily for 5 days; repeat in 9 days (Reinemeyer 1995) !TCATS: For the treatment of lungworms: a) 20-40 mg/kg PO every other day for 5-6 treatments (Kirk 1989) b) For Aelurostrongylus abstrusus: 100 mg PO daily every other day for 5 treatments; give atropine (0. 5 mg SC, 15 minutes before administering); or 15 mg/kg PO every other day for 3 treatments, then 3 days later: 30 mg/kg PO, then 2 days later: 60 mg/kg. For Capillaria aerophilia: 4. 4 mg/kg SC for 2 days, then 8. 8 mg/kg once 2 weeks later; or 5 mg/kg PO once daily for 5 days, followed by 9 days of no therapy, repeat two times (T odd, Paul, and Di Pietro 1985) c) 25 mg/kg every other day for 10-14 days (Roudebush 1985) d) For Capillaria aerophilia: 10 mg/kg PO once daily for 5 days; repeat in 9 days (Reinemeyer 1995) For treatment of Ollulanus tricuspis: a) 5 mg/kg SC (T odd, Paul, and Di Pietro 1985) As a microﬁlaricide: a) 10 mg/kg PO for 7 days (Dillon 1986) As an immune-stimulant: a) For adjunctive therapy of feline plasma-cell gingivitis/phar-yngitis: 25 mg PO every other day for 3 doses (De Novo, Pot-ter, and Woolfson 1988) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: For nematodes: 12. 5-20 mg/kg PO (for gastric nematodes) or SC (for extragastric nematodes) (Ivey and Morrisey 2000) !THORSES: As an immunostimulant: a) Dosages have ranged from 2. 5 mg/kg injected at 7 day inter-vals, and 2. 2 mg/kg PO every 24 hours for 3 days, then off for 4 days for a period of 4-6 weeks. Anecdotal reports of beneﬁcial effects in the treatment of nasal viral papillomas, COPD, and EPM have been suggested. (Bentz 2006a) !TCATTLE: For treatment of susceptible nematodes (also refer to speciﬁc la-bel directions for approved products): a) For removal of mature and immature Dictyocaulus vivapu-rus: 5. 5-11 mg/kg PO, either given in feed or as a drench or oral bolus. May also be administered SC at 3. 3-8 mg/kg. (Bennett 1986) b) 7. 5 mg/kg PO (Brander, Pugh, and Bywater 1982) !TLLAMAS: For treatment of susceptible nematodes: a) 5-8 mg/kg IM, or PO (Fowler 1989) b) 5-8 mg/kg PO or SC for 1 day (Cheney and Allen 1989) !TSWINE: For treatment of susceptible nematodes (also refer to speciﬁc la-bel directions for approved products): a) For removal of mature and immature Metastrongylus: 8 mg/ kg PO in feed or water (Bennett 1986) b) 8 mg/kg PO in feed or water (Howard 1986) c) 7. 5 mg/kg PO (Brander, Pugh, and Bywater 1982) !TSHEEP & GOATS: For treatment of susceptible nematodes (also refer to speciﬁc la-bel directions for approved products): a) For removal of mature and immature Dictyocaulus vivapu-rus: 8 mg/kg PO (Bennett 1986) b) 7. 5 mg/kg PO (Brander, Pugh, and Bywater 1982) !TBIRDS: a) Using 13. 65% injectable: For intestinal nematodes: 5-15 m L/gallon of drinking water for 1-3 days; repeat in 10 days. If birds refuse to drink, with-hold water prior to treating. For gavage in Australian Parakeets (or desert species that re-fuse to drink water): 15 mg/kg; repeat in 10 days	pppbs.pdf
532 LEVETIRACETAM For parenteral use: 4-8 mg/kg IM or SC; repeat in 10-14 days. May cause vomiting, ataxia, or death. Do not use in de-bilitated birds. For immunostimulation: 0. 3 m L/gallon of water for several weeks As a parenteral immunostimulant: 2 mg/kg IM or SC. 3 doses at 14 day intervals (Clubb 1986) b) As a nebulized immunostimulant: 1 m L (of 13. 65% levami-sole phosphate) in 15 m L saline (Spink 1986) c) For Capillaria infections: 15-30 mg/kg orally as a single bo-lus or through a crop tube; or 2. 25 mg/gallon of drinking water for 4-5 days. Repeat treatment in 10-14 days. (Flam-mer 1986) d) Poultry: 18-36 mg/kg, PO (Brander, Pugh, and Bywater 1982) e) Ratites: For Libyastrongylus douglassi: Give 30 mg/kg PO or IM at one month of age, then once a month for 7 treatments, then 4 times yearly (Jenson 1998) Monitoring T ! Clinical efﬁcacy T ! Adverse effects/toxicity observation Client Information T ! Levamisole is not approved for use in dairy animals of breeding age. T ! Follow directions on the product label unless otherwise directed by veterinarian. Animals that are severely parasitized or in condi-tions with constant helminth exposure should be retreated 2-4 weeks after initial treatment. T ! Do not administer injectable products IV. T ! Report serious adverse effects to veterinarian. Chemistry/Synonyms The levo-isomer of dl-tetramisole, levamisole has a greater safety margin than does the racemic mixture. It is available commercially in two salts, a phosphate and a hydrochloride. Levamisole hydro-chloride occurs as a white to pale cream colored, odorless or nearly odorless, crystalline powder. One gram is soluble in 2 m L of water. Levamisole HCl may also be known as: cloridrato de levamizol, ICI-59623, levamisoli hydrochloridum, NSC-177023, R-12564, RP-20605, l-tetramisole hydrochloride, Amtech®, Ascaridil®, Decaris®, Ergamisol®, Immunol®, Ketrax®, Levasole®, Meglum®, Prohibit®, Solaskil®, Vermisol®, and Vizole®. Storage/Stability/Compatibility Levamisole hydrochloride products should be stored at room tem-perature (15-30°C), unless otherwise instructed by the manufac-turer; avoid temperatures greater than 40°C. Levamisole phosphate injection should be stored at temperatures at or below 21°C (70°F); refrigeration is recommended and freezing should be avoided. Levamisole tablets should not be crushed nor suspensions made from them. Dosage Forms/Regulatory Status/Withdrawal Times In cattle, sheep, and swine a level of 0. 1 ppm has been established for negligible residues in edible tissues. VETERINARY-LABELED PRODUCTS: Levamisole Phosphate Injection: 136. 5 mg/m L (13. 65%) in 500 m L vials. Levamisole Injectable (Agri Labs), Levasole® Injectable Solu-tion 13. 65% (Schering Plough); Approved for use in cattle. Slaughter withdrawal (at labeled dosages) = 7 days. T o prevent residues in milk, do not administer to dairy animals of breeding age. Levamisole Hydrochloride Water Medication: 18. 15 g in 0. 71 oz bot-tle. Levamisole Soluble Pig Wormer (Agri Labs, Durvet, Aspen); (OTC); Levasole® Soluble Pig Wormer (Schering-Plough), Amtech® Levamisole HCl Pig Wormer (IVX); (OTC). Approved for use in swine. Slaughter withdrawal (at labeled dosages) = 72 hours Levamisole Hydrochloride Antihelmintic Oral: Levasole® Soluble Drench Powder 46. 8 grams/packet (Schering-Plough); (OTC). Ap-proved for use in cattle (Not in dairy animals of breeding age), and sheep. Slaughter withdrawal (at labeled dosages) = 48 hours (cattle); 72 hours (sheep) Levamisole Hydrochloride Soluble Drench Powder 46. 8 grams/pack-et; 544. 5 g/21. 34 oz bottle. Prohibit® (Agri Labs) (OTC). Approved for use in cattle and sheep. Slaughter withdrawal (at labeled dosages) cattle = 48 hours, sheep = 72 hours. T o prevent residues in milk, do not administer to dairy animals of breeding age. Levamisole HCl Oral Tablets/Boluses: 184 mg bolus: Levasole® Sheep Wormer Bolus (Schering Plough); (OTC). Approved for use in sheep. Slaughter withdrawal (at labeled dosages) = 72 hours. Levamisole 2. 19 gram bolus: Levasole® Cattle Wormer Boluses (Scher-ing-Plough); (OTC). Approved for use in beef (not for use in dairy animals of breeding age). Slaughter withdrawal (at labeled dosages) = 48 hours. HUMAN-LABELED PRODUCTS: Levamisole HCl Tablets: 50 mg levamisole base; Ergamisol® (Jans-sen); (Rx) LEVETIRACETAM (lee-ve-tye-ra-se-tam) Keppra® ANTICONVULSANT Prescriber Highlights TT May be useful as a third drug adjunct for refractory ca-nine epilepsy or when either phenobarbital or bromides are not tolerated; may also be useful in cats, but less is known TT Limited clinical experience; investigations ongoing re-garding efﬁcacy, adverse effects TT Appears to be well tolerated in dogs & cats TT Not substantially metabolized by liver; does not induce hepatic enzymes TT Dosage frequency (three times daily) problematic; cost may be prohibitive Uses/Indications Levetiracetam may be useful as a third antiseizure medication in dogs that are not well controlled with phenobarbital and bromides or when either bromides or phenobarbital are not tolerated. Some evidence suggests that in dogs suffering from phenobarbital liver toxicity, the addition of levetiracetam will allow reduction of their phenobarbital dosage without increasing seizure frequency. Levetiracetam may also be useful as add-on therapy in cats. Pharmacology/Actions The exact mechanism for levetiracetam's antiseizure activity is not well understood. It may selectively prevent hypersynchronization of epileptiform burst-ﬁring and propagation of seizure activity. It does not affect normal neuronal excitability.	pppbs.pdf
LEVETIRACETAM 533 T TPharmacokinetics Little published pharmacokinetic data is available for dogs; elimi-nation half-life is about 4 hours and volume of distribution is about 0. 5 L/kg. In a very small sample size, levetiracetem half-life in cats was around 5 hours. In humans, levetiracetam is rapidly, and nearly completely, absorbed after oral administration. Peak levels occur about one hour after dosing. Presence of food in the gut delays the rate, but not the extent, of drug absorbed. Less than 10% of the drug is bound to plasma proteins. While not extensively metabolized, the drug's acetamide group is enzymatically hydrolyzed to the carboxy-lic acid metabolite that is apparently not active. Hepatic CYP P450 isoenzymes are not involved. Half-life in humans is about 7 hours; about 66% of a given dose is excreted unchanged via renal mecha-nisms, primarily glomerular ﬁltration and active tubular secretion. Clearance can be signiﬁcantly reduced in patients with impaired renal function. Contraindications/Precautions/Warnings Levetiracetam is contraindicated in patients who have previously exhibited hypersensitivity to it or any of its components. It should be used with caution in patients with renal impairment; dosage amounts or dosing frequency changes should be considered. In hu-mans, renal elimination of levetiracetam correlates with creatinine clearance. Adverse Effects Levetiracetam appears to be very well tolerated in the limited num-ber of dogs treated thus far. Changes in behavior, somnolence, and gastrointestinal effects could occur. In cats, the drug appears to have a wide safety margin, but less clinical use has occurred in that species. Transient inappetance has been reported in some cats receiving the drug. In humans, it is recommended to withdraw the drug slowly to prevent “withdrawal” seizures. Reproductive/Nursing Safety In pregnant dogs or cats, levetiracetam should be used with cau-tion. In humans, the FDA categorizes levetiracetam as a category C drug for use during pregnancy (Animal studies have shown an ad-verse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). At high dosages, levetiracetam has caused increased embryofetal mortality in rabbits and rats. At dosages equivalent to the maximum human therapeutic dose, levetiracetam caused mi-nor skeletal abnormalities and retarded offspring growth in rats. Levetiracetam is excreted into maternal milk and its safety in nurs-ing offspring is unknown. Use with caution in nursing patients. Overdosage/Acute Toxicity Levetiracetam is a relatively safe agent. Dogs given 1200 mg/kg/day (approximately 20 times therapeutic dosage) developed only saliva-tion and vomiting. Human patients given 6000 mg/kg during drug testing developed only drowsiness. Other effects noted in human overdoses (doses not speciﬁed) after the drug was released include depressed levels of consciousness, agitation, aggression and respi-ratory depression. Treatment is basically supportive; the drug can be removed with hemodialysis. In the circumstance of a signiﬁcant overdose in animals, contact an animal poison control center for further recommendations. Drug Interactions No clinically signiﬁcant adverse drug interactions were located. Laboratory Considerations No speciﬁc laboratory interactions or considerations noted. Doses !TDOGS: a) As an add-on treatment for epilepsy in dogs refractory to phenobarbital and bromides: 20 mg/kg PO every 8 hours (Munana 2004b) b) As an add-on treatment for epilepsy in dogs refractory to phenobarbital and/or bromides: 7. 1-23. 8 mg/kg PO every 8 hours (Steinberg and Faissler 2004) c) 10-20 mg/kg PO q8h (Dickinson 2007) d) 10-20 mg/kg PO q8-12h (Podell 2006a) e) Initially, 20 mg/kg PO q8h. May increase dose in 20 mg/kg increments until efﬁcacy achieved, side effects become appar-ent, or the drug becomes cost prohibitive. (Dewey 2005a) !TCATS: a) As an add-on to phenobarbital treatment for epilepsy: Ini-tially, 20 mg/kg PO three times daily; slowly increase to effect (Pearce 2006b) Monitoring !TAt this point, in both humans and dogs, blood levels of levetirac-etam are not monitored for either efﬁcacy or toxicity. !TVeterinarians should have the owner keep a record of seizure activity to document efﬁcacy and report any potential levetirac-etam-associated adverse effects. Client Information !TClients should understand that limited experience has occurred with levetiracetam in dogs. Although it appears to be well toler-ated, information on its safety and efﬁcacy proﬁle is still being generated. !The current dosage frequency recommendation (q8h) may be difﬁcult to adhere to, but the drug may not be effective if not followed. !The cost of this medication can be very substantial; potentially several hundred dollars per month (depending on dog's size). Chemistry/Synonyms A pyrrolidone-derivative antiepileptic agent, levetiracetam occurs as an odorless, bitter-tasting, white to off-white crystalline powder. It is very soluble in water and soluble in ethanol. It is a chiral mol-ecule with one asymmetric carbon atom. Levetiracetam is not re-lated chemically to other antiseizure medications. Levetiracetam may also be known as: S-Etriacetam, UCB-22059, UCB-L059, and Keppra ®. Storage/Stability Levetiracetam tablets or oral solution should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Levetiracetam Tablets (ﬁlm-coated, scored): 250 mg, 500 mg, 750 mg & 1000 mg; Keppra ® (UCB); (Rx) Levetiracetam Oral Solution: 100 mg/m L in 480 m L; Keppra ® (UCB), (Rx) Levetiracetam Solution for Injection: 100 mg/m L (45 mg sodium chloride & 8. 2 mg sodium acetate trihydrate/5 m L) in 5 m L vials; Keppra ® (UCB Pharma); (Rx)	pppbs.pdf
534 LEVOTHYROXINE SODIUM LEVOTHYROXINE SODIUM (lee-voe-thye-rox-een) S oloxine®, Synthroid® THYROID HORMONE Prescriber Highlights TT Thyroid hormone for hypothyroidism in all species TT Contraindications: Acute myocardial infarction, thyrotoxi-cosis, or untreated adrenal insufﬁciency TT Caution: Concurrent hypoadrenocorticism (treated), car-diac disease, diabetes, or elderly patients TT Adverse Effects: Only associated with OD's (tachycardia, polyphagia, PU/PD, excitability, nervousness, & excessive panting); some cats may appear apathetic TT Drug-drug; drug-lab interactions Uses/Indications Levothyroxine sodium is indicated for the treatment of hypothy-roidism in all species. Pharmacology/Actions Thyroid hormones affect the rate of many physiologic processes including: fat, protein, and carbohydrate metabolism, increas-ing protein synthesis, increasing gluconeogenesis, and promoting mobilization and utilization of glycogen stores. Thyroid hormones also increase oxygen consumption, body temperature, heart rate and cardiac output, blood volume, enzyme system activity, and growth and maturity. Thyroid hormone is particularly important for adequate development of the central nervous system. While the exact mechanisms how thyroid hormones exert their effects are not fully understood, it is known that thyroid hormones (primarily tri-iodothyronine) act at the cellular level. In humans, triiodothyronine (T 3) is the primary hormone re-sponsible for activity. Approximately 80% of T 3 found in the pe-ripheral tissues is derived from thyroxine (T 4) which is the prin-ciple hormone released by the thyroid. Pharmacokinetics In dogs, peak plasma concentrations after oral dosing reportedly occur 4-12 hours after administration and the serum half-life is approximately 12-16 hours. There is wide variability from animal to animal, however. Contraindications/Precautions/Warnings Levothyroxine (and other replacement thyroid hormones) are contraindicated in patients with acute myocardial infarction, thy-rotoxicosis, or untreated adrenal insufﬁciency. It should be used with caution, and at a lower initial dosage, in patients with concur-rent hypoadrenocorticism (treated), cardiac disease, diabetes, or in those who are aged. Adverse Effects When administered at an appropriate dose to patients requiring thyroid hormone replacement, there should not be any adverse ef-fects associated with therapy. For adverse effects associated with overdosage, see below. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category A for use dur-ing pregnancy (Adequate studies in pregnant women have not dem-onstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Minimal amounts of thyroid hormones are excreted in milk and should not affect nursing offspring. Overdosage/Acute Toxicity Chronic overdosage will produce signs of hyperthyroidism, includ-ing tachycardia, polyphagia, PU/PD, excitability, nervousness and excessive panting. Dosage should be reduced and/or temporarily withheld until signs subside. Some (10%?) cats may exhibit signs of “apathetic” (listlessness, anorexia, etc. ) hyperthyroidism. A single acute overdose in small animals is less likely to cause severe thyrotoxicosis than with chronic overdosage. Vomiting, diar-rhea, hyperactivity to lethargy, hypertension, tachycardia, tachyp-nea, dyspnea, and abnormal pupillary light reﬂexes may be noted in dogs and cats. In dogs, clinical signs may appear within 1-9 hours after ingestion. If ingestion occurred within 2 hours, treatment to reduce absorption of drug should be accomplished using standard protocols (emetics, cathartics, charcoal) unless contraindicated by the patient's condition. Treatment is supportive and symptomatic. Oxygen, artiﬁcial ventilation, cardiac glycosides, beta-blockers (e. g., propranolol), ﬂuids, dextrose, and antipyretic agents have all been suggested for use if necessary; contact an animal poison control center for further guidance. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving levothyroxine and may be of signiﬁcance in veterinary patients: T ! AMIODARONE : May decrease the metabolism of T4 to T3 T ! ANTACIDS, ORAL : May reduce levothyroxine absorption; separate doses by 4 hours T ! ANTIDEPRESSANTS, TRICYCLIC/TETRACYCLIC : Increased risk for CNS stimulation and cardiac arrhythmias T ! ANTIDIABETIC AGENTS (insulin, oral agents ): Levothyroxine may in-crease requirements for insulin or oral agents T ! CHOLESTYRAMINE : May reduce levothyroxine absorption; separate doses by 4 hours T ! CORTICOSTEROIDS (high dose): Decreased conversion of T4 to T3 T ! DIGOXIN : Potential for reduced digoxin levels T ! FERROUS S ULFATE : May reduce levothyroxine absorption; separate doses by 4 hours T ! HIGH FIBER DIET : May reduce levothyroxine absorption T ! KETAMINE : May cause tachycardia and hypertension T ! PHENOBARBITAL : Possible increased metabolism of thyroxine; dos-age adjustments may be needed T ! PROPYLTHIOURACIL : Decreased conversion of T4 to T3 T ! RIFAMPIN : Possible increased metabolism of thyroxine; dosage ad-justments may be needed T ! SERTRALINE : May increase levothyroxine requirements T ! SUCRALFATE : May reduce levothyroxine absorption; separate dos-es by 4 hours T ! SYMPATHOMIMETIC AGENTS (epinephrine, norepinephrine, etc. ): Levothyroxine can potentiate effects T ! WARFARIN : Thyroid hormones increase the catabolism of vitamin K-dependent clotting factors that may increase the anticoagula-tion effects in patients on warfarin	pppbs.pdf
LEVOTHYROXINE SODIUM 535 TLaboratory Considerations The following drugs may have effects on thyroid function tests; evaluate results accordingly: !TEFFECTS ON SERUM T4: aminoglutethimide?, anabolic steroids/ androgens?, antithyroid drugs (PTU, methimazole)?, aspara-ginase?, barbiturates?, corticosteroids?, danazol?, diazepam?, estrogens B (Note : estrogens may have no effect on canine T 3 or T4 concentrations), ﬂuorouracil B, heparin?, insulin B, lithium carbonate?, mitotane (o,p-DDD)?, nitroprusside?, phenylbuta-zone?, phenytoin?, propranolol B, salicylates (large doses)?, and sulfonylureas?. !TEFFECTS ON SERUM T3: antithyroid drugs (PTU, methimazole)?, barbiturates?, corticosteroids?, estrogens B, ﬂuorouracil B, hepa-rin?, lithium carbonate?, phenytoin?, propranolol?, salicylates (large doses)?, and thiazides B. !TEFFECTS ON T3 UPTAKE RESIN: anabolic steroids/androgens B, an-tithyroid drugs (PTU, methimazole)?, asparaginase B, corticos-teroids B, danazol B, estrogens?, ﬂuorouracil?, heparin B, lithium carbonate?, phenylbutazone B, and salicylates (large doses)B. !TEFFECTS ON SERUM TSH: aminoglutethimide B, antithyroid drugs (PTU, methimazole)B, corticosteroids?, danazol?, and lithium carbonate B. !TEFFECTS ON FREE THYROXINE INDEX (FTI): antithyroid drugs (PTU, methimazole)?, barbiturates?, corticosteroids?, heparin B, lithi-um carbonate?, and phenylbutazone?. Doses !TDOGS: For hypothyroidism: a) Use a trade name product. Initially give 20 micrograms/kg (0. 02 mg/kg) body weight PO twice daily with a maximum dose of 0. 8 mg twice daily. Four to eight weeks later evaluate clinical response and draw a T4 level 4-6 hours post dos-ing. If positive clinical response and 1) low normal T4: increase dose and recheck in 4 weeks; 2) high normal to slightly high-er than normal T4: no change in dosing and recheck in 6 months; 3) 40% or more greater than high normal: decrease dose or consider once a day therapy and recheck in 4 weeks (if once a day dosing get a level prior to dosing as well). If a negative clinical response and 1) low normal T4: increase dose and recheck in 8 weeks (may need to: increase dose again; change to 3 times a day dosing or reevaluate diagno-sis); 2) high normal to 40% or more greater than high nor-mal: re-evaluate diagnosis. For myxedema coma: 5 mcg/kg IV q12h initially as oral ad-ministration may be poorly absorbed (Scott-Moncrieff and Guptill-Y oran 2000) b) Initiate treatment at 22 micrograms/kg PO twice daily (0. 1 mg/10 lbs body weight twice daily); reevaluate dosage after monitoring clinical response and serum levels after 4-8 weeks. If clinical response is satisfactory and T4 is elevated (* 60 nmol/L) may reduce dosage to 22 micrograms/kg once daily. If clinical response is not satisfactory, either reevaluate the need for T4 supplementation or increase the dose. Daily dosage of 20-40 micrograms/day appears to be adequate for most dogs. (Refsal and Nachreiner 1995) c) 0. 022 mg/kg (22 mcg/kg) PO twice daily or 0. 044/kg mg (44 mcg/kg) once daily. Monitor by resolution of clinical signs, pre-and post dosing T otal T4 (in the normal range), or by endogenous TSH concentrations that decrease into the nor-mal range. (Greco 1999) d) 0. 02 mg/kg PO twice daily to start; (0. 02-0. 04 mg/kg PO once daily or, if necessary divided twice daily to maintain). Alternatively, give 0. 5 mg/m2 which may prevent hyper-thyroid effects, particularly in large breed dogs. (Ferguson 2002) !TCATS: For hypothyroidism: a) 0. 05-0. 1 mg per cat PO once daily. Monitoring and dosage adjustments as above for dogs. (Scott-Moncrieff and Guptill-Y oran 2000) b) Initially, 0. 05-0. 1 mg once daily. Wait a minimum of 4-6 weeks to assess cat's clinical response to treatment. Then ob-tain a serum T 4 level prior to, and 6-8 hours after, dosing. Increase or decrease dose and/or dosing frequency after re-viewing these values and clinical response. If levothyroxine is ineffective, may try liothyronine. (Feldman and Nelson 1987d) !THORSES: For hypothyroidism: a) 10 mg in 70 m L of corn syrup once daily. Monitor T 4 levels one week after initiation of therapy. Obtain one blood sam-ple just before administration and on sample 2-3 hours after dosing. (Chen and Li 1987) For adjunctive treatment of equine metabolic syndrome to lower the risk for laminitis: a) 48 mg (total dose) in the feed once daily for 3-6 months. When discontinuing treatment, wean off the drug by reduc-ing dose to 24 mg a day for 2 weeks, then 12 mg a day for 2 weeks. The beneﬁts of longer treatment at lower dosages of levothyroxine have not been evaluated. (Frank 2007) !TBIRDS: For hypothyroidism: a) One 0. 1 mg tablet in 30 m L-120 m L of water daily; stir water and offer for 15 minutes and remove. Use high dose for bud-gerigars and low dose for water drinkers. Used for respiratory clicking, vomiting in budgerigars and thyroid responsive problems. (Clubb 1986) !TREPTILES: For hypothyroidism in tortoises: a) 0. 02 mg/kg PO every other day (Gauvin 1993) Monitoring !Therapeutic efﬁcacy should be judged ﬁrst via clinical effects, and, if necessary serum T4 !TSerum T 4; after therapy is started wait at a week before measur-ing T 4. Draw level preferably just prior to the next dose. Dosage should generally be reduced if serum thyroxine levels exceed 100 ng/m L or signs of thyrotoxicosis develop. Client Information !TClients should be instructed in the importance of compliance with therapy as prescribed. !TAlso, review the signs that can be seen with too much thyroid supplementation (see Overdosage section above). Chemistry/Synonyms Prepared synthetically for commercial use, levothyroxine sodium is the levo isomer of thyroxine that is the primary secretion of the thyroid gland. It occurs as an odorless, light yellow to buff-colored, tasteless, hygroscopic powder that is very slightly soluble in water and slightly soluble in alcohol. The commercially available powders for injection also contain mannitol.	pppbs.pdf
536 LIDOCAINE HCL 100 micrograms of levothyroxine is approximately equivalent to 65 mg (1 grain) of desiccated thyroid. Levothyroxine sodium may also be known as: T 4, T4 thyroxine sodium, levothyroxin natrium, levothyroxinum natricum, 3,5,3',5'-tetra-iodo-L-thyronine sodium, thyroxine sodium, L-thyroxine so-dium, thyroxinum natricum, tirossina, and tiroxina sodica; many trade names are available. Storage/Stability/Compatibility Levothyroxine sodium preparations should be stored at room tem-perature in tight, light-resistant containers. The injectable product should be reconstituted immediately before use; unused injection should be discarded after reconstituting. Do not mix levothyroxine sodium injection with other drugs or IV ﬂuids. Levothyroxine sodium is reportedly unstable in aqueous solu-tions. If using a commercial liquid preparation, it is suggested to obtain validated stability data for the product. Dosage Forms/Regulatory Status All levothyroxine products require a prescription, but are not nec-essarily FDA approved. There have been bioavailability differences between products reported. It is recommended to use a reputable product and not to change brands indiscriminately. VETERINARY-LABELED PRODUCTS: Levothyroxine Sodium Tablets: 0. 1 mg, 0. 2 mg, 0. 3 mg, 0. 4 mg, 0. 5 mg, 0. 6 mg, 0. 7 mg, 0. 8 mg, (1 mg Soloxine®); Amtech® Levothy-roxine Sodium Tablets (IVX); Levosyn® (V. E. T. ); Soloxine® (Virbac); Thyro-Tabs® (Vet-A-Mix); Thyrosyn® (Vedco); Thyroxine-L Tablets® (Butler); Thyrozine® (Phoenix Pharmaceutical); Thyrokare® Tablets (Neogen); (Rx). Labeled for use in dogs. Levothyroxine Sodium Tablets Chewable (Veterinary) 0. 1 mg, 0. 2 mg, 0. 3 mg, 0. 4 mg, 0. 5 mg, 0. 6 mg, 0. 7 mg, 0. 8 mg; Canine Thyroid Chewable Tablets® (Pala-T ech); Nutrived® T-4 Chewable Tablets (V e-dco); Heska Thyromed® Chewable Tablets (Heska); (Rx). Labeled for use in dogs. Levothyroxine Oral Solution: 1 mg/m L in 30 m L bottles: Leventa® Oral Solution (Intervet); (Rx) Labeled for use in dogs. Levothyroxine Sodium Powder (Veterinary): 0. 22% (1 gram of T 4 in 454 grams of powder): One level teaspoonful contains 12 mg of T 4. Available in 1 lb. and 10 lb. containers; Equine Thyroid Supplement® (Pala-T ech); Thyrozine Powder® (Phoenix Pharmaceutical); Levox-ine® Powder (First Priority); Thyro-L® (Vet-A-Mix); Throxine-L® Powder (Butler); Equi-Phar Thyrosyn Powder® (Vedco); Thyrokare® Powder (Neogen); (Rx). Labeled for use in horses. HUMAN-LABELED PRODUCTS: Levothyroxine Sodium Tablets: 0. 025 mg, 0. 05 mg, 0. 075 mg, 0. 088 mg, 0. 1 mg, 0. 112 mg, 0. 125 mg, 0. 137 mg, 0. 15 mg, 0. 175 mg, 0. 2 mg & 0. 3 mg; Synthroid® (Abbott); Levothroid® (Forest); Levoxyl® (Jones Pharma); Thyro-Tabs® (Lloyd); Unithroid® (Lannett); generic; (Rx) Levothyroxine Powder for Injection lyophilized: 200 micrograms & 500 micrograms in 10 m L vials; generic; (Rx) LIDOCAINE HCL (SYSTEMIC) (lye-doe-kane) Xylocaine® ANTIARRHYTHMIC/LOCAL ANESTHETIC Prescriber Highlights TT Local anesthetic & antiarrhythmic agent; may be use-ful to prevent post-operative ileus, reperfusion injury in horses TT Contraindications: Known hypersensitivity to the amide-class local anesthetics, severe degree of SA, AV, or intra-ventricular heart block (if not being artiﬁcially paced), or Adams-Stokes syndrome TT Caution: Liver disease, congestive heart failure, shock, hypovolemia, severe respiratory depression, marked hypoxia, bradycardia, or incomplete heart block having VPC's, unless the heart rate is ﬁrst accelerated TT Cats might be more sensitive to the CNS effects of lido-caine; use with caution TT Patients susceptible to malignant hyperthermia should receive intensiﬁed monitoring TT Adverse Effects: Most common adverse effects reported are dose related (serum level) & mild. CNS signs include drowsiness, depression, ataxia, muscle tremors, etc. ; nausea & vomiting (usually transient). Adverse cardiac effects usually only at high plasma concentrations TT When an IV bolus is given too rapidly, hypotension may occur TT Do NOT use the product containing epinephrine intravenously TT Drug interactions Uses/Indications Besides its use as a local and topical anesthetic agent, lidocaine is used to treat ventricular arrhythmias, principally ventricular tachy-cardia and ventricular premature complexes in all species. Cats may be more sensitive to the drug and some clinicians feel that it should not be used in this species as an antiarrhythmic, but this remains controversial. In horses, lidocaine may be useful to prevent post-operative ileus and reperfusion injury. Pharmacology/Actions Lidocaine is considered to be a class IB (membrane-stabilizing) an-tidysrhythmic agent. It is thought that lidocaine acts by combining with fast sodium channels when inactive which inhibits recovery after repolarization. Class IB agents demonstrate rapid rates of at-tachment and dissociation to sodium channels. At therapeutic lev-els, lidocaine causes phase 4 diastolic depolarization attenuation, decreased automaticity, and either a decrease or no change in mem-brane responsiveness and excitability. These effects will occur at se-rum levels that will not inhibit the automaticity of the SA node, and will have little effect on A V node conduction or His-Purkinje conduction. Lidocaine apparently has some enhancing effects on intestinal motility in patients with postoperative ileus. The mechanism for this effect is not well understood, but probably involves more than just blocking increased sympathetic tone. Lidocaine has been shown to be a scavenger of reactive oxygen species (ROS) and lipid peroxidation	pppbs.pdf
LIDOCAINE HCL 537 Pharmacokinetics Lidocaine is not effective orally as it has a high ﬁrst-pass effect. If very high oral doses are given, toxic signs occur (due to active metabolites?) before therapeutic levels can be reached. Following a therapeutic IV bolus dose, the onset of action is generally within 2 minutes and has duration of action of 10-20 minutes. If a con-stant infusion is begun without an initial IV bolus, it may take up to an hour for therapeutic levels to be reached. IM injections may be given every 1. 5 hours in the dog, but because monitoring and adjusting dosages are difﬁcult, it should be reserved for cases where IV infusions are not possible. After injection, the drug is rapidly redistributed from the plasma into highly perfused organs (kidney, liver, lungs, heart) and dis-tributed widely throughout body tissues. It has a high afﬁnity for fat and adipose tissue and is bound to plasma proteins, primarily alpha 1-acid glycoprotein. It has been reported that lidocaine bind-ing to this protein is highly variable and concentration dependent in the dog and may be higher in dogs with inﬂammatory disease. Lidocaine is distributed into milk. The apparent volume of distri-bution (V d) has been reported to be 4. 5 L/kg in the dog. Lidocaine is rapidly metabolized in the liver to active metabo-lites (MEGX and GX). The terminal half-life of lidocaine in hu-mans is 1. 5-2 hours and has been reported to be 0. 9 hours in the dog. The half-lives of lidocaine and MEGX may be prolonged in patients with cardiac failure or hepatic disease. Less than 10% of a parenteral dose is excreted unchanged in the urine. Contraindications/Precautions/Warnings Cats tend to be more sensitive to the CNS effects of lidocaine; use with caution. Lidocaine is contraindicated in patients with known hypersensitivity to the amide-class local anesthetics, a severe degree of SA, A V or intraventricular heart block (if not being artiﬁcially paced), or Adams-Stokes syndrome. The use of lidocaine in pa-tients with Wolff-Parkinson-White (WPW) syndrome is controver-sial. Some manufacturers state its use is contraindicated, but several physicians have used the drug in people. Lidocaine should be used with caution in patients with liver dis-ease, congestive heart failure, shock, hypovolemia, severe respirato-ry depression, or marked hypoxia. It should also be used with cau-tion in patients with bradycardia or incomplete heart block having VPC's, unless the heart rate is ﬁrst accelerated. Patients susceptible to developing malignant hyperthermia should receive lidocaine with intensiﬁed monitoring. When preparing lidocaine for intravenous injection, be cer-tain of the concentration and do not use products containing epinephrine. Adverse Effects At usual doses and if the serum level remains within the proposed therapeutic range (1-5 micrograms/m L), serious adverse reactions are quite rare. The most common adverse effects reported are dose related (serum level) and mild. CNS signs include drowsiness, de-pression, ataxia, muscle tremors, etc. Nausea and vomiting may oc-cur, but are usually transient. Adverse cardiac effects generally only occur at high plasma concentrations and are usually associated with PR and QRS interval prolongation and QT interval shortening. Lidocaine may increase ventricular rates if used in patients with atrial ﬁbrillation. If an IV bolus is given too rapidly, hypotension may occur. Be certain not to use the product that contains epinephrine intravenously. Reproductive/Nursing Safety In humans, the FDA categorizes systemic lidocaine 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), systemic lidocaine 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. ) Lidocaine is excreted in concentrations of approximately 40% of that found in the serum and would unlikely to pose signiﬁcant risk to nursing offspring. Overdosage/Acute Toxicity In dogs, if serum levels of >8 micrograms/m L are attained, toxicity may result. Signs may include ataxia, nystagmus, depression, sei-zures, bradycardia, hypotension and, at very high levels, circulatory collapse. Because lidocaine is rapidly metabolized, cessation of ther-apy or reduction in infusion rates with monitoring may be all that is required for minor signs. Seizures or excitement may be treated with diazepam, or a short or ultrashort acting barbiturate. Longer acting barbiturates (e. g., pentobarbital) should be avoided. Should circulatory depression occur, treat with ﬂuids, pressor agents and, if necessary, begin CPR. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving lidocaine and may be of signiﬁcance in veterinary patients: !TANTIARRHYTHMICS, OTHER (e. g., procainamide, quinidine, propranolol, phenytoin ): When administered with lidocaine may cause additive or antagonistic cardiac effects and toxicity may be enhanced !TCIMETIDINE : Lidocaine levels or effects may be increased !TPHENYTOIN : May increase lidocaine metabolism; decrease levels !TPROPRANOLOL : Lidocaine levels or effects may be increased !TSUCCINYLCHOLINE : Large doses of lidocaine may prolong succinyl-choline-induced apnea Laboratory Considerations !TLidocaine may cause increased creatine kinase levels (CK). Doses !TDOGS: a) Initial bolus of 2 mg/kg slowly IV, up to 8 mg/kg; or rapid IV infusion of 0. 8 mg/kg/minute, if effective, then give constant rate infusion of 25-80 mcg/kg/minute (0. 025-0. 08 mg/kg/ minute) (Ware 2000) b) For rapid conversion of life-threatening, incessant, unstable ventricular tachycardia: Initial IV bolus of 1-2 mg/kg prefer-ably over 30 seconds to judge response, higher doses may be required but rarely need to give 4 mg/kg. Once effectiveness determined, begin constant rate infusion at 25-80 mcg/kg/ minute. Adjust dose to attain efﬁcacy but without side ef-fects. T o prevent adverse effects total dose should not exceed 8 mg/kg over approximately one hour. Alternatively may give lidocaine at 4 mg/kg IM, but not if shock is present. Effects generally are seen in 10-15 minutes, and persist for about 90 minutes. (Moise 2000) c) For ventricular arrhythmias: Initial dosage of 2-8 mg/kg IV slowly is given to effect while monitoring ECG; then follow-ing by a CRI of 25-75 mcg/kg/minute starting at a high dose and tapering down when possible. (Macintire 2006a)	pppbs.pdf
538 LIDOCAINE HCL T!TCATS: CAUTION: Cats are reportedly very sensitive to the CNS effects of lidocaine, monitor carefully and treat seizures with diazepam. a) Initially, IV bolus of 0. 25-0. 5 mg/kg given slowly; can re-peat at 0. 15-0. 25 mg/kg in 5-20 minutes; if effective, 10-20 mcg/kg/minute (0. 01-0. 02 mg/kg/min) as a constant rate IV infusion (Ware 2000) b) 0. 25-0. 5 mg/kg slow IV, with the possibility of repeating up to twice more if needed. If diluting for accurate dosing, use an insulin/tuberculin syringe. May be used as ﬁrst-line ther-apy, or after propranolol, if it was ineffective. (Cote 2004) !THORSES: (Note : ARCI UCGFS Class 2 Drug) For ventricular tachyarrhythmias: a) Initially IV bolus of 1-1. 5 mg/kg. Will generally distinguish between ventricular tachyarrhythmias (effective) and su-praventricular tachyarrhythmias (no effect). T o maintain ef-fect, a constant IV infusion will be required. (Hilwig 1987) b) 0. 25-0. 5 mg/kg IV (slowly) every 5-10 minutes up to a total dose of 1. 5 mg/kg (Mogg 1999) For postoperative ileus: a) Initially, IV bolus of 1. 3 mg/kg followed by a IV infusion of 0. 05 mg/kg/minute for 24 hours (Malone, Turner et al. 1999) Monitoring !TECG !TSigns of toxicity (see Adverse Effects and Overdosage) !TIf available and indicated, serum levels may be monitored. Therapeutic levels are considered to range from 1-6 micro-grams/m L. Client Information !This drug should only be used systemically by professionals fa-miliar with its use and in a setting where adequate patient moni-toring can be performed. Chemistry/Synonyms A potent local anesthetic and antiarrhythmic agent, lidocaine HCl occurs as a white, odorless, slightly bitter tasting, crystalline powder with a melting point between 74°-79°C and a p K a of 7. 86. It is very soluble in water and alcohol. The p H of the commercial injection is adjusted to 5-7, and the p H of the commercially available infusion in dextrose 5% is adjusted to 3. 5-6. Lidocaine may also be known as: lidocaini hydrochloridum, and lignocaine hydrochloride; many trade names are available; a com-mon trade name is Xylocaine® (Astra). Storage/Stability/Compatibility/Preparation Lidocaine for injection should be stored at temperatures less than 40°C and preferably between 15-30°C; avoid freezing. Lidocaine is physically compatible with most commonly used IV infusion solutions, including D5W, lactated Ringer's, saline, and combinations of these. It is also reportedly physically compat-ible with: aminophylline, bretylium tosylate, calcium chloride/glu-ceptate/gluconate,carbenicillin disodium,chloramphenicol sodium succinate, chlorothiazide sodium, cimetidine HCl, dexamethasone sodium phosphate, digoxin, diphenhydramine HCl, dobutamine HCl, ephedrine sulfate, erythromycin lactobionate, glycopyrrolate, heparin sodium, hydrocortisone sodium succinate, hydroxyzine HCl, insulin (regular), mephentermine sulfate, metaraminol bi-tartrate, methicillin sodium, metoclopramide HCl, nitrofurantoin sodium, oxytetracycline HCl, penicillin G potassium, pentobarbi-tal sodium, phenylephrine HCl, potassium chloride, procainamide HCl, prochlorperazine edisylate, promazine HCl, sodium bicarbon-ate, sodium lactate, tetracycline HCl, verapamil HCl, and Vitamin B-Complex with C. Lidocaine may not be compatible with dopamine, epinephrine, isoproterenol, or norepinephrine as these require low p H's for sta-bility. Lidocaine is reportedly physically incompatible when mixed with: ampicillin sodium, cefazolin sodium, methohexital sodium, or phenytoin sodium. Compatibility is dependent upon factors such as p H, concentration, temperature, and diluent used; consult specialized references or a hospital pharmacist for more speciﬁc information. T o prepare IV infusion solution using the veterinary 2% solu-tion add 1 gram (50 m L of 2% solution to 1 liter of D 5W or other compatible solution, this will give an approximate concentration of 1 mg/m L (1000 micrograms/m L). When using a mini-drip (60 drops/m L) IV set, each drop will contain approximately 17 micro-grams. In small dogs and cats, a less concentrated solution may be used for greater dosage accuracy. When preparing solution be certain that you are not using the lidocaine product that contains epinephrine. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: There are injectable lidocaine products labeled for use in veterinary medicine (dogs, cats, horses, and cattle) as an injectable anesthetic, but it is not approved for use as an antiarrhythmic agent. Information regarding its use in food-producing species is conﬂicting; when using a food animal it is suggested to contact FARAD (see appendix). Lidocaine HCl for Injection: 2% (20 mg/m L) in 100 m L & 250 m L multi-use vials; (contains preservatives). Manufacturers include: Ve-dco, Phoenix Pharmaceutical, Aspen, Agri Labs, IVX, Butler, & RXV; (Rx) The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Lidocaine Hydrochloride Injection: 0. 5%, 1%, 1. 5%, 2% & 4% in 5 m L, 10 m L, 20 m L, 30 m L & 50 m L single-& multi-dose vials, 2 m L & 5 m L amps, 5 m L syringe with laryngotracheal cannula & 1. 8 m L car-tridges; Xylocaine® & Xylocaine MPF® (Astra Zeneca); generic; (Rx) Premixed with D5W for IV infusion in concentrations of 2 mg/m L, 4 mg/m L, and 5 mg/mg, injections with epinephrine, topical liquids, patches, ointment, cream, lotion, gel, spray, & jelly available.	pppbs.pdf
LINCOMYCIN HCL 539 LINCOMYCIN HCL (lin-koe-mye-sin) Lincocin®, Lincomix® LINCOSAMIDE ANTIBIOTIC Prescriber Highlights TT Lincosamide antibiotic similar to clindamycin; broad spectrum against many anaerobes, gram-positive aerobic cocci, Toxoplasma, etc. TT Contraindications: Horses, Rodents, Ruminants, Lago-morphs; Hypersensitivity to lincosamides TT Caution: Liver or renal dysfunction; consider reducing dosage if severe TT Adverse Effects: Gastroenteritis, pain at injection site if given IM; rapid IV administration can cause hypotension & cardiopulmonary arrest TT Distributed into milk; may cause diarrhea in nursing animals TT Drug interactions Uses/Indications Lincomycin has dosage forms approved for use in dogs, cats, swine, and in combination with other agents for chickens. Because clin-damycin is generally better absorbed, more active, and probably less toxic, it has largely supplanted the use of lincomycin for oral and injectable therapy in small animals, but some clinicians believe that clindamycin does not offer enough clinically signiﬁcant improve-ments over lincomycin to justify its higher cost. For further infor-mation, refer to the Pharmacology or Doses sections. Pharmacology/Actions The lincosamide antibiotics lincomycin and clindamycin, share mechanisms of action and have similar spectrums of activity al-though lincomycin is usually less active against susceptible organ-isms. Complete cross-resistance occurs between the two drugs; at least partial cross-resistance occurs between the lincosamides and erythromycin. They may act as bacteriostatic or bactericidal agents, depending on the concentration of the drug at the infection site and the susceptibility of the organism. The lincosamides are be-lieved to act by binding to the 50S ribosomal subunit of susceptible bacteria, thereby inhibiting peptide bond formation. Most aerobic gram-positive cocci are susceptible to the lin-cosamides (Strep. faecalis is not), including staphylococcus and streptococci. Other organisms that are generally suscep-tible include: Corynebacterium diphtheriae, Nocardia asteroides, Erysepelothrix, and Mycoplasma spp. Anaerobic bacteria that may be susceptible to the lincomycin include: Clostridium perfringens. C. tetani (not C. difﬁcile), Bacteroides (including many strains of B. fragilis), Fusobacterium, Peptostreptococcus, Actinomyces, and Peptococcus. Pharmacokinetics The pharmacokinetics of lincomycin have not apparently been ex-tensively studied in veterinary species. Unless otherwise noted, the following information applies to humans. The drug is rapidly ab-sorbed from the gut, but only about 30-40% of the total dose is ab-sorbed. Food both decreases the extent and the rate of absorption. Peak serum levels are attained about 2-4 hour after oral dosing. IM administration gives peak levels about double those reached after oral dosing, and peak at about 30 minutes post injection. Lincomycin is distributed into most tissues. Therapeutic levels are achieved in bone, synovial ﬂuid, bile, pleural ﬂuid, peritoneal ﬂuid, skin, and heart muscle. CNS levels may reach 40% of those in the serum if meninges are inﬂamed. Lincomycin is bound from 57-72% to plasma proteins, depending on the drug's concentra-tion. The drug crosses the placenta and can be distributed into milk at concentrations equal to those found in plasma. Lincomycin is partially metabolized in the liver. Unchanged drug and metabolites are excreted in the urine, feces and bile. Half-lives can be prolonged in patients with renal or hepatic dysfunction. The elimination half-life of lincomycin is reportedly 3-4 hours in small animals. Contraindications/Precautions/Warnings Although there have been case reports of parenteral administration of lincosamides to horses, cattle and sheep, the lincosamides are considered contraindicated for use in rabbits, hamsters, guinea pigs, horses, and ruminants because of serious gastrointestinal effects that may occur, including death. Lincomycin is contraindicated in patients with known hyper-sensitivity to it or having a preexisting monilial infection. Adverse Effects Adverse effects reported in dogs and cats include gastroenteritis (emesis, loose stools, and infrequently bloody diarrhea in dogs). IM injections reportedly cause pain at the injection site. Rapid intrave-nous administration can cause hypotension and cardiopulmonary arrest. Swine may develop gastrointestinal disturbances while receiving the medication. Reproductive/Nursing Safety Lincomycin crosses the placenta and cord blood concentrations are approximately 25% of those found in maternal serum. Safe use during pregnancy has not been established, but neither has the drug been implicated in causing 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 trimes-ters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although speciﬁc studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) Because lincomycin is distributed into milk, nursing animals of mothers given lincomycin may develop diarrhea. Overdosage/Acute Toxicity There is little information available regarding overdoses of this drug. In dogs, oral doses of up to 300 mg/kg/day for up to one year or parenterally at 60 mg/kg/day apparently did not result in toxicity. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving lincomycin and may be of signiﬁcance in veterinary patients: T ! CYCLOSPORINE : Lincomycin may reduce levels T ! ERYTHROMYCIN : In vitro antagonism when used with lincomycin; concomitant use should probably be avoided T ! KAOLIN : Kaolin (found in several over-the-counter antidiarrheal preparations) has been shown to reduce the absorption of linco-	pppbs.pdf
540 LINCOMYCIN HCL mycin by up to 90% if both are given concurrently; if both drugs are necessary, separate doses by at least 2 hours !TNEUROMUSCULAR BLOCKING AGENTS (e. g., pancuronium ): Lincomycin possesses intrinsic neuromuscular blocking activity and should be used cautiously with other neuromuscular blocking agents Laboratory Considerations !TSlight increases in liver function tests (AST, ALT, Alk. Phosph. ) may occur. There is apparently not any clinical signiﬁcance as-sociated with these increases. Doses !TDOGS: For susceptible infections: a) For skin and soft tissue infections: 15. 4 mg/kg PO q8h or 22 mg/kg PO q12h. Treatment for superﬁcial pyoderma 21-42 days; for deep, resistant pyoderma 56 days; For systemic infections: 22 mg/kg IM, SC, or IV (must be diluted and given as a slow drip infusion) q24h or 11 mg/kg IM or SC q12h for 12 days or less. For bacteremia, sepsis: 11-22 mg/kg IV q8h for 12 days or less. (Greene, Hartmannn et al. 2006) b) For pyoderma: 20 mg/kg twice daily (Halliwell 2002) c) For superﬁcial pyodermas: 20 mg/kg PO q12h (White 2007) d) For pyoderma: 22 mg/kg PO twice daily; good for ﬁrst time pyodermas. (Logas 2005b) !TCATS: For susceptible infections: a) For skin and soft tissue infections: 11 mg/kg IM q12h or 22 mg/kg IM q24h. Treatment for 12 days or less; For systemic infections: 15 mg/kg PO q8h or 22 mg/kg PO q12h. Treatment for 12 days or less. (Greene, Hartmannn et al. 2006) !TFERRETS: For susceptible infections: a) 10-15 mg/kg PO three times daily; 10 mg/kg IM twice daily (Williams 2000) !TSWINE: For susceptible infections: a) For mycoplasmal (M. hyopneumoniae) pneumonia: Fed at 200 grams per ton of feed for 21 days or 11 mg/kg IM once daily (Amass 1999) b) 11 mg/kg IM once daily for 3-7 days; or added to drinking water at a rate of 250 mg/gallon (average of 8. 36 mg/kg/day) (Label directions; Lincocin®—Upjohn) Monitoring !TClinical efﬁcacy !TAdverse effects; particularly severe diarrheas Client Information !TClients should be instructed to report the incidence of severe, protracted, or bloody diarrhea to the veterinarian. Chemistry/Synonyms An antibiotic obtained from cultures of Streptomyces lincolnensis, lincomycin is available commercially as the monohydrate hydro-chloride. It occurs as a white to off-white, crystalline powder that is freely soluble in water. The powder may have a faint odor and has a p Kaof 7. 6. The commercially available injection has a p H of 3-5. 5 and occurs as a clear to slightly yellow solution. Lincomycin may also be as: U-10149, NSC-70731, Anbycin®, Frademicina®, Fredcina®, Linco®, Lincocin®, Linco Med®, Lincomix®, Linco-Ped®, Lincono®, and Macrolin®. Storage/Stability/Compatibility Lincomycin capsules, tablets and soluble powder should be stored at room temperature (15-30°C) in tight containers. Lincomycin injectable products should be stored at room temperature; avoid freezing. Lincomycin HCl for injection is reportedly physically compat-ible f o r a t l e a s t 2 4 h o u r s i n t h e f o l lowing IV infusion solutions and drugs: D 5W, D 5W in sodium chloride 0. 9%, D 10W, sodium chlo ride 0. 9%, Ringer's injection, amikacin sulfate, cephalot-hin sodium, chloramphenicol sodium succinate, cimetidine HCl, cytarabine, heparin sodium, penicillin G potassium/sodium (4 hours only), polymyxin B sulfate, tetracycline HCl, and vitamin B-complex with C. Drugs that are reportedly physically incompatible when mixed with lincomycin, data conﬂicts, or compatibility is concentration and/or time dependent include: ampicillin sodium,carbenicillin dis-odium, methicillin sodium, and phenytoin sodium. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital phar-macist for more speciﬁc information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Lincomycin Oral Tablets: 100 mg, 200 mg, 500 mg; Lincocin® (Phar-macia); (Rx). Approved for use in dogs and cats. Lincomycin Oral Solution: 50 mg/m L in 20 m L dropper bottles; Lin-cocin® Aquadrops (Pharmacia); (Rx). Approved for use in dogs and cats. Lincomycin Sterile Injection: 100 mg/m L in 20 m L vials; Lincocin® (Pharmacia); (Rx). Approved for use in dogs and cats. Lincomycin Sterile Injection: 25 mg/m L, 100 mg/m L & 300 mg/m L in 100 m L vials; approved for use in swine. Slaughter withdrawal (when used as labeled) = 48 hours. Lincocin® Sterile Solution (Phar-macia and Upjohn); Lincomix® Injectable (Pharmacia); Linco Med® (Bimeda); generic; (OTC) There are also several lincomycin combination feed/water additive products for use in swine and/or poultry. HUMAN-LABELED PRODUCTS: Lincomycin Capsules: 500 mg (as hydrochloride); Lincocin® (Up-john); (Rx) Lincomycin Injection: 300 mg (as hydrochloride)/m L in 2 m L and 10 m L vials; Lincocin® (Upjohn), (Rx)	pppbs.pdf
LIOTHYRONINE 541 LIOTHYRONINE SODIUM (lye-oh-thye-roe-neen) Cytomel®, Triostat® THYROID HORMONE Prescriber Highlights TT Form of T3 (active thyroid hormone) used for hypothy-roidism particularly in animals unresponsive to T4 TT Shorter duration of effect than levothyroxine TT Contraindications: Acute myocardial infarction, thyrotoxi-cosis, or untreated adrenal insufﬁciency TT Caution: Concurrent hypoadrenocorticism (treated), car-diac disease, diabetes, or elderly TT Adverse Effects: Only associated with OD's (tachycardia, polyphagia, PU/PD, excitability, nervousness, & excessive panting); some cats may appear apathetic TT Drug-drug; drug-lab interactions Uses/Indications Because of its shorter duration of action, liothyronine is generally not considered the drug of ﬁrst choice in treating hypothyroidism. Infrequently, animals not responding to levothyroxine may respond to liothyronine. Pharmacology/Actions Thyroid hormones affect the rate of many physiologic processes including: fat, protein, and carbohydrate metabolism, increas-ing protein synthesis, increasing gluconeogenesis, and promoting mobilization and utilization of glycogen stores. Thyroid hormones also increase oxygen consumption, body temperature, heart rate and cardiac output, blood volume, enzyme system activity, and growth and maturity. Thyroid hormone is particularly important for adequate development of the central nervous system. While the exact mechanisms how thyroid hormones exert their effects are not well understood, it is known that thyroid hormones (primarily tri-iodothyronine) act at the cellular level. In humans, triiodothyronine (T 3) is the primary hormone re-sponsible for activity. Approximately 80% of T 3 found in the pe-ripheral tissues is derived from thyroxine (T 4) which is the prin-ciple hormone released by the thyroid. Pharmacokinetics In dogs, peak plasma levels of liothyronine occur 2-5 hours after oral dosing. The plasma half-life is approximately 5-6 hours. In contrast to levothyroxine, it is believed that liothyronine is nearly completely absorbed by dogs and absorption is not as affected by stomach contents, intestinal ﬂora changes, etc. Contraindications/Precautions/Warnings Liothyronine (and other replacement thyroid hormones) are con-traindicated in patients with acute myocardial infarction, thyro-toxicosis, or untreated adrenal insufﬁciency. It should be used with caution, and at a lower initial dosage, in patients with concurrent hypoadrenocorticism (treated), cardiac disease, diabetes, or in el-derly patients. Adverse Effects When administered at an appropriate dose to patients requiring thyroid hormone replacement, there should not be any adverse ef-fects associated with therapy. For adverse effects associated with overdosage, see below. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category A for use dur-ing pregnancy (Adequate studies in pregnant women have not dem-onstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) Minimal amounts of thyroid hormones are excreted in milk and should not adversely affect nursing offspring. Overdosage/Acute Toxicity Chronic overdosage will produce signs of hyperthyroidism, includ-ing tachycardia, polyphagia, PU/PD, excitability, nervousness, and excessive panting. Dosage should be reduced and/or temporarily withheld until signs subside. Some (10%?) cats may exhibit signs of “apathetic” (listlessness, anorexia, etc. ) hyperthyroidism. Acute massive overdosage can produce signs resembling thy-roid storm. After oral ingestion, treatment to reduce absorption of drug should be accomplished using standard protocols (emet-ics or gastric lavage, cathartics, charcoal) unless contraindicated by the patient's condition. Treatment is supportive and symptomatic. Oxygen, artiﬁcial ventilation, cardiac glycosides, beta-blockers (e. g., propranolol), ﬂuids, dextrose, and antipyretic agents have all been suggested for use if necessary. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving liothyronine and may be of signiﬁcance in veterinary patients: T ! ANTIDEPRESSANTS, TRICYCLIC/TETRACYCLIC : Increased risk for CNS stimulation and cardiac arrhythmias T ! ANTIDIABETIC AGENTS (insulin, oral agents ): Levothyroxine may in-crease requirements for insulin or oral agents T ! CHOLESTYRAMINE : May reduce liothyronine absorption; separate doses by 4 hours T ! DIGOXIN : Potential for reduced digoxin levels T ! KETAMINE : May cause tachycardia and hypertension T ! SYMPATHOMIMETIC AGENTS (epinephrine, norepinephrine, etc. ): Levothyroxine can potentiate effects T ! WARFARIN : Thyroid hormones increase the catabolism of vitamin K-dependent clotting factors that may increase the anticoagula-tion effects in patients on warfarin Laboratory Considerations The following drugs may have effects on thyroid function tests; evaluate results accordingly: T ! EFFECTS ON SERUM T4: aminoglutethimide?, anabolic steroids/ androgens?, antithyroid drugs (PTU, methimazole)?, aspara-ginase?, barbiturates?, corticosteroids?, danazol?, diazepam?, estrogens B ( Note : estrogens may have no effect on canine T 3 or T4 concentrations), ﬂuorouracil B, heparin?, insulin B, lithium carbonate?, mitotane (o,p-DDD)?, nitroprusside?, phenylbuta-zone?, phenytoin?, propranolol B, salicylates (large doses)?, and sulfonylureas?. T ! EFFECTS ON SERUM T3: antithyroid drugs (PTU, methimazole)?, barbiturates?, corticosteroids?, estrogens B, ﬂuorouracil B, hepa-rin?, lithium carbonate?, phenytoin?, propranolol?, salicylates (large doses)?, and thiazides B. T ! EFFECTS ON T3 UPTAKE RESIN: anabolic steroids/androgens B, an-tithyroid drugs (PTU, methimazole)?, asparaginase B, corticos-teroids B, danazol B, estrogens?, ﬂuorouracil?, heparin B, lithium carbonate?, phenylbutazone B, and salicylates (large doses)B. T ! EFFECTS ON SERUM TSH: aminoglutethimide B, antithyroid drugs (PTU, methimazole)B, corticosteroids?, danazol?, and lithium carbonate B.	pppbs.pdf
542 LISINOPRIL T ! EFFECTS ON FREE THYROXINE INDEX (FTI): antithyroid drugs (PTU, methimazole)?, barbiturates?, corticosteroids?, heparin B, lith-ium carbonate?, and phenylbutazone?. Doses T ! DOGS: For hypothyroidism: a) Initially, 4-6 micrograms/kg PO q8h. Some dogs may re-quire less frequent dosing (Nelson 1989b) b) If poor absorption of levothyroxine is suspected: 4-6 mcg/ kg q8h (Scott-Moncrieff and Guptill-Y oran 2000) T ! CATS: For hypothyroidism: a) Initially, 4. 4 micrograms/kg PO 2-3 times a day (Feldman and Nelson 1987d) Monitoring T ! Similar to levothyroxine, but T 4 levels will remain low. When monitoring T 3 levels, draw serum just prior to dosing and again 2-4 hours after administering the drug. Client Information T ! Clients should be instructed in the importance of compliance with therapy as prescribed T ! Also, review the signs that can be seen with too much thyroid supplementation Chemistry/Synonyms LISINOPRIL (lye-sin-oh-pril) Prinivil®, Zestril® ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITOR Prescriber Highlights TT ACE inhibitor used primarily as a vasodilator in the treat-ment of heart failure or hypertension; may also be of beneﬁt in the treatment of chronic renal failure or pro-tein losing nephropathies TT May be less expensive than other ACE inhibitors & prob-ably can be dosed once daily TT Not as much information available or experience as enal-april in dogs or cats TT Contraindications: Hypersensitivity to ACE inhibitors TT Caution: Renal insufﬁciency (doses may need to be re-duced), patients with hyponatremia, coronary or cerebro-vascular insufﬁciency, preexisting hematologic abnormali-ties, or a collagen vascular disease (e. g., SLE) TT Adverse Effects: GI distress (anorexia, vomiting, diar-rhea); Potentially: weakness, hypotension, renal dysfunc-tion, & hyperkalemia A synthetically prepared sodium salt of the naturally occurring hormone T 3, liothyronine sodium occurs as an odorless, light tan crystalline powder. It is very slightly soluble in water and slightly soluble in alcohol. Each 25 micrograms of liothyronine is approxi-mately equivalent to 60-65 mg (1 grain) of thyroglobulin or desic-cated thyroid and 100 micrograms or less of levothyroxine. Liothyronine sodium may also be known as: T 3, T3 thyronine sodium, L-triiodothyronine, sodium L-triiodothyronine, liothy-roninum natricum, sodium liothyronine, l-tri-iodothyronine so-dium, 3,5,3'-Tri-iodo-L-thyronine sodium, Cynomel®, Cytomel®, Dispon®, Neo-Tiroimade®, T3 ®, Tertroxin®, Thybon®, Thyrotardin N®, Ti-Tre®, Triiodothyronine Injection®, Triostat®, Triyodisan®, and Triyotex ®. Storage/Stability/Compatibility Liothyronine tablets should be stored at room temperature (15-30°C) in tight containers. The injection should be stored refrigerated (2-8°C). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Liothyronine Sodium Tablets: 5 mcg, 25 mcg & 50 mcg; Cytomel® (Monarch); (Rx) Liothyronine Sodium Injection: 10 mcg/m L in 1 m L vials; Triostat® (Monarch); Liothyronine Sodium (X-Gen); (Rx) Uses/Indications The principle uses of lisinopril in veterinary medicine at present are as a vasodilator in the treatment of heart failure or hypertension. Recent studies have demonstrated that ACE inhibitors, particularly when used in conjunction with furosemide, do improve the quality of life in dogs with heart failure. It is not clear, however, whether it has any signiﬁcant effect on survival times. Lisinopril may also be of beneﬁt in treating the effects associated with valvular heart disease (mitral regurgitation) and left to right shunts. It is being explored as adjunctive treatment in chronic renal failure and in protein los-ing nephropathies. Lisinopril may have advantages over other ACE inhibitors in that it may be dosed once daily and less expensive. Disadvantages are that it is only available in human labeled dosage forms and there is much less published information on its use (efﬁcacy, safety, dos-ing) in veterinary species. Pharmacology/Actions Unlike enalapril, lisinopril does not need to be converted in the liver to an active metabolite. Lisinopril prevents the formation of angio-tensin-II (a potent vasoconstrictor) by competing with angiotensin-I for the enzyme angiotensin-converting enzyme (ACE). ACE has a much higher afﬁnity for lisinopril than for angiotensin-I. Because angiotensin-II concentrations are decreased, aldosterone secretion is reduced and plasma renin activity is increased. Lisinopril has a higher afﬁnity for ACE than either enalaprilat or captopril. The cardiovascular effects of lisinopril in patients with CHF include decreased total peripheral resistance, pulmonary vascular resistance, mean arterial and right atrial pressures, and pulmonary capillary wedge pressure, no change or decrease in heart rate, and increased cardiac index and output, stroke volume, and exercise tolerance. Renal blood ﬂow can be increased with little change in hepatic blood ﬂow. In animals with glomerular disease, ACE in-hibitors probably decrease proteinuria and help to preserve renal function.	pppbs.pdf
LISINOPRIL 543 Pharmacokinetics In dogs, lisinopril's bioavailability ranges from 25-50% with peak levels occurring about 4 hours after dosing. Lisinopril is distributed poorly into the CNS. It is unknown if it is distributed into maternal milk, but it does cross the placenta. Half-lives are increased in pa-tients with renal failure or severe CHF. Duration of action in dogs has been described as being 24 hours, but effects tend to drop off with time. Contraindications/Precautions/Warnings Lisinopril is contraindicated in patients who have demonstrated hypersensitivity to the ACE inhibitors. It should be used with cau-tion and close supervision in patients with renal insufﬁciency and doses may need to be reduced. Lisinopril should be used with caution in patients with hy-ponatremia or sodium depletion, coronary or cerebrovascular in-sufﬁciency, preexisting hematologic abnormalities, or a collagen vascular disease (e. g., SLE). Patients with severe CHF should be monitored very closely upon initiation of therapy. Adverse Effects Lisinopril's adverse effect proﬁle in dogs is reportedly similar to oth-er ACE inhibitors, principally GI distress (anorexia, vomiting, diar-rhea). Potentially, cough, weakness, hypotension, renal dysfunction, and hyperkalemia could occur. Because it lacks a sulfhydryl group (unlike captopril), there is less likelihood that immune-mediated reactions will occur, but rashes, neutropenia, and agranulocytosis have been reported in humans. Reproductive/Nursing Safety Lisinopril crosses the placenta. High doses in rodents have caused decreased fetal weights and increases in fetal and maternal death rates; teratogenic effects have not been reported. Current recommendations for humans are to discontinue ACE inhibitors as soon as pregnancy is detected. 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 adequate studies in humans. ) In humans, the FDA categorizes this drug as category D for use during the second and third trimesters of pregnancy (There is evidence of human fetal risk, but the potential beneﬁts from the use of the drug in pregnant women may be acceptable despite its potential risks. ) It is not known whether lisinopril is excreted in milk; use with caution. Overdosage/Acute Toxicity There were 598 exposures to lisinopril reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org ) dur-ing 2005-2006. In these cases 555 were dogs with 22 showing clini-cal signs and the remaining cases were 41 cats and 2 birds with no clinical signs. Common ﬁndings in dogs recorded in decreasing frequency included lethargy, tachycardia, vomiting, hypersalivation and hypotension. In overdose situations, the primary concern is hypotension; supportive 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 overdoses should be managed using gut-emptying protocols when warranted. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving lisinopril and may be of signiﬁcance in veterinary patients: !TANTIDIABETIC AGENTS (insulin, oral agents ): Possible increased risk for hypoglycemia; enhanced monitoring recommended !TDIURETICS (e. g., furosemide, hydrochlorothiazide ): Potential for in-creased hypotensive effects; some veterinary clinicians recom-mend reducing furosemide doses (by 25-50%) when adding ACE-inhibitors to therapy in CHF !TDIURETICS, POTASSIUM-SPA RING (e. g., spironolactone, triamterene ): Increased hyperkalemic effects, enhanced monitoring of serum potassium recommended !THYPOTENSIVE AGENTS, OTHER : Potential for increased hypotensive effect !TLITHIUM : Increased serum lithium levels possible; increased moni-toring required !TNSAIDS : May reduce the anti-hypertensive or positive hemody-namic effects of enalapril; may increase risk for reduced renal function !TPOTASSIUM SUPPLEMENTS : Increased risk for hyperkalemia Laboratory Considerations !TACE inhibitors may cause a reversible decrease in localization I123/I134and excretion of iodohippurate sodium, or Technetium Tc99 pententate renal imaging in the affected kidney in patients with renal artery stenosis, which may lead to confusion in test interpretation. Doses !TDOGS: For adjunctive treatment of heart failure: a) 0. 5 mg/kg PO q12-24 hours (Ware and Keene 2000) b) Usually: 0. 5 mg/kg PO once daily (q24h); a dose of 0. 25-0. 5 mg/kg PO q12h or 1 mg/kg PO once daily may be more ef-fective, but further studies needed to determine clinically ef-fective doses (Kittleson 2000) c) 0. 5 mg/kg PO q24h (Fuentes 2003) !TCATS: For adjunctive treatment of heart failure: a) 0. 25-0. 5 mg/kg PO once daily (Fox 2000) Monitoring !TClinical signs of CHF !TSerum electrolytes, creatinine, BUN, urine protein !TCBC with differential, periodic !TBlood pressure (if treating hypertension or signs associated with hypotension arise) Client Information !TDo not abruptly stop or reduce therapy without veterinarian's guidance !TContact veterinarian if vomiting or diarrhea persist or are severe or if animal's condition deteriorates. Chemistry/Synonyms An oral angiotensin-converting enzyme inhibitor (ACE inhibitor) lisinopril is directly active and not a prodrug like enalapril. It occurs as a white crystalline powder. One mg is soluble in 10 m L of water; 70 m L of methanol. It is practically insoluble in alcohol, chloro-form, or ether. Lisinopril may also be known as: L-154826, lisinoprilum, and MK-521; many trade names are available. Storage/Stability Store lisinopril tablets at room temperature in tight containers, un-less otherwise directed by manufacturer.	pppbs.pdf
544 LOMUSTINE Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Lisinopril Tablets: 2. 5 mg, 5 mg, 10 mg, 20 mg, 30 mg and 40 mg; Prinivil® (Merck); Zestril® (Astra Zeneca); generic; (Rx) Also available are ﬁxed dose combinations of lisinopril with hydro-chlorothiazide. LOMUSTINE (CCNU) (loe-mus-teen) Cee Nu® Prescriber Highlights TT Antineoplastic usually used for CNS neoplasms, mast cell tumors, or as a rescue agent for lymphosarcoma TT Cautions (risk vs. beneﬁt): Anemia, bone marrow depres-sion, pulmonary function impairment, current infection, impaired renal function, sensitivity to lomustine, or patients that have received previous chemotherapy or radiotherapy TT Adverse Effects: GI effects (anorexia, vomiting, diarrhea), stomatitis, alopecia, corneal de-epithelization, &, rarely, renal toxicity, hepatotoxicity, & pulmonary inﬁltrates or ﬁbrosis. Most serious: bone marrow depression (anemia, thrombocytopenia, leukopenia); nadirs in dogs generally occur about 1-3 weeks after treatment TT Teratogenic Uses/Indications Lomustine may be useful in the adjunctive treatment of CNS neo-plasms, lymphomas, and mast cell tumors in dogs and cats. Pharmacology/Actions While lomustine's mechanism of action is not totally understood, it is believed it acts as an alkylating agent; however, other mecha-nisms such as carbamoylation and cellular protein modiﬁcation may be involved; net effects are DNA and RNA synthesis inhibition. Lomustine is cell cycle-phase nonspeciﬁc. Pharmacokinetics Lomustine is absorbed rapidly and extensively from the GI tract and some absorption occurs after topical administration. Lomustine or its active metabolites are widely distributed in the body. While lo-mustine is not detected in the CSF, its active metabolites are de-tected in substantial concentrations. Lomustine is metabolized ex-tensively in the liver to both active and inactive metabolites that are then eliminated primarily in the urine. Lomustine half-life in humans is very short (about 15 minutes), but its biologic activity is signiﬁcantly longer due to the longer elimination times of active metabolites. Contraindications/Precautions/Warnings Lomustine should be used only when its potential beneﬁts out-weigh its risks with the following conditions: anemia, bone marrow depression, pulmonary function impairment, current infection, impaired renal function, sensitivity to lomustine, or patients who have received previous chemotherapy or radiotherapy. Adverse Effects The most serious adverse effects are bone marrow depression (ane-mia, thrombocytopenia, leukopenia) and hepatotoxicity. CBC na-dirs in dogs generally occur about 1-6 weeks after treatment has begun. In dogs, lomustine may cause delayed, cumulative dose-related, chronic, irreversible hepatotoxicity (Kristal, Rassnick et al. 2004). There are some anecdotal reports of SAMe being successfully used to treat lomustine hepatotoxicity. Other potential adverse ef-fects include GI effects (anorexia, vomiting, diarrhea), stomatitis, alopecia, corneal de-epithelization and rarely, renal toxicity, and pulmonary inﬁltrates or ﬁbrosis. Cross-resistance may occur between lomustine and carmustine. Reproductive/Nursing Safety Lomustine is a teratogen in lab animals. Use only during pregnancy when the beneﬁts to the mother outweigh the risks to the offspring. Lomustine can suppress gonadal function. In humans, the FDA cat-egorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential beneﬁts from the use of the drug in pregnant women may be acceptable despite its potential risks. ) Lomustine and its metabolites have been detected in maternal milk. Nursing puppies should receive milk replacer when the bitch is receiving lomustine. Overdosage/Acute Toxicity No speciﬁc information was located. Because of the potential toxic-ity of the drug, overdoses should be treated aggressively with gut emptying protocols employed when possible. For further informa-tion, refer to an animal poison control center. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving lomustine and may be of signiﬁcance in veterinary patients: T ! IMMUNOSUPPRESSIVE DRUGS, OTHER (e. g., azathioprine, cyclophosph-amide, corticosteroids ): Use with other immunosuppressant drugs may increase the risk of infection. T ! MYELOSUPPRESSIVE DRUGS, OTHER (e. g., chloramphenicol, ﬂucytosine, amphotericin B, or colchicine ): The principal concern with lomus-tine is with its concurrent use with other drugs that are also my-elosuppressive, including many of the other antineoplastics and other bone marrow depressant drugs. Bone marrow depression may be additive. T ! VACCINES, LIVE VIRUS : Live virus vaccines should be used with cau-tion, if at all, during lomustine therapy. Doses For more information on using lomustine as part of chemotherapy protocols, refer to the protocols found in the appendix or other dos-ages/protocols found in numerous references, including: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). T ! DOGS: For the treatment of neoplasms: a) As a rescue agent as part of a protocol for relapsed (after CHOP) canine lymphomas: Lomustine at 70 mg/m2 (for dogs 15 kg or more) or 60 mg/m2 (for dogs <15 kg) PO ev-ery 3 weeks for a total of 5 doses or until disease progression;	pppbs.pdf
LOPERAMIDE HCL 545 Asparaginase at 400 U/kg SC with the ﬁrst two lomustine doses and then discontinued; Prednisone started at 2 mg/kg PO once daily and tapered to 1 mg/kg PO every other day. If neutrophil count <500 cells/mc L at one week after lomus-tine, then doses were decreased by 10 mg/m2 for subsequent doses. All doses were rounded down to the nearest 10 mg dose. (Saba, Thamm et al. 2007) b) As a rescue agent for relapsed canine lymphomas: 90 mg/m2 PO every 21 days for 3 cycles, then every 4-6 weeks thereaf-ter (Moore, London et al. 1999) c) As a rescue agent for mast cell tumors when other treatment options have failed: 70-90 mg/m2 PO every 21 days (Chun 2007b) d) 60-80 mg/m2 PO q4-6 weeks (Brewer 2003) e) 80 mg/m2 PO every 3 weeks (Lana 2002) f) For cutaneous lymphosarcoma: Isotretinoin at 3-4 mg/kg PO daily. Prednisone (1 mg/kg/day) may be useful to allevi-ate pruritus. Lomustine at 50 mg/m2 PO q21-30 days may be effective (White 2005c) g) For systemic histiocytosis: lomustine at 70 mg/m2 PO every 3 weeks; cyclosporine 5-10 mg/kg once daily (q24h); pred-nisone 2 mg/kg PO q12-24h. (Hillier 2006d) h) For canine cutaneous epitheliotropic lymphoma (ELSA): 60 mg/m2 PO every three weeks. Authors concluded that lomus-tine seemed to be safe and well tolerated. Response duration was short, but high response rate supports incorporating lomustine into protocols to treat ELSA. Additional prospec-tive investigations are warranted. (Risbon, de Lorimeir et al. 2006) i) For brain tumors: Initially, 60 mg/m2 PO; if toxicity is mini-mal the dosage is increased slowly to 80 mg/m2. Treatments given every 5-8 weeks. CBC done every week between treat-ments. (Fulton 1991) T ! CATS: For the treatment of neoplasms: a) 60 mg/m2 PO q6 weeks (Brewer 2003) b) 60 mg/m2 PO q6 weeks or 10 mg (total dose) PO every three weeks. (Kitchell 2005) Monitoring T ! CBC with platelets one week after dosing and prior to next dose; If platelets less than 200,000/mcl; stop therapy until thrombocy-topenia is resolved T ! Liver function tests; initially before starting treatment and then every 3-4 months Chemistry/Synonyms A nitrosourea derivative alkylating agent, lomustine occurs as a yellow powder that is practically insoluble in water and soluble in alcohol. Lomustine may also be known as: CCNU, lomustinum, NSC-79037, RB-1509, WR-139017, Belustine®, CCNU®, Cecenu ®, Cee Nu®, Ci NU®, Citosta®, Lomeblastin®, Lucostin®, Lucostine®, and Prava ®. Storage/Stability Store capsules in well-closed containers at room temperature. Expiration dates of two years are assigned after manufacture. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Lomustine Capsules: 10 mg, 40 mg & 100 mg with mannitol; Dose Pack (two 100 mg capsules, two 40 mg capsules and two 10 mg cap-sules); Cee Nu® (Bristol Labs Oncology); (Rx) LOPERAMIDE HCL (loe-per-a-mide) Imodium® OPIATE ANTIDIARRHEAL Prescriber Highlights TT Synthetic opiate GI motility modiﬁer TT Contraindications: Known hypersensitivity to narcotic analgesics, diarrhea caused by a toxic ingestion until the toxin is eliminated from the GI tract TT Caution: Respiratory disease, hepatic encephalopathy, hypothyroidism, severe renal insufﬁciency, adrenocorti-cal insufﬁciency (Addison's), head injuries, or increased intracranial pressure, & acute abdominal conditions (e. g., colic), & in geriatric or severely debilitated patients; use loperamide cautiously in Collie-type breeds TT Adverse Effects: DOGS: Constipation, bloat, & sedation. Potential for: paralytic ileus, toxic megacolon, pancreati-tis, & CNS effects. CAT S: Use is controversial, may exhibit excitatory behavior. TT Dose carefully in small, small animals Uses/Indications Loperamide is used as a GI motility modiﬁer in small animals. Use in cats is controversial and many clinicians do not recommend us-ing in cats. Pharmacology/Actions Among their other actions, opiates inhibit GI motility and exces-sive GI propulsion. They also decrease intestinal secretion induced by cholera toxin, prostaglandin E 2 and diarrheas caused by factors in which calcium is the second messenger (non-cyclic AMP/GMP mediated). Opiates may also enhance mucosal absorption. Pharmacokinetics In dogs, loperamide reportedly has a faster onset of action and lon-ger duration of action than diphenoxylate, but clinical studies con-ﬁrming this appear to be lacking. In humans, loperamide's half-life is about 11 hours. It is unknown if the drug enters milk or crosses the placenta. Contraindications/Precautions/Warnings All opiates should be used with caution in patients with hypothy-roidism, severe renal insufﬁciency, adrenocortical insufﬁciency, (Addison's), and in geriatric or severely debilitated patients. Opiate antidiarrheals should be used with caution in patients with head injuries or increased intracranial pressure and acute abdominal conditions (e. g., colic), as it may obscure the diagnosis or clinical course of these conditions. It should be used with ex-treme caution in patients suffering from respiratory disease or from acute respiratory dysfunction (e. g., pulmonary edema secondary to smoke inhalation). Opiate antidiarrheals should be used with ex-	pppbs.pdf
546 LOPERAMIDE HCL treme caution in patients with hepatic disease with CNS clinical signs of hepatic encephalopathy. Hepatic coma may result. Many clinicians recommend not using diphenoxylate or loper-amide in dogs weighing less than 10 kg, but this is probably a result of the potency of the tablet or capsule forms of the drugs. Dosage titration using the liquid forms of these agents should allow their safe use in dogs when indicated. Because loperamide is potentially a neurotoxic substrate of P-glycoprotein, it should be used with caution in those herding breeds (e. g., Collies, Shelties, Australian shepherds, etc. ) that may have the gene mutation that causes a non-functional protein. Adverse Effects In dogs, constipation, bloat, and sedation are the most likely ad-verse reactions encountered when usual doses are used. Potentially, paralytic ileus, toxic megacolon, pancreatitis, and CNS effects could be seen. Use of antidiarrheal opiates in cats is controversial; this species may react with excitatory behavior. Reproductive/Nursing Safety In humans, the FDA categorizes loperamide as category B for use during pregnancy ( Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) It is not known whether loperamide is excreted in maternal milk. Safety during nursing has not been established. Overdosage/Acute Toxicity In dogs, doses of 1. 25 to 5 mg/kg/day produced vomiting, depres-sion, severe salivation, and weight loss. Breeds with a defective MDR-1 gene are more sensitive to CNS depression with loperamide than other breeds. There were 903 exposures to loperamide reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org ) dur-ing 2000-2006. In these cases 862 were dogs with 395 showing clin-ical signs and 33 cats with 11 showing clinical signs. The remaining cases were 3 rodents, 4 birds and 1 rabbit, none of which showed clinical signs. Common ﬁndings in dogs recorded in decreasing fre-quency included vomiting, lethargy, diarrhea, depression, hypersal-ivation, hypothermia, bradycardia and anorexia. Common ﬁndings in cats recorded in decreasing frequency included diarrhea, vomit-ing, anorexia, hypersalivation and vocalization. Treatment should follow standard decontamination protocols. Naloxone may be used to treat severe effects; higher than usual doses may be required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving loperamide and may be of signiﬁcance in veterinary patients: !TAMIODARONE : By inhibiting P-gp may increase loperamide plasma concentrations !TCARV EDILOL : By inhibiting P-gp may increase loperamide plasma concentrations !TERYTHROMYCIN : By inhibiting P-gp may increase loperamide plas-ma concentrations !TKETOCONAZOLE, ITRACONAZOLE : By inhibiting P-gp may increase loperamide plasma concentrations !TQUINIDINE : By inhibiting P-gp may increase loperamide plasma concentrations !TTAMOXIFEN : By inhibiting P-gp may increase loperamide plasma concentrations !TVERAPAMIL : By inhibiting P-gp may increase loperamide plasma concentrations Laboratory Considerations !TPlasma amylase and lipase values may be increased for up to 24 hours following administration of opiates. Doses !TDOGS: As an antidiarrheal: Note : Collies and related breeds may be overly sensitive to lop-eramide a) 0. 08 mg/kg, PO three times daily (De Novo 1988), (Washa-bau 2004) b) 0. 1-0. 2 mg/kg PO q8-12h (Willard 2003a) c) 0. 1 mg/kg PO three times a day; probably should not be given longer than 5 days and is potentially contraindicated when diarrhea is suspected to be caused by enteric infections (Hall and Simpson 2000) d) 0. 1-0. 2 mg/kg PO q8h (Jergens 1995) e) 0. 08 mg/kg PO 3-4 times a day (Cote 2000) f) 0. 1-0. 2 mg/kg PO q6-12h (Leib 2004b) !TCATS: Note : Use of antidiarrheal opiates in cats is controversial; this species may react with excitatory behavior. a) For Diarrhea: Using the suspension 0. 04-0. 06 mg/kg PO twice daily (Tams 1999) b) 0. 08-0. 16 mg/kg PO q12h (Willard 2003a) !TRABBITS, RODENTS, SMALL MAMMALS: a) Rabbits: 0. 1 mg/kg in 1 m L of water PO q8h for 3 days, then once daily for 2 days (Ivey and Morrisey 2000) b) Mice, Rats, Gerbils, Hamsters, Guinea pigs, Chinchillas: 0. 1 mg/kg PO q8h for 3 days, then once daily for 2 days; give in 1 m L of water (Adamcak and Otten 2000) Monitoring !TClinical efﬁcacy !TFluid and electrolyte status in severe diarrhea !TCNS effects if using high dosages Client Information !TIf diarrhea persists or if animal appears listless or develops a high fever, contact veterinarian. Chemistry/Synonyms A synthetic piperidine-derivative antidiarrheal, loperamide occurs as a white to faintly yellow powder with a p K a of 8. 6 that is soluble in alcohol and slightly soluble in water. Loperamide may also be known as PJ 185, or R 18553; a com-mon trade name is Imodium®. Storage/Stability/Compatibility Loperamide capsules or oral solution should be stored at room temperature in well-closed containers. It is recommended that the oral solution not be diluted with other solvents.	pppbs.pdf
LORAZEPAM 547 Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Loperamide HCl Oral Liquid: 1 mg/5 m L (0. 2 mg/m L), 1 mg/7. 5 m L and 1 mg/m L in 60 m L, 90 m L, 118 m L and 120 m L; Imodium® A-D (Mc Neil-CPC); Pepto ® Diarrhea Control (Procter and Gamble); ge-neric; (OTC) Loperamide HCl Capsules and Tablets: 2 mg; Imodium® A-D Caplets (Mc Neil-CPC); Neo-Diaral® (Roberts); K-Pek II® (Rugby); generic; (OTC & Rx) LORAZEPAM (lor-ayz-eh-pam) Ativan® BENZODIAZEPINE Prescriber Highlights TT Benzodiazepine that can be useful as an anxiolytic in dogs & cats & as an alternative to diazepam for treating status epilepticus TT Can be administered intranasally or IV for status epilepticus TT Adverse Effects (most likely): Increased appetite, activity or behavior changes (lethargy/somnolence to hyperexcit-ability/aggression) Uses/Indications Lorazepam may be useful in treating status epilepticus in dogs and the adjunctive treatment of behavior disorders (fears, phobias, anxiety) in dogs and cats. Although, in veterinary medicine, when compared with diazepam, there is much less experience using lora-zepam, it has some advantages. Lorazepam is not metabolized by the liver into active metabolites, appears as effective as diazepam, may have longer anticonvulsant duration of action (not proven in dogs), and can be easier to administer (intranasal, IM, sublingual/ buccal). In human medicine, lorazepam is now frequently used in place of diazepam for treating status epilepticus and anxiolytic indica-tions. It is also used for treating cancer chemotherapy-induced nausea and emesis, alcohol withdrawal, and akathisia secondary to antipsychotic medications. Pharmacology/Actions Lorazepam and other benzodiazepines depress the subcortical lev-els (primarily limbic, thalamic, and hypothalamic) of the CNS thus producing anxiolytic, sedative, skeletal muscle relaxant, and anti-convulsant effects. The exact mechanism of action is unknown, but postulated mechanisms include: antagonism of serotonin, increased release of and/or facilitation of gamma-aminobutyric acid (GABA) activity, and diminished release or turnover of acetylcholine in the CNS. Benzodiazepine speciﬁc receptors have been located in the mammalian brain, kidney, liver, lung, and heart. Receptors are lack-ing in the white matter In all species studied. Pharmacokinetics In dogs, intravenous administration of 0. 2 mg/kg gave peak levels of about 165 ng/m L and remained above 30 ng/m L (considered neces-sary for anticonvulsant activity in humans) for 60 minutes. After in-tranasal administration of 0. 2 mg/kg to dogs (Mariani, Clemmons et al. 2003), peak levels of about 106 ng/m L were achieved; in 3/6 dogs studied, levels stayed above 30 ng/m L for 60 minutes. Levels reached 30 ng/m L between 3-9 minutes after intranasal adminis-tration. While elimination half-life has been reported as approxi-mately 1 hour in dogs, concentrations in the brain may persist longer than in the serum as lorazepam has a high afﬁnity for ben-zodiazepine receptors in the CNS. Rectal administration of loraze-pam in dogs does not appear to yield serum concentrations high enough for efﬁcacious treatment of status epilepticus due to a high ﬁrst-pass effect. Lorazepam is converted into glucuronide forms in the liver in most species. These metabolites are not active. Primary elimination route is via the urine in dogs. In cats, elimination is approximately 50% in the urine (primarily as the glucuronide) and 50% in the feces. In humans, absolute bioavailability is about 90% after oral ad-ministration and, unlike diazepam, it is relatively rapidly and com-pletely absorbed after IM dosing. Sublingual administration has similar bioavailability as oral dosing, but serum levels peak sooner. Elimination half-life appears to be much longer in humans (12 hours) than in dogs (≈1 hour). Contraindications/Precautions/Warnings Lorazepam is contraindicated in patients known to be hypersen-sitive to benzodiazepines, or with severe respiratory insufﬁciency unless being mechanically ventilated. When using for negative behaviors, withdraw the drug gradu-ally or a rebound effect may occur. Physical dependency has been induced in dogs. If long-term regular usage has occurred, withdraw the drug gradually. Injectable lorazepam must not be given intra-arterially; arterio-spasm may occur resulting in necrosis. Adverse Effects In small animals, benzodiazepines can cause increased appetite, aggression, increased activity/excitement, and vocalization. With initiation of therapy, dosage increases, or at higher dosages, ataxia, somnolence and lethargy can occur. Reproductive/Nursing Safety For humans, lorazepam is designated by the FDA 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. ) However, studies in animals generally suggest that the drug is relatively safe for use during preg-nancy at usual dosages. Except in one study in mice that were given approximately 400X the human dose producing offspring with an increased rate of cleft palate formation, animal studies have not shown signiﬁcant increased rates of teratogenicity. If high doses are used just prior to delivery, “ﬂoppy infant” syndrome has been seen in humans. Small amounts of lorazepam are distributed into milk, but it should be safe to use during nursing. Overdosage/Acute Toxicity Overdoses of lorazepam are generally limited to CNS depression (confusion, lethargy, somnolence, decreased reﬂexes, etc. ). Very large overdoses can cause ataxia, hypotension, coma, and death (very rare). Treatment of acute orally-ingested toxicity consists of standard protocols for removing and/or binding the drug in the gut and sup-portive systemic measures. In patients with normal renal function, forced diuresis with intravenous ﬂuids/electrolytes and mannitol may enhance excretion of lorazepam. The use of analeptic agents (CNS stimulants such as caffeine) is generally not recommended. Flumazenil may be considered for adjunctive treatment of serious	pppbs.pdf
548 LUFENURON T Toverdoses of benzodiazepines, but its use does not replace proper supportive therapy. Flumazenil is not recommended in patients with seizure-disorders as it may induce seizures. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving lorazepam and may be of signiﬁcance in veterinary patients: T ! CNS DEPRESSANTS (e. g., opiates, barbiturates, sedatives, anticonvul-sants ): Additive CNS effects T ! PROBENECID : Decreased renal clearance of lorazepam T ! SCOPOLAMINE : Increased CNS depression, irrational behavior T ! THEOPHYLLINE : Decreased sedation from lorazepam T ! VALPROATE : Increased lorazepam serum concentration Laboratory Considerations No speciﬁc concerns noted Doses T ! DOGS/CAT S: a) Dogs: as an alternative to diazepam for status epilepticus: 0. 2 mg/kg IV, IM or intranasal once. (Hopper 2006a) b) For fears, anxieties, phobias: Dogs: 0. 02-0. 1 mg/kg PO once daily to three times a day; may be used on an as needed basis. Cats: 0. 125 mg-0. 25 mg (G-H of a 0. 5 mg tablet) once a day to twice a day; may be used on an as needed basis. (Landsberg 2005b) c) As an anxiolytic: Dogs/Cats: 0. 05-0. 25 mg/kg PO q12-24h. (Virga 2005b) Monitoring T ! No speciﬁc monitoring is required beyond clinical efﬁcacy and adverse effects Client Information T ! his medication may increase appetite, diligent food restriction may be required T ! May cause changes in activity levels and can cause either lethargy or increased activity/excitement T ! Do not stop treatment abruptly without veterinarian's guid-ance; animals receiving this medication on a regular basis for a prolonged period of time may develop withdrawal signs if not “weaned off ” the drug T ! Although liver toxicity has not yet been reported in animals re-ceiving this medication, a drug (diazepam) similar to lorazepam has rarely caused liver toxicity in cats. If vomiting, lack of ap-petite, or yellowing of the whites of eyes or mucous membranes occur contact veterinarian immediately. T ! ablets are relatively tasteless and readily disintegrate in saliva. If pilling is difﬁcult, place inside the patient's cheek and follow in a minute or so with a small treat to facilitate swallowing of saliva/ medication. Chemistry/Synonyms Lorazepam occurs as a white or practically white, practically odorless powder. It is insoluble in water and sparingly soluble in alcohol. Lorazepam may also be known as BRN-07599084, CB-8133, Ro-7-8408, Wy-4036, lorazapamum, anxiedin, azurogen, bonatran-quan, delormetazepam, lorazin, lorazon, lorenin, norlormetazepam, novhepar, novolorazem, o-Chloroxazepam, sinestron, Ativan®, and Lorazepam Intensol®; many international trade names are avail-able. Storage/Stability/Compatibility Lorazepam tablets should be stored in well-closed containers at room temperature (20-25°C). The oral solution and injection should be stored refrigerated (2-8°C) and protected from light. The injection must be further diluted just prior before to intra-venous injection with an equal volume of D5W, normal saline, or sterile water for injection. Do not shake the syringe vigorously, but gently invert repeatedly until the injection is diluted and completely mixed in solution. Do not use if solution is discolored or a precipi-tate forms. IV injections should be administered slowly, 2 mg over 2-5 minutes. Although not part of the label information, lorazepam can be further diluted in D5W or NS for IV infusion. When used in this manner, lorazepam injection is most soluble in ﬁnal concentrations from 0. 1-0. 2 mg/m L. For example, if using the 2 mg/m L injection, further dilution with 9 m L or 19 m L of D5W or NS would yield a ﬁnal concentration of 0. 2 or 0. 1 mg/m L. The injection is very vis-cous; mix well before use. As precipitation/crystallization can oc-cur, observe the solution before and during the infusion. D5W may be less prone to crystallization formation than is NS. Solutions for infusion mixed in this manner should be used within 12 hours of preparation. Medications reported to be compatible (partial listing): ! !Syringe : hydromorphone T ! Y-Site : albumin, amikacin, amphotericin B cholesteryl, atracuri-um, cefotaxime, ciproﬂoxacin, cisplatin, dexamethasone, diltiaz-em, dobutamine, doxorubicin, famotidine, fentanyl, gentamicin, heparin, morphine, propofol, ranitidine, and vancomycin Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See appendix for more information. HUMAN-LABELED PRODUCTS: Lorazepam Tablets: 0. 5, 1, & 2 mg; generic; (Rx; C-IV) Lorazepam Concentrated Oral Solution: 2 mg/m L in 10 m L and 30 m L bottles with dropper (contains 0. 6 g of PEG 400 in propylene gly-col per m L of solution); Lorazepam Intensol® (Roxane); (Rx; C-IV) Lorazepam Injection: 2 mg/m L and 4 mg/m L in 1 m L preﬁlled sy-ringes, 1 m L single use vials and 10 m L multidose vials (contains 0. 18 m L of PEG 400 in propylene glycol; 2% benzyl alcohol added as a preservative); Ativan® (Baxter), generic; (Rx; C-IV) LUFENURON (loo-fen-yur-on) Program®, Sentinel® CHITIN SYNTHESIS INHIBITOR Prescriber Highlights TT Used for ﬂea control in dogs & cats; potentially an anti-fungal agent TT Adverse Effects: None at recommended doses	pppbs.pdf
LUFENURON 549 Uses/Indications Lufenuron is approved for use in dogs and cats 6 weeks of age and older for the control of ﬂea populations. The combination prod-uct of lufenuron and milbemycin (Sentinel®) is indicated for use in puppies and dogs 4 weeks and older for prevention and control ﬂea populations, prevention of heartworm disease, control of adult hookworms, and the removal and control of adult roundworms and whipworms. Lufeneron showed initial promise as a treatment for fungal in-fections, but the early enthusiasm has dampened considerably as efﬁcacy appears doubtful. Pharmacology/Actions Lufenuron acts by inhibiting chitin synthesis, polymerization, and deposition in ﬂeas, thereby preventing eggs from developing into adults. It is believed that lufeneron's nonspeciﬁc effect on chitin synthesis is related to serine protease inhibition. Lufeneron's mech-anism of action, theoretically, would also have effect on fungi. Lufenuron does not kill adult ﬂeas. Pharmacokinetics Approximately 40% of an oral dose is absorbed with the remainder eliminated in the feces. T o maximize oral absorption, the manu-facturer recommends administering in conjunction with or imme-diately after (within 30 minutes) a full meal. The drug is absorbed in the small intestine and stored in lipose tissue that acts as depot reservoir to slowly redistribute the drug back into the circulation. While the drug concentrates in the milk of lactating animals, it ap-parently does not cause ill effects in nursing animals. After cats receive the injectable product, 2-3 weeks are required before blood levels attain effective concentrations. Cats require a substantially higher oral dosage per kg than do dogs for equivalent efﬁcacy. The drug is apparently not metabolized, but excreted un-changed into the bile and eliminated in the feces. Contraindications/Precautions/Warnings The cat labeled injectable product should not be used in dogs; se-vere local reactions are possible. Adverse Effects Adverse effects reported in dogs and cats after oral lufenuron in-clude: vomiting, lethargy/depression, pruritus/urticaria, diarrhea, dyspnea, anorexia, and reddened skin. The manufacturer reports that the adverse reaction rate is less than 5 animals in one million doses. After receiving the injectable product, a small lump at the injec-tion site has been noted in some cats. A few weeks may be required for this to dissipate. Reproductive/Nursing Safety The oral lufenuron products are considered safe to use in pregnant, breeding, or lactating animals; safety of the injectable product in reproducing cats has not been formally established at this time. Overdosage/Acute Toxicity Growing puppies were dosed at levels up to 30X for 10 months without overt effect on growth or viability noted. Cats receiving oral dosages of up to 17X apparently were unaffected. Drug Interactions Limited data available; the manufacturer states that when used with a variety of adulticides, vaccines, antibiotics, anthelminthics, and steroids no adverse effects or interactions were noted in either dogs or cats. Doses !TDOGS: a) For control of ﬂea populations: See the label directions for Program with Capstar for using lufenuron with nitenpyram. For control of ﬂeas, heartworm prevention, hookworm, as-carid or whipworms: see the label directions for Lufenuron/ Milbemycin with Nitenpyram (Sentinel® and Capstar®— Novartis) b) For adjunctive therapy for dermatophytosis: 50-100 mg/kg PO once every 14 days for two treatments, then once a month until at least two negative fungal cultures are obtained (Man-tousek 2003) !TCATS: a) For control of ﬂea populations: See the label directions Pro-gram and Program with Capstar for using lufenuron with or without nitenpyram. b) For adjunctive therapy for dermatophytosis: 50-100 mg/ kg PO once every 14 days for two treatments, then once a month until at least two negative fungal cultures are ob-tained. (Mantousek 2003) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: 30 mg/kg PO every month (Ivey and Morrisey 2000) Monitoring !TEfﬁcacy Client Information !TMust be used every 30 days to maximize efﬁcacy. !TAll animals in a household should be treated. !TAbsorption of the drug is enhanced if given with a fatty meal. If animal vomits within 2 hours after dosing, the drug should be re-dosed. If a dose is missed, re-dose and then resume a monthly dosage regimen (dogs receiving the lufenuron/milbemycin prod-uct should be tested in 6 months or more for heartworm expo-sure with an antigen test). !TDo not split tablets. Chemistry/Synonyms A benzoylphenylurea derivative, lufenuron is classiﬁed as an insect development inhibitor. The drug is lipophilic. Lufenuron may also be known as CGA-184699, Capstar®, Program® and Sentinel®. Storage/Stability The commercially available tablets and suspension should be stored at room temperature (15-30°C). The manufacturer states that in-termittent exposure or exposure less than 48 hours to tempera-tures outside of storage recommendations for the tablets or sus-pension should not affect potency. Lufenuron tablets are assigned a 4 year expiration date after manufacture; the suspension 3 years after manufacture; and Sentinel® tablets 3 years after manufacture. Opened pouches of the suspension are not recommended for stor-age or use for the following dosing cycle. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Lufenuron Oral Suspension: in six tube packs; 135 mg (for cats up to 10 lb,—orange), 270 mg (for cats 11-20 lb,—green), cats over 20 lbs are provided the appropriate combination of packs. ; Program® Suspension (Novartis); (Rx). Approved for use in cats and kittens (6 weeks of age or older).	pppbs.pdf
550 LYSINE Lufenuron 6 Month Injectable for Cats: 100 mg/m L in 10 syringe packages: 0. 4 m L (40 mg) preﬁlled syringe (for cats up to 8. 8 lb), 0. 8 m L (80 mg) preﬁlled syringe (for cats 8. 9-17. 6 lb); Program® 6 Month Injectable (Novartis); (Rx). Approved for use in cats and kit-tens 6 weeks of age or older. Lufenuron Oral Flavor Tabs for Dogs and Cats: For dogs up to 10 lb: 45 mg; For dogs 11 to 20 lb: 90 mg; For dogs 21 to 45 lb: 204. 9 mg; For dogs 46 to 90 lb: 409. 8 mg; Dogs over 90 lbs receive the appropriate combination of lufeneron tablets; For cats up to 6 lbs. 90 mg; 7-15 lb: 204. 9 mg; cats over 15 lb. receive the appropriate combination of lufeneron tablets Program® Flavor Tabs (Novartis); (OTC). Approved for use in dogs, puppies, cats, & kittens (4 weeks of age or older). Lufenuron and Nitenpyram Oral Tablets for Dogs: For dogs up to 10 lb: 45 mg Lufeneron, 11. 4 mg nitenpyram; For dogs 11 to 20 lb: 90 mg lufenuron, 11. 4 mg nitenpyram; For dogs 21 to 25 lb: 204. 9 mg lufenuron, 11. 4 mg nitenpyram; For dogs 26 to 45 lb: 204. 9 mg lufenuron, 57 mg nitenpyram; For dogs 46 to 90 lb: 409. 8 mg lufenuron, 57 mg nitenpyram; Dogs over 90 lbs receive the appropri-ate combination of Lufeneron tablets and 57 mg nitenpyram tablets; Program® Flavor Tabs and Capstar® Flea Management System for Dogs (Novartis); (OTC). Approved for use in dogs and puppies (6 weeks of age or older). Lufenuron and Nitenpyram Oral Tablets for Cats: For cats 2 to 6 lb: 90 mg lufenuron, 11. 4 mg nitenpyram; For cats 7 to 15 lb: 204. 9 mg lufenuron, 11. 4 mg nitenpyram; For cats 16 to 25 lb: appropriate combination of tabs provided lufenuron, 11. 4 mg nitenpyram; Pro-gram® Flavor Tabs (OTC); and Capstar® Flea Management System for Cats (Novartis); (OTC) Milbemycin/Lufenuron Oral Tablets with Nitenpyram Oral Tablets for Dogs: For dogs 2 to 10 lb: 46 mg milbemycin/Lufeneron, 11. 4 mg nitenpyram; For dogs 11 to 25 lb: 115 mg milbemycin/lufenuron, 11. 4 mg nitenpyram; For dogs 26-50 lb: 230 mg milbemycin/ lufenuron, 57 mg nitenpyram; For dogs 51 to 100 lb: 460 mg milbe-mycin/lufenuron, 57 mg nitenpyram; For dogs100 to125 lb: (appro-priate number supplied) milbemycin/lufenuron, 57 mg nitenpyram; Sentinel® Flavor Tabs with Capstar® (Novartis); (Rx). Approved for use in dogs and puppies 4 weeks of age or older. HUMAN-APPROVED PRODUCTS: None LYSINE L-LYSINE (lye-seen) NUTRITIONAL AMINO AC ID Prescriber Highlights TT Amino acid that may be effective in suppressing FHV-1 infections in cats TT Adverse effects unlikely if mixed with food TT Long-term treatment required Uses/Indications Lysine may be effective in suppressing FHV-1 infections in cats. Pharmacology/Actions Lysine is an amino acid that is thought to compete with arginine for incorporation into many herpes viruses. As it is believed that argin-ine is required for producing infective viral particles, when lysine is incorporated, the virus becomes less infective. Pharmacokinetics No speciﬁc information was located. Contraindications/Precautions/Warnings No speciﬁc contraindications. Adverse Effects Adverse effects are unlikely when mixed with food. Patients (hu-man) taking lysine have occasionally complained of abdominal pain and diarrhea; one patient developing tubulointerstitial ne-phritis has been reported. Reproductive/Nursing Safety Lysine showed no teratogenic effects when given to pregnant rats, although safety has not been established in other species. Overdosage/Acute Toxicity Signiﬁcant toxicity is unlikely. Gastrointestinal effects (nausea, vomiting, diarrhea) may occur. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving lysine and may be of signiﬁcance in veterinary patients: T ! ARGININE : Arginine may negate the anti-herpesvirus effects of lysine T ! CALCIUM, ORAL : Concomitant use with calcium supplements may increase calcium absorption from the gut and decrease calcium loss in the urine Laboratory Considerations No speciﬁc concerns noted Doses T ! CATS: T o prevent or reduce recurrent feline herpesvirus ocular infec-tions: a) 500 mg PO twice daily for life (Glaze 2002) b) 500 mg mixed with food daily (Nasisse 2002) c) 250 mg PO twice daily (Powell 2002), (August 2007) As adjunctive therapy for feline herpesvirus dermatologic infections: a) 250 mg PO twice daily (Grifﬁes 2002) b) 250 mg PO once to twice daily (Boord 2002) Monitoring T ! No speciﬁc monitoring is required for lysine except those that would be required to monitor the herpes infection in the pa-tient. Client Information T ! Lysine is easiest to administer by crushing tablets or emptying capsules and then mixing with food. T ! Clients should understand that lysine does not cure the infection, but helps to control it (reduces the severity and frequency) and that lifetime therapy may be required.	pppbs.pdf
MAGNESIUM HYDROXIDE 551 T ! When purchasing, avoid products that contain propylene glycol. Chemistry/Synonyms An aliphatic amino acid, lysine has the chemical name L-2,6-diaminohexanoic acid and has a molecular weight of 146. 2. It may be commercially available as the acetate or hydrochloride salts, or as the base. Lysine may also be known as: L-lysine, L-Lysine Powder-Pure®, Lys, K, Enisyl®, Incremin®, and Viralys®. Storage/Stability Unless otherwise speciﬁed on the label, lysine should be stored at room temperature in tight containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Note : There are many products containing lysine as one of many in-gredients. The following products were located with veterinary label-ing where lysine is sole active ingredient: L-lysine Gel: 250 mg per 1. 25 m L: Viralys® G e l (Vet Solutions); (OTC). Labeled for use in cats and kittens. L-lysine Powder: (in a palatable base) approximately 250 mg per rounded scoop: Viralys® Powder (Vet Solutions); (OTC). Labeled for use in cats and kittens. L-Lysine Powder Feed Additive: in 16 oz. jars and 5 lb. pails; L-Lysine Powder-Pure® (AHC); (OTC) Labeled for use in horses. HUMAN-LABELED PRODUCTS: L-Lysine Tablets & Capsules: 312 mg, 334 mg, 500 mg & 1000 mg; Enisyl® (Person & Covey); generic; (OTC) Lysine is considered a nutrient in the USA, therefore, it is exempt from FDA approval requirements. There are many products available including tablets and capsules that usually range in strengths from 250 mg to 1000 mg. Combination products are also available. Lysodren® — see Mitotane Magnesium-containing Laxatives-see Saline/Hyperosmotic Laxatives; Magnesium Hydroxide MAGNESIUM HYDROXIDE MAGNESIUM/ALUMINUM ANTACIDS (mag-nee-zee-um hye-droks-ide) ORAL A NTACID/LAXATIVE Prescriber Highlights TT Used as a gastric antacid for ulcers, etc., but use largely supplanted by newer agents TT In ruminants, can be useful to increase rumen p H TT Magnesium salts contraindicated in patients with renal disease TT Magnesium salts may cause diarrhea TT Chronic use may lead to electrolyte abnormalities TT Many potential drug interactions Uses/Indications Magnesium hydroxide in combination with aluminum salts have been used in veterinary medicine for the adjunctive treatment of esophagitis, gastric hyperacidity, peptic ulcer and gastritis. In foals and small animals, because of difﬁculty in administration, the fre-quent dosing that is often required, and availability of the hista-mine-2 blocking agents (cimetidine, ranitidine, etc. ), proton-pump inhibitors (e. g., omeprazole) and sucralfate, antacids have largely been relegated to adjunctive roles in therapy for these indications. Magnesium hydroxide alone (milk of magnesia) is sometimes used as an oral laxative in small animals. In ruminants, magnesium hydroxide is used to increase rumen p H and as a laxative in the treatment of rumen overload syndrome (aka acute rumen engorgement, rumen acidosis, grain overload, engorgement toxemia, rumen impaction). Pharmacology/Actions Oral antacids used in veterinary medicine are generally relatively non-absorbable salts of aluminum, calcium or magnesium. Up to 20% of an oral dose of magnesium can be absorbed, however. Antacids decrease HCl concentrations in the GI. One gram of these compounds generally neutralizes 20-35 m Eq of acid (in vitro). Although the p H of the gastric ﬂuid can rarely be brought to near-neutral conditions, at a p H of 3. 3, 99% of all gastric acid is neu-tralized, thereby reducing gastric acid back-diffusion through the gastric mucosa and reducing the amount of acid presented to the duodenum. Pepsin proteolytic activity is reduced by raising the p H and can be minimized if the p H of the gastric contents can be in-creased to >4. Contraindications/Precautions/Warnings Magnesium-containing antacids are contraindicated in patients with renal disease. Some products have signiﬁcant quantities of so-dium or potassium and should be used cautiously in patients who should have these electrolytes restricted in their diet. Aluminum-containing antacids may inhibit gastric emptying; use cautiously in patients with gastric outlet obstruction. Adverse Effects In monogastric animals, the most common side effects of antacid therapy are constipation with aluminum-and calcium-containing antacids, and diarrhea or frequent loose stools with magnesium containing antacids. Many products contain both aluminum and magnesium salts in the attempt to balance the constipating and laxative actions of the other. If the patient is receiving a low phosphate diet, hypophos-phatemia can develop if the patient chronically receives aluminum antacids. Magnesium-containing antacids can cause hypermagne-semia in patients with severe renal insufﬁciency. If administering calcium carbonate in high doses or chronically, signiﬁcant quantities of calcium can be absorbed from the gut re-sulting in hypercalcemia in susceptible patients. Calcium carbon-ate has also been implicated in causing a gastric acid rebound phe-nomena. Patients with signiﬁcant renal impairment or dehydration and electrolyte imbalance can develop the milk-alkali syndrome. If the patient is receiving a low phosphate diet, hypophosphatemia can develop if the patient chronically receives calcium carbonate antacids. In ruminants, alkalinization of the rumen may enhance the ab-sorption of ammonia, histamine or other basic compounds.	pppbs.pdf
552 MAGNESIUM HYDROXIDE Reproductive/Nursing Safety In a system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), these drugs are categorized as class: A (Probably safe. Although speciﬁc studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse ef-fects in laboratory animals or women. ) Overdosage/Acute Toxicity See the Adverse Effects section above. If necessary, GI and elec-trolyte imbalances that can occur with chronic or acute overdose should be treated symptomatically. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving oral magnesium hy-droxide and may be of signiﬁcance in veterinary patients: !TQUINIDINE : Increased absorption or pharmacologic effect may occur !TSODIUM POLYSTYRENE SULFONATE (Kayexalate®): Antacids may de-crease the potassium lowering effectiveness of the drug and in patients in renal failure may cause metabolic alkalosis !TSUSTAINED-or EXTENDED-RELEASE MEDICATIONS : When magnesium hydroxide is used at laxative dosages, it may alter the absorption of these drugs by altering GI transit times !TSYMPATHOMIMETIC AGENTS : Increased absorption or pharmaco-logic effect may occur Oral magnesium salts can decrease the amount absorbed or the pharmacologic effect the drugs listed below; separate oral doses of magnesium hydroxide and these drugs by two hours to help reduce this interaction. !!ALLOPURINOL !!AZOLE ANTIFUNGALS (Ketoconazole, Itraconazole ) !!CHLOROQUINE !!CORTICOSTEROIDS !!DIGOXIN !!ETHAMBUTOL !!FLUOROQUINOLONES !!H-2 ANTAGONISTS (Ranitidine, Famotidine, etc. ) !!IRON SALTS !!ISONIAZID !!PENICILLAMINE !!PHENOTHIAZINES !!TETRACYCLINES !TTHYROID HORMONES Doses !TDOGS: For adjunctive therapy for gastric ulcers: a) Aluminum hydroxide suspension or aluminum hydroxide/ magnesium hydroxide suspension: 2-10 m L PO q2-4h (Hall and Twedt 1988) As an antacid: a) Magnesium hydroxide (Milk of Magnesia): 5-30 m L PO once to twice daily (Morgan 1988) !TCATS: As an antacid: a) Magnesium hydroxide (Milk of Magnesia): 5-15 m L PO once to twice daily (Morgan 1988) !TCATTLE: For rumen overload syndrome: a) For adult animals: Up to 1 gm/kg (Mg OH) mixed in 2-3 gallons of warm water and given PO per tube. May repeat (use smaller doses) at 6-12 hour intervals. If the rumen has been evacuated, do not exceed 225 grams initially. Dehydra-tion and systemic acidosis must be concomitantly corrected. b) Calves: As above but use Jth-Gth the amount (Wass et al. 1986a) !THORSES: For adjunctive gastroduodenal ulcer therapy in foals: a) Aluminum/magnesium hydroxide suspension: 15 m L 4 times a day (Clark and Becht 1987) !TSHEEP & GOATS: For rumen overload syndrome: a) As above for cattle, but use Jth-Gth the amount (Wass et al. 1986a) Monitoring !TMonitoring parameters are dependent upon the indication for the product. Patients receiving high dose or chronic therapy should be monitored for electrolyte imbalances outlined above. Client Information !TOral magnesium hydroxide products are available without pre-scription (OTC); do not give on a regular basis without veteri-nary supervision Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Oral Boluses 17. 9-27 grams of magnesium hydroxide ( Note : prod-ucts may also contain ginger, capsicum and methyl salicylate); Mag-nalax® (Aspen), Carmilax® (Pﬁzer), Polymag® (Butler), Rumen Bo-lus® (Durvet), Instamag® (Vedco), Magnalax® (Phoenix), Polyox ®II (Bimeda), Laxade® (Agri Pharm); (OTC) Oral Powder, each pound of powder contains: 350-361 grams of magnesium hydroxide ( Note : products may also contain ginger, cap-sicum and methyl salicylate); Carmilax Powder® (Pﬁzer), Magnalax® (Phoenix), Polyox ® (Bimeda), Laxade® (Agri Pharm); (OTC) Milk of Magnesia (Magnesium Hydroxide) 80 mg/m L in gallons; ge-neric, (Neogen); (OTC) HUMAN-LABELED PRODUCTS: The following is a list of some magnesium hydroxide products avail-able, it is not meant to be all-inclusive. Magnesium Hydroxide Tablets chewable: 311 mg Phillips' Chewable® (Sterling Health) Liquid: 400 mg/5 m L in 360 m L, pt and gal and UD 15 and 30 m L; 800 mg/5 m L in 240 m L; Phillips' Milk of Magnesia®(Sterling Health), Concentrated Phillips' Milk of Magnesia® (Sterling Health), etc. Aluminum Hydroxide and Magnesium Hydroxide Suspension ( Note : There are too many products and concentrations to list in this reference; a representative product is Maalox® Suspen-sion (Rorer) which contains 225 mg aluminum hydroxide and 200 mg magnesium hydroxide per 5 m L. ) All aluminum and magnesium hydroxide preparations are OTC. Other dosage forms that are available commercially include: tablets, chewable tablets, and aerosol foam suspension.	pppbs.pdf
MAGNESIUM 553 MAGNESIUM MAGNESIUM SULFATE, PARENTERAL MAGNESIUM CHLORIDE, PARENTERAL (mag-nee-zee-um) PARENTERAL ELECTROLYTE For information on the use of oral magnesium hydroxide, refer to the previous monograph. Magnesium oxide and oral magnesium sulfate are also detailed in the monograph for Saline/Hyperosmotic laxatives. Prescriber Highlights TT Parenteral electrolyte for hypomagnesemia, for adjunc-tive therapy of malignant hyperthermia in swine, as an anticonvulsant, & for refractory ventricular arrhythmias TT Contraindications: Signiﬁcant myocardial damage or heart block TT Caution: Impaired renal function TT Adverse Effects: Usually as a result of OD (drowsiness or other CNS depressant effects, muscular weakness, brady-cardia, hypotension, respiratory depression, & increased Q-T intervals on ECG). Very high levels: Neuromuscular blocking activity &, eventually, cardiac arrest TT Must monitor to avoid hypermagnesemia TT Do not confuse m Eq/m L & mg/m L concentrations & dosages Uses/Indications Parenteral magnesium sulfate is used as a source of magnesium in magnesium deﬁcient states (hypomagnesemia), for adjunctive therapy of malignant hyperthermia in swine, and also as an anti-convulsant. It may be of beneﬁt in the treatment of refractory ven-tricular ﬁbrillation. Pharmacology/Actions Magnesium is used as a cofactor in a variety of enzyme systems and plays a role in muscular excitement and neurochemical transmission. Pharmacokinetics IV magnesium results in immediate effects; IM administration may require about 1 hour for effect. Magnesium is about 30-35% bound to proteins and the remainder exists as free ions. It is excret-ed by the kidneys at a rate proportional to the serum concentration and glomerular ﬁltration. Contraindications/Precautions/Warnings Parenteral magnesium is contraindicated in patients with my-ocardial damage or heart block. Magnesium should be given with caution to patients with impaired renal function. Patients receiving parenteral magnesium should be observed and monitored carefully to avoid hypermagnesemia. Adverse Effects Magnesium sulfate (parenteral) adverse effects are generally the re-sult of magnesium overdosage and may include drowsiness or other CNS depressant effects, muscular weakness, bradycardia, hypoten-sion, hypocalcemia, respiratory depression and increased Q-T in-tervals on ECG. Very high magnesium levels may cause neuromus-cular blocking activity and, eventually, cardiac arrest. When using IV for hypomagnesemia, reduce potassium supple-mentation or hyperkalemia may result. Reproductive/Nursing Safety 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. ) The possibility of fetal harm appears remote; however, use only if clearly needed. Magnesium is excreted in milk, but is unlikely to pose signiﬁcant risk to nursing offspring. Overdosage/Acute Toxicity See Adverse Effects above. Treatment of hypermagnesemia is de-pendent on the serum magnesium level and any associated clini-cal effects. Ventilatory support and administration of intravenous calcium [10-50 mg/kg IV; (Macintire 2003)] may be required for severe hypermagnesemia. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving parenteral magnesium sulfate or HCl and may be of signiﬁcance in veterinary patients: T ! CALCIUM : Concurrent use of calcium salts may negate the effects of parenteral magnesium T ! CNS DEPRESSANT DRUGS (e. g., barbiturates, general anesthetics ): Ad-ditive CNS depression may occur. T ! DIGOXIN : Because serious conduction disturbances can occur, par-enteral magnesium should be used with extreme caution with digitalis cardioglycosides T ! NEUROMUSCULAR BLOCKING AGENTS : Excessive neuromuscular blockade possible Doses Note : Do not confuse m Eq/m L and mg/m L concentrations and dosages; One gram of magnesium sulfate hexahydrate contains 8. 1 m Eq of magnesium. Magnesium chloride contains 9. 25 m Eq of magnesium per gram. T ! DOGS & CAT S: For hypomagnesemia: a) Use magnesium sulfate as an IV CRI at 1 m Eq/kg/24 hours; often seen in refractory hypokalemic patients (Reiser 2006) b) 0. 75-1 m Eq/kg/day administered by a constant rate infusion in D 5W. Concentrate should be diluted to at least 20%. A lower dose of 0. 3-0. 5 m Eq/kg/day may be used for an ad-ditional 3-5 days as complete repletion occurs slowly. (Hol-land and Chastain 1995) c) For chronic hypomagnesemia (once parenteral repletion has occurred): Using oxide or hydroxide salts, 1-2 m Eq/kg/day PO. Diarrhea may occur. (Fascetti 2003) d) For hypomagnesemia associated with diabetic ketoacido-sis in cats: T otal magnesium concentrations of less than 1. 5 mg/d L should be treated with magnesium sulfate as an IV CRI of 0. 5-1 m Eq/kg administered over 24 hours. (Waddell 2007b)	pppbs.pdf
554 MAGNESIUM TFor refractory ventricular arrhythmias: a) Magnesium sulfate: 30 mg/kg slowly IV ( Note : This converts to a dose of 0. 243 m Eq/kg—Plumb) (Macintire 2006a) b) If needed for life-threatening ventricular arrhythmias: 0. 15-0. 3 m Eq/kg may be administered over 5-15 minutes. (Holland and Chastain 1995) !THORSES: For VTach: a) 4 mg/kg IV boluses every 2 minutes or a 2 mg/kg/min IV infusion to a total dose of 50 mg/kg ( Note : Do not use mag-nesium plus calcium containing solutions) (Mogg 1999) For adjunctive treatment of perinatal asphyxia syndrome in foals: a) Magnesium sulfate 50 mg/kg diluted to 1% and given IV over one hour, then decrease to 25 mg/kg/hr as a constant rate infusion for 24 hours (Vaala 2003b) b) as above in “a”, but after the ﬁrst hour: 25 mg/kg/hr CRI for 1-3 days. (Bentz 2006b) !TRUMINANTS: For hypomagnesemia (grass and other magnesium-related teta-nies): a) Cattle: Magnesium sulfate 20-50%: 200m L SC, followed by a slow IV infusion of 500 m L of a calcium/magnesium so-lution (Calcium borogluconate 23%; Mg Cl 2 6%) (Phillips 1988a) b) Cattle: 350 m L (250 m L of 25% calcium borogluconate and 100 m L of 10% of magnesium sulfate) by slow IV. If not a proprietary mixture, give calcium ﬁrst. Relapses occur fre-quently after IV therapy, and 350 m L SC of magnesium sul-fate 20% may give more sustained magnesium levels. Alter-nating calcium and magnesium may prevent adverse effects. Continue control measures for 4-7 days to prevent relapse. c) Sheep and Goats: 50-100 m L of above solution (calcium/ magnesium). For whole milk tetany in calves 2-4 months of age: a) Magnesium sulfate 10% 100 m L; followed by oral magne-sium oxide at daily doses of 1 gram PO (0-5 weeks old), 2 gram PO (5-10 weeks old), and 3 grams PO (10-15 weeks old) (Merrall and West 1986) !TSWINE: For adjunctive therapy of malignant hyperthermia syndrome: a) Magnesium sulfate 50%: Incremental doses of 1 gram in-jected slowly IV until heart rate and muscle tone are reduced. Use calcium if magnesium-related cardiac arrest occurs (Booth 1988) Monitoring !Toxicity, including serum magnesium !TPhysical signs associated with hypomagnesemia !TSerum calcium, potassium if indicated Chemistry/Synonyms Magnesium sulfate occurs as small, usually needle-like, colorless crystals with a cool, saline, bitter taste. It is freely soluble in water and sparingly soluble in alcohol. Magnesium sulfate injection has a p H of 5. 5-7. One gram of magnesium sulfate hexahydrate contains 8. 1 m Eq of magnesium. Magnesium chloride contains 9. 25 m Eq of magnesium per gram. Magnesium Sulfate may also be known as: 518, epsom salts, magnesii sulfas, magnesium sulfuricum heptahydricum, magne-sium sulphate, sal amarum, sel anglais, and sel de sedlitz; many trade names are available. Storage/Stability/Compatibility Magnesium sulfate and magnesium chloride for injection should be stored at room temperature (15-30°C); avoid freezing. Refrigeration may result in precipitation or crystallization. Magnesium sulfate is reportedly physically compatible with the following intravenous solutions: dextrose 5%, LRS, and Normal saline. It is also compatible with calcium gluconate, cephalothin sodium, chloramphenicol sodium succinate, cisplatin, hydrocor-tisone sodium succinate, isoproterenol HCl, methyldopate HCl, metoclopramide HCl (in syringes), norepinephrine bitartrate, penicillin G potassium, potassium phosphate, and verapamil HCl. Additionally, at Y-sites: acyclovir sodium, amikacin sulfate, ampicil-lin sodium, carbenicillin disodium, cefamandole naftate, cefazolin sodium, cefoperazone sodium, ceforanide, cefotaxime sodium, ce-foxitin sodium, cephalothin sodium, cephapirin sodium, clindamy-cin phosphate, doxycycline phosphate, erythromycin lactobionate, esmolol HCl, gentamicin sulfate, heparin sodium, kanamycin sul-fate, labetolol HCl, metronidazole (RTU), moxalactam disodium, nafcillin sodium, oxacillin sodium, piperacillin sodium, potassium chloride, tetracycline HCl, ticarcillin disodium, tobramycin sulfate, trimethoprim/sulfamethoxazole, vancomycin HCl, and vitamin B-complex with C. Magnesium sulfate is reportedly physically incompatible when mixed with alkali hydroxides, alkali carbonates, salicylates and many metals, including the following solutions or drugs: fat emul-sion 10 %, calcium gluceptate, dobutamine HCl, polymyxin B sul-fate, procaine HCl, and sodium bicarbonate. Compatibility is de-pendent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more speciﬁc information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: There are no parenteral magnesium-only products approved for veterinary medicine. There are, however, several proprietary magne-sium-containing products available that may also include calcium, phosphorus, potassium, and/or dextrose; refer to the individual product's labeling for speciﬁc dosage information. Trade names for these products include: Norcalciphos® (Pﬁzer); Cal-Dextro® Special, and #2 (Fort Dodge); and CMPK®; and Cal-Phos® #2 (T ech America). They are legend (Rx) drugs. HUMAN-LABELED PRODUCTS: Magnesium Sulfate Injection: 10% (0. 8 m Eq/m L), 12. 5% (1 m Eq/ m L), and 50% (4 m Eq/m L) in 2 m L, 10m L and 20 m L amps, 2 m L ﬁll in 5 m L vials, 2 m L, 5 m L, 10 m L, 20 m L and 50 m L vials and multi-dose vials and 5 and 10 m L disposable syringes; generic; (Rx) Magnesium Chloride Injection: 20% (1. 97 m Eq/m L) in 50 m L multi-dose vials; 10% (0. 8 m Eq/m L) in 20 m L, 50 m L vials & 20 m L amps; 12. 5% (1 m Eq/m L) in 20 m L vials; 50% (4 m Eq/m L) in 2 m L, 5 m L, 10 m L, 20 m L & 50 m L vials, 5 m L & 10 m L syringes, & 2 m L & 10 m L amps; generic; (Rx) There are many oral magnesium products in various dosage forms available.	pppbs.pdf
MANNITOL 555 MANNITOL (man-i-tole) OSMOTIC DIURETIC Prescriber Highlights TT Osmotic diuretic used for acute oliguric renal failure, to reduce intraocular & intracerebral pressures, to enhance urinary excretion of some toxins &, with other diuretics, to rapidly reduce edema or ascites (caution) TT Contraindications: Anuria secondary to renal disease, severe dehydration, intracranial bleeding (unless during craniotomy), severe pulmonary congestion, or pulmonary edema TT Halt treatment if progressive heart failure, pulmonary congestion, or progressive renal failure/damage develop TT Adverse Effects: Fluid & electrolyte imbalances, GI (nau-sea, vomiting), cardiovascular (pulmonary edema, CHF, tachycardia), & CNS effects (dizziness, headache, etc. ) TT Adequate urine output, ﬂuid, & electrolyte monitoring & treatment mandatory TT Be certain crystals are dissolved in solution before administering Uses/Indications Mannitol is used to promote diuresis in acute oliguric renal failure, reduce intraocular and intracerebral pressures, enhance urinary ex-cretion of some toxins, (e. g., aspirin, some barbiturates, bromides, ethylene glycol) and, in conjunction with other diuretics, to rapidly reduce edema or ascites when appropriate (see Contraindications-Precautions below). In humans, it is also used as an irrigating solu-tion during transurethral prostatic resections. Pharmacology/Actions After intravenous administration, mannitol is freely ﬁltered at the glomerulus and poorly reabsorbed in the tubule. The increased os-motic pressure prevents water from being reabsorbed at the tubule. T o be effective, there must be sufﬁcient renal blood ﬂow and ﬁltra-tion for mannitol to reach the tubules. Although water is propor-tionately excreted at a higher rate, sodium, other electrolytes, uric acid, and urea excretions are also enhanced. Mannitol may have a nephro-protective effect by preventing the concentration of nephrotoxins from accumulating in the tubular ﬂuid. Additionally, it may minimize renal tubular swelling via its osmotic properties, increase renal blood ﬂow and glomerular ﬁltra-tion by causing renal arteriole dilatation, decreased vascular resis-tance, and decreased blood viscosity. Mannitol does not appreciably enter the eye or the CNS, but can decrease intraocular and CSF pressure through its osmotic effects. Rebound increases in CSF pressures may occur after the drug is dis-continued. Pharmacokinetics Although long believed to be unabsorbed from the GI, up to 17% of an oral dose is excreted unchanged in the urine after oral dosing in humans. After intravenous dosing, mannitol is distributed to the extracellular compartment and does not penetrate the eye. Unless the patient has received very high doses, is acidotic, or there is loss of integrity of the blood-brain barrier, it does not cross into the CNS. Only 7-10% of mannitol is metabolized, the remainder is excreted unchanged in the urine. The elimination half-life of mannitol is ap-proximately 100 minutes in adult humans. Half-lives in cattle and sheep are reported to be between 40-60 minutes. Contraindications/Precautions/Warnings Mannitol is contraindicated in patients with anuria secondary to renal disease, severe dehydration, intracranial bleeding (unless during craniotomy), severe pulmonary congestion or pulmonary edema. When using for increased CSF pressure, an intact capillary membrane is required for efﬁcacy. If this membrane is disrupted, mannitol can leak into the brain interstitium and increase cerebral edema. Mannitol therapy should be stopped if progressive heart failure, pulmonary congestion, progressive renal failure or damage (in-cluding increasing oliguria and azotemia) develops after mannitol therapy is instituted. Mannitol is relatively contraindicated for treating secondary glaucomas, as it may cross the damaged “blood-aqueous barrier” and increase intraocular pressure (IOP). Do not administer more than a test dose of mannitol until de-termining whether the patient has some renal function and urine output. Adequate ﬂuid replacement must be administered to de-hydrated animals before mannitol therapy is begun. Do not give mannitol with whole blood products, unless at least 20 m Eq/L of sodium chloride is added to the solution or pseudo-agglutination may result. Be certain any crystals in solution are redissolved before admin-istering; an in-line IV ﬁlter is also recommended. Adverse Effects Fluid and electrolyte imbalances are the most severe adverse effects generally encountered during mannitol therapy. Adequate moni-toring and support are imperative. When used for oliguric renal failure, the potential exists for vol-ume overload should oliguria persist. Other adverse effects that may be encountered include GI (nau-sea, vomiting), cardiovascular (pulmonary edema, CHF, tachycar-dia), and CNS effects (dizziness, headache, etc. ). Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) It is not known whether this drug is excreted in milk, but it is unlikely that it would pose signiﬁcant risk to nursing offspring. Overdosage/Acute Toxicity Inadvertent overdosage can cause excessive excretion of sodium, potassium, and chloride. If urine output is inadequate, water intox-ication or pulmonary edema may occur. Treat by halting mannitol administration and monitoring and correcting electrolyte and ﬂuid imbalances. Hemodialysis is effective in clearing mannitol. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving mannitol and may be of signiﬁcance in veterinary patients: T ! LITHIUM : Mannitol can increase the renal elimination of lithium T ! SOTALOL : Mannitol's effects on potassium and magnesium may increase the risk for QT prolongation	pppbs.pdf
556 MANNITOL Laboratory Considerations !TMannitol can interfere with blood inorganic phosphorus c o n-centrations and blood ethylene glycol determinations. Doses !TDOGS & CAT S: For treatment of oliguric renal failure: a) After correcting ﬂuid, electrolyte, acid/base balance and de-termining that the patient is not anuric: Mannitol (20-25% solution) 0. 25-0. 5 gm/kg IV over 5-10 minutes. If diuresis occurs, may repeat q4-6 hours or administered as a constant infusion (8-10% solution) for ﬁrst 12-24 hours of therapy. (Polzin 2005a) b) After rehydration, but not ﬂuid overloaded give mannitol at 0. 25-0. 5 gm/kg IV slowly over 5-10 minutes; repeat dose at 30-40 minute intervals up to 1. 5 gm/kg total. Author prefers using furosemide for ARF. (Bersenas 2007) c) In ﬂuid replete animals: 0. 5 gram/kg IV over 20-30 min-utes; if signiﬁcant diuresis is accomplished within 30 min-utes, may administer as a CRI of 60-120 mg/kg/hr IV or as intermittent boluses repeated every 4-6 hours. Mannitol is contraindicated in patients who are still dehydrated, hyperv-olemic, or anuric. (Waddell 2007a) d) After rehydration, give mannitol 0. 5 gm/kg IV slowly; repeat dose at 15-minute intervals up to 1. 5 gm/kg total. Urine pro-duction should begin within 15 minutes; monitor carefully for dehydration and give ﬂuids as necessary to maintain bal-ance. (Breitschwerdt 1988) For adjunctive treatment of acute glaucoma: a) Drug of ﬁrst choice in the acute patient; 0. 5-1 g/kg IV given over 15-20 minutes; withhold water for 3-4 hours. IOP re-duction begins in 20-30 minutes and has a 4-6 hour du-ration of effect. Efﬁcacy reduced in patients with anterior uveitis. (Wilkie 2002) b) If latanaprost (Xalatan®) has not affected pupil size and started to reduce IOP after one hour, give mannitol (20%) at 1-2 g/kg IV over a period of 20 minutes and withhold water for 1-2 hours. Peak effect is about 90 minutes after adminis-tration. (Millichamp 2006) For adjunctive treatment of increased CSF pressure/cerebral edema: a) 0. 5-1. 5 g/kg IV over 10-20 minutes. Maximum effect oc-curs 10-20 minutes after administration and the effects last for 2-5 hours. May repeat every 6-8 hours based on clinical response and intracranial pressure monitoring. Do not use if patient hypovolemic. Monitor serum osmolality and electro-lytes. (Mc Donnell 2004) b) 0. 25-1 gram/kg IV q4-6h as needed (Barton 2002b) c) Secondary to trauma: 100-500 mg/kg slow IV, if a positive effect is seen, may repeat every 2 hours for 3 doses. Crystal-loid infusion may need to be adjusted to prevent dehydration or hypovolemia. Furosemide at 0. 75 mg/kg may be adminis-tered prior to mannitol to reduce CSF formation. (Rudloff 2006a) d) Secondary to trauma: 0. 5-1 gram/kg IV followed 20 min-utes later by furosemide (1 mg/kg IV). Potential risk for worsening intracranial hemorrhage, but patients that are dy-ing before your eyes can beneﬁt from this aggressive therapy. (Mazzaferro 2007) T o measure glomerular ﬁltration rate in dogs: a) 1. 1-2. 2 grams/kg IV slowly over 15-30 minutes (Mc Con-nell and Hughey 1987) !TCATTLE, SWINE, SHEEP, GOATS: For adjunctive treatment of cerebral edema: a) 1-3 gm/kg IV (usually with steroids and/or DMSO) (Dill 1986) As a diuretic for oliguric renal failure: a) 1-2 gm/kg (5-10m L of 20% solution) IV after rehydration; monitor urine ﬂow and ﬂuid balance (Osweiler 1986) !THORSES: a) 0. 25-2 gm/kg as a 20% solution by slow IV infusion (Schultz 1986) Monitoring !TSerum electrolytes, osmolality !TBUN, serum creatinine !TUrine output !TCentral venous pressure, if possible !TLung auscultation Client Information !TMannitol should be administered by professional staff in a set-ting where adequate monitoring can occur. Chemistry/Synonyms An osmotic diuretic, mannitol occurs as an odorless, sweet-tasting, white, crystalline powder with a melting range of 165°-168° and a p Ka of 3. 4. One gram is soluble in about 5. 5 m L of water (at 25°C); it is very slightly soluble in alcohol. The commercially available in-jectable products have approximate p H's of 4. 5-7. Mannitol may also be known as: cordycepic acid, E421, man-ita, manitol, manna sugar, mannite, mannitolum, Eufusol M 20, Am-Vet® Mannitol Injection 20%, Isotol ®, Manicol®, Manniject®, Maniton®, Mannistol®, Mannit-Losung®, Mannite®, Mede-Prep ®, Osmofundin 15% N®, Osmofundin 20%, Osmofundina®, Osmofundina® Concentrada,Osmorol®,Osmosteril® 20%, Resectisol® and Thomaemannit®. Storage/Stability/Compatibility Mannitol solutions are recommended to be stored at room tem-perature; avoid freezing. Crystallization may occur at low temperatures in concentra-tions greater than 15%. Resolubolization of the crystals can be ac-complished by heating the bottle in hot (up to 80°C) water. Cool to body temperature before administering. An in-line IV ﬁlter is recommended when administering concentrated mannitol solu-tions. Alternatively, heated storage chambers (35°-50°C) have been suggested to assure that soluble product is available at all times. Microwaving glass ampules/vials has been suggested, but explo-sions have been documented and this procedure cannot be recom-mended. Supersaturated solutions of mannitol in PVC bags may show a white ﬂocculent precipitate that will tend to reoccur even after heating. Drugs reported to be physically compatible with mannitol in-clude: amikacin sulfate, bretylium tosylate, cefamandole naftate, cefoxitin sodium, cimetidine HCl, dopamine HCl, gentamicin sul-fate, metoclopramide HCl, netilmicin sulfate, tobramycin sulfate, and verapamil HCl. Mannitol should not be added to whole blood products to be used for transfusion. Sodium or potassium chloride can cause man-nitol to precipitate out of solution when mannitol concentrations are 20% or greater. Mannitol may be physically incompatible when mixed with strongly acidic or alkaline solutions. Mannitol is reportedly stable when mixed with cisplatin for a short period of time, but advanced premixing of the drugs should be avoided because a complex may form between them.	pppbs.pdf
MARBOFLOXACIN 557 Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Mannitol for injection 20%: 20 g/100 m L in 100 m L single-dose vi-als. Am-Vet® Mannitol Injection 20% (IVX); generic (Phoenix Pharm, Neogen); (Rx). Labeled for use in canine species. Mannitol for Injection 18%: 180 mg/m L in 100 m L vials; Manniject® (Butler); generic (Vedco); (Rx). Labeled for use in dogs HUMAN-LABELED PRODUCTS: Mannitol for Injection Mannitol Injection: 5% (50 mg/m L; 275 m Osm/l) in 1000 m L; 10% (100 mg/m L; 550 m Osm/l) in 500 m L and 1000 m L; 15% (150 mg/m L; 825 m Osm/l) in 150 m L & 500 m L; 20% (200 mg/m L; 1100 m Osm/l) in 250 m L and 500 m L; 25% (250 mg/m L; 1375 m Osm/l) in 50 m L vials and syringes (12. 5 grams/vial); generic; (Rx) Mannitol Solution: Genitourinary Irrigants: 5 g/100 m L in distilled wa-ter (275 m Osm/L) in 2000 m L; Resectisol® (Kendall Mc Gaw); (Rx) MARBOFLOXACIN (mar-boe-ﬂox-a-sin) Zeniquin® FLUORO QUINOLONE ANTIBIOTIC Prescriber Highlights TT Veterinary oral ﬂuoroquinolone antibiotic effective against a variety of pathogens TT Not effective against anaerobes TT Contraindications: Hypersensitivity to ﬂuoroquinolones; Relatively contraindicated for young, growing animals due to cartilage abnormalities TT Caution: Hepatic or renal insufﬁciency, seizure patients, or dehydration TT Adverse Effects: GI distress; does not appear to cause ocular toxicity in cats TT Drug interactions Uses/Indications Marboﬂoxacin is labeled for the treatment of susceptible bacterial infections in dogs and cats. Pharmacology/Actions Marboﬂoxacin is a bactericidal agent. The bactericidal activity of marboﬂoxacin is concentration dependent, with susceptible bac-teria cell death occurring within 20-30 minutes of exposure. Like other ﬂuoroquinolones, marboﬂoxacin has demonstrated a signiﬁ-cant post-antibiotic effect for both gram-and + bacteria and is ac-tive in both stationary and growth phases of bacterial replication. Its mechanism of action is not thoroughly understood, but it is believed to act by inhibiting bacterial DNA-gyrase (a type-II topoi-somerase), preventing DNA supercoiling and DNA synthesis. Marboﬂoxacin has a similar spectrum of activity as the other vet-erinary commercially available agents. These agents have good ac-tivity against many gram-negative bacilli and cocci, including most species and strains of Pseudomonas aeruginosa, Klebsiella s p p., E. coli, Enterobacter, Campylobacter, Shigella, Salmonella, Aeromonas, Haemophilus, Proteus, Y ersinia, Serratia, and Vibrio species. Other organisms that are generally susceptible include Brucella s p p., Chlamydia trachomatis, Staphylo cocci (including penicillinase-producing and methicillin-resistant strains), Mycoplasma, and Mycobac terium spp. (not the etiologic agent for Johne's Disease). The ﬂuoroquinolones have variable activity against most strep-tococci and are not usually recommended to use for these infec-tions. These drugs have weak activity against most anaerobes and are ineffective in treating anaerobic infections. Resistance does occur by mutation, particularly with Pseudomonas aeruginosa, Klebsiella pneumonia, Acinetobacter, and Enterococci, but plasmid-mediated resistance is thought to occur only rarely. Pharmacokinetics In dogs, marboﬂoxacin is characterized as being rapidly absorbed after oral administration with a bioavailability of 94%. Peak plasma levels occur in about 1. 5 hours. Protein binding is low and the ap-parent volume of distribution is 1. 2-1. 9 L/kg. Elimination half-life averages 9-12 hours. The drug is eliminated unchanged in the urine (40%) and bile/feces. Only about 15% of a dose is metabo-lized in the liver. In cats, absorption after oral dosing is nearly complete and peak serum levels occur about 1-2 hours post-dose. T erminal elimina-tion half-life is about 13 hours. Renal impairment does not signiﬁcantly alter dosing requirements. Contraindications/Precautions/Warnings Like other quinolones, marboﬂoxacin is labeled as contraindicat-ed in small and medium breed dogs up to 8 months of age, large breeds to 12 months old, and giant breeds to 18 months old. It is also labeled as contraindicated in cats under 12 months of age. Quinolones are also contraindicated in patients hypersensitive to them. Marboﬂoxacin can (rarely) cause CNS stimulation and should be used with caution in patients with seizure disorders. The FDA has prohibited the use of this drug in food-producing animals. Adverse Effects With the exception of potential cartilage abnormalities in young animals (see Contraindications above), the adverse effect proﬁle of marboﬂoxacin is usually limited to GI distress (vomiting, anorexia, soft stools, diarrhea) and decreased activity. Other ﬂuoroquinolones have, in rare incidences, caused elevat-ed hepatic enzymes, ataxia, seizures, depression, lethargy, and ner-vousness in dogs. Hypersensitivity reactions or crystalluria could potentially occur. It is not known if marboﬂoxacin can also cause the ocular tox-icity that has been reported with high dose enroﬂoxacin in cats. While unlikely, FDA 's Adverse Drug Reaction database has received 14 reports (as of July 3, 2007) of blindness associated with mar-boﬂoxacin. Causal effect cannot be proven, but use higher dosages carefully. Reproductive/Nursing Safety Safety of marboﬂoxacin during pregnancy has not been established. Overdosage/Acute Toxicity It is unlikely an acute overdose of marboﬂoxacin would result in signs more serious than either anorexia or vomiting, but the ad-verse effects noted above could occur. Dogs receiving 55 mg/kg per day for 12 days developed anorexia, vomiting, dehydration, trem-ors, red skin, facial swelling, lethargy, and weight loss.	pppbs.pdf
558 MAROPITANT CITRATE Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving marboﬂoxacin or re-lated ﬂuoroquinolones and may be of signiﬁcance in veterinary patients: T ! ANTACIDS/DAIRY PRODUCTS : Containing cations (Mg++, Al+++, Ca++) may bind to marboﬂoxacin and prevent its absorption; separate doses of these products by at least 2 hours T ! ANTIBIOTICS, OTHER (aminoglycosides, 3rd-generation cephalosporins, penicillins—extended-spectrum ): Synergism may occur, but is not predictable, against some bacteria (particularly Pseudomonas aeruginosa) with these compounds. Although marboﬂoxacin has minimal activity against anaerobes, in vitro synergy has been re-ported when used with clindamycin against strains of Peptostrep-tococcus, Lactobacillus and Bacteroides fragilis. T ! CYCLOSPORINE : Fluoroquinolones may exacerbate the neph-rotoxicity and reduce the metabolism of cyclosporine (used systemically) T ! FLUNIXIN : Has been shown in dogs to increase the AUC and elimi-nation half-life of enroﬂoxacin and enroﬂoxacin increases the AUC and elimination half-life of ﬂunixin; it is unknown if mar-boﬂoxacin also causes this effect or if other NSAIDs interact with marboﬂoxacin in dogs T ! GLYBURIDE : Severe hypoglycemia possible T ! IRON, ZINC (oral): Decreased marboﬂoxacin absorption; separate doses by at least two hours T ! METHOTREXATE : Increased MTX levels possible with resultant toxicity T ! NITROFUR ANTOIN : May antagonize the antimicrobial activity of the ﬂuoroquinolones and their concomitant use is not recommended T ! PHENYTOIN : Marboﬂoxacin may alter phenytoin levels T ! PROBENECID : Blocks tubular secretion of ciproﬂoxacin and may also increase the blood level and half-life of marboﬂoxacin T ! SUCRALFATE : May inhibit absorption of marboﬂoxacin; separate doses of these drugs by at least 2 hours T ! THEOPHYLLINE : Marboﬂoxacin may increase theophylline blood levels T ! WARFARIN : Potential for increased warfarin effects Laboratory Considerations T ! In some human patients, the ﬂuoroquinolones have caused in-creases in liver enzymes, BUN, and creatinine and decreases in hematocrit. The clinical relevance of these mild changes is not known at this time. Doses T ! DOGS & CAT S: a) For susceptible infections (urinary tract, skin and soft tis-sue): 2. 75-5. 5 mg/kg PO once daily. Give for 2-3 days be-yond cessation of clinical signs (skin/soft tissue infections); and for at least 10 days (urinary tract). If no improvement noted after 5 days, reevaluate diagnosis. Maximum duration of treatment is 30 days. (Package insert; Zeniquin®—Pﬁzer) Monitoring T ! Clinical efﬁcacy T ! Adverse effects Client Information T ! Give as the veterinarian prescribes; do not stop treating just be-cause the animal appears well. Chemistry/Synonyms A synthetic ﬂuoroquinolone antibiotic, marboﬂoxacin is soluble in water, but solubility decreases as p H increases. Marboﬂoxacin may also be known as Ro 9-1168, Marbocyl®, or Zeniquin®. Storage/Stability Marboﬂoxacin tablets should be stored below 30°C. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Marboﬂoxacin Oral Tablets: 25 mg, 50 mg, 100 mg, 200 mg; Ze-niquin® (Pﬁzer); (Rx). Approved for use in dogs and cats. Must not be used in food animals. HUMAN-LABELED PRODUCTS: None MAROPITANT CITRATE (mar-oh-pit-ent) Cerenia® NEUROKININ (NK1) RECEPTOR A NTAGONIST ANTIEMETIC Prescriber Highlights TT Veterinary approved antiemetic for use in dogs 16 weeks of age & older; also used extra-label in cats TT Acts at the emetic center; therefore effective for emesis mediated via either peripheral or central mechanisms TT Subcutaneous injection is approved for the prevention & treatment of acute vomiting; TT Oral form is approved for the prevention of acute vomit-ing & the prevention of vomiting due to motion sickness; different oral dosages for each indication TT Oral dose is higher than subcutaneous dose due to de-creased bioavailability of the oral tablet Monograph by Dinah Jordan, Pharm D, DICVP Uses/Indications Maropitant citrate injectable solution is indicated for the preven-tion and treatment of acute vomiting in dogs; maropitant citrate tablets are indicated for the prevention of acute vomiting and the prevention of vomiting due to motion sickness in dogs. Both are also used extra-label in cats. Pharmacology/Actions Maropitant is a neurokinin-1 (NK1) receptor antagonist, which acts in the central nervous system by inhibiting Substance P, the key neurotransmitter involved in vomiting. Maropitant suppresses both peripheral & centrally mediated emesis. Pharmacokinetics In dogs, maropitant is rapidly absorbed after oral (PO) & subcu-taneous (SC) administration. Peak plasma concentrations (Tmax) occur in less than 1 hour following 1 mg/kg subcutaneous admin-istration and less than 2 hours after oral administration of 2 or 8 mg/kg. After oral administration bioavailability is 24% (2 mg/ kg) and 37% (8 mg/kg), suggesting ﬁrst pass metabolism which becomes saturated at the higher dose. Feeding status does not af-fect bioavailability.	pppbs.pdf
MAROPITANT CITRATE 559 TMaropitant follows non-linear pharmacokinetics (PK) at oral therapeutic doses but approximately linear PK at higher doses (20-50 mg/kg). Bioavailability is 91% following subcutaneous ad-ministration of 1 mg/kg. An accumulation ratio of 1. 5 occurs after once daily use of maropitant for 5 consecutive days at 1 mg/kg SC or 2 mg/kg PO. Accumulation ratio is 2. 18 after 2 consecutive days at 8 mg/kg PO daily. Hepatic metabolism of maropitant involves two cytochrome P450 enzymes: CYP2D15 (low capacity, high afﬁnity) and CYP 3A12 (high capacity, low afﬁnity). The non-linear kinetics at oral doses of 2-16 mg/kg may be due to saturation of the low capacity enzyme and increased involvement of CYP3A12 at higher doses. Twenty-one metabolites have been identiﬁed with the major (phar-macologically active) metabolite being CJ-18,518, a product of hy-droxylation. Plasma protein binding of maropitant is high (99. 5%). Half-life is 8. 84 hours (range: 6. 07-17. 7 hrs) for 1 mg/kg SC; 4. 03 hours (range: 2. 58-7. 09 hrs) for 2 mg/kg. Maropitant is eliminated primarily by the liver. Urinary recovery of maropitant and its major metabolite is minimal (<1%). Large inter-patient pharmacokinetic variations have been observed. No information on the pharmacokinetics of maropitant in cats was located. Contraindications/Precautions/Warnings Use with caution in dogs with hepatic dysfunction. Use with caution with other medications that are highly protein bound, although clinical signiﬁcance has not been determined. Adverse Effects Maropitant is well tolerated in dogs. Pre-travel vomiting and hyper-salivation are the two most common side effects seen after adminis-tration of the tablets at the higher dosage required for prevention of motion sickness. Swelling or pain at the injection site has been re-ported following SC administration of the drug. Diarrhea (4-8%) & anorexia (1. 5-5. 2%) were the most common side effects noted during U. S. ﬁeld studies. Reproductive/Nursing Safety The safe use of maropitant has not been evaluated in dogs used for breeding, pregnant or lactating bitches. Maropitant should only be used in pregnant or lactating bitches following a beneﬁt/risk assess-ment by the veterinarian. Overdosage/Acute Toxicity Single dose toxicity was studied in mice and rats after oral and intra-venous administration. No adverse events were reported after oral administration of up to 30 mg/kg (mice) and 100 mg/kg (rats) and after IV administration of 6. 5 mg/kg (mice) and 2. 5 mg/kg (rats). The clinical signs of overdosage in mice and rats were similar and independent from the route of administration and included de-creased activity, irregular or labored respiration, ataxia and tremors. Salivation, nasal discharge and “raspy” breathing were also noted in rats after oral dosing, while the excretion of reddish urine was ob-served in some mice and rats following intravenous administration. In dogs, tolerance has been conﬁrmed in doses of up to 3 times the recommended oral dose of 8 mg/kg, for 3 times longer than the proposed maximum duration of treatment. A GLP compliant study revealed no adverse events in dogs after repeated oral doses deliv-ered by oral gavage (5 mg/kg PO q 24h x 93 days). In the same study at 20 mg/kg/day, effects included emesis in two females on day 1, body weights losses of 8-15% when compared to those at start of study, ECG changes (slight increases in P-R interval, P wave dura-tion and QRS amplitude were noted over the course of treatment), slightly lower serum albumin and slightly higher adrenal weights (females) at 20 mg/kg/day in both sexes. Oral toxicokinetic studies with the primary metabolite were conducted in mice, rats, rabbits and dogs, indicating that the me-tabolite was well tolerated. Drug Interactions At the time of writing, no speciﬁc drug interactions have been identiﬁed. During ﬁeld safety and efﬁcacy studies, a number of medications were used concomitantly with maropitant. Many dogs received multiple medications. The most common concomitant medication was metronidazole. Other commonly used concomi-tant medications included: dextrose/Ringers solution IV, sodium chloride IV, amoxicillin, ampicillin, cefazolin, cephalexin, enro-ﬂoxacin, sulfamethoxazole/trimethoprim, famotidine, sucralfate, cimetidine, dexamethasone, ivermectin, ivermectin/pyrantel, pyr-antel, lufenuron/milbemycin, milbemycin, moxidectin, vitamin B, and vaccines. There were no problems observed with any of these drugs in conjunction with maropitant. Laboratory Considerations No speciﬁc concerns noted. Doses !TDOGS: (Note : The following dosages have also been used extra-label in cats—Jordan) Prevention of acute vomiting: 1 mg/kg SC given at least one hour prior to anticipated eme-togenic event and q24h thereafter for up to 5 consecutive days. 2 mg/kg PO given at least two hours prior to anticipated emetogenic event and q24h thereafter for up to 5 consecu-tive days. Treatment of acute vomiting: 1 mg/kg SC q24h for up to 5 consecutive days. Note: If a longer duration of therapy is needed, a 48 hour washout period is recommended due to accumulation of the drug. Prevention of vomiting due to motion sickness: 8 mg/kg (minimum dose) PO given at least two hours prior to travel and q24h for up to 2 consecutive days; Note : If a longer duration of therapy is needed, a 72 hour washout period is recommended. (Label Information; Cerenia®—Pﬁzer) Monitoring !TClinical efﬁcacy measured by decreased episodes of vomiting !TAdverse effects Client Information !Tablets should not be tightly wrapped or embedded in food/ snacks as this may delay dissolution of tablets !TAvoid prolonged fasting before administration of tablets !TFeeding a small meal or snack one hour before administration of tablets for motion sickness will minimize the occurrence of pre-trip vomiting following administration of tablets Chemistry/Synonyms Classiﬁed as a substituted quinuclidine, maropitant's molecular weight is 678. 81. The chemical name is (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine citrate. Maropitant may also be known as CJ-11,972.	pppbs.pdf
560 MECHLORETHAMINE HCL Storage/Stability Maropitant injectable solution contains a preservative and is de-signed for multi-dose use. The vial should be stored at controlled room temperature 20-25°C (68-77°F) with excursions permitted between 15-30°C (59-86°F). The product label states the drug should be used within 28 days of ﬁrst vial puncture in accordance with FDA requirements. Although the product may be chemically stable beyond this time, multiple punctures may lead to contami-nation of the product; therefore, extended use beyond the labeled discard date is discouraged. Maropitant tablets are packaged in foil to protect them from moisture uptake, which was observed in less-protective packaging. A European stability study indicated that tablets removed from the blister pack and halved showed no loss of potency during the 48 hour testing period. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Maropitant Citrate Injectable Solution: 10 mg/m L in 20 m L multi-dose vials; Cerenia® (Pﬁzer); (Rx). Labeled for use in dogs. Maropitant Citrate Oral Tablets: 16, 24, 60, and 160 mg in blister packs (4 tablets per pack; carton of 10); Tablets are peach-colored and scored with the tablet strength and MPT imprinted on one side and the Pﬁzer logo imprinted on the other side; Cerenia® (Pﬁzer); (Rx). Labeled for use in dogs. HUMAN-LABELED PRODUCTS: None MECHLORETHAMINE HCL (me-klor-eth-a-meen) Mustargen® ANTINEOPLASTIC Prescriber Highlights TT Antineoplastic for lymphoreticular neoplasms or pleural & peritoneal effusions (intracavitary) TT Contraindications (relative; risk vs. beneﬁt): Anemia, bone marrow depression, tumor cell inﬁltration into bone marrow, current infection, sensitivity to mechlorethamine, or patients who have received previous chemotherapy or radiotherapy TT Adverse Effects: Bone marrow depression, GI effects (vomiting, nausea), ototoxicity (high dosages or regional perfusions); Potentially: alopecia, hyperuricemia, hepato-toxicity, peripheral neuropathy, & GI ulcers TT Teratogen TT Avoid extravasation Uses/Indications In small animals, mechlorethamine may be useful for the adjunctive treatment of lymphoreticular neoplasms or, with intracavitary ad-ministration, for treating pleural and peritoneal effusions. A change in owners of the pharmaceutical product has reportedly resulted in very large price increases for this medication and some veterinary oncologists are substituting dactinomycin for the mechlorethamine in MOPP rescue protocols. Pharmacology/Actions Mechlorethamine is an alkylating agent, thereby interfering with DNA replication, RNA transcription, and protein synthesis. It is cell cycle-phase nonspeciﬁc. With intracavitary administration, mechlorethamine causes sclerosing and an inﬂammatory response on serous membranes, thereby causing adherence of serosal surfaces. Pharmacokinetics Because mechlorethamine is so irritating to tissues it must be given IV for systemic use. It is incompletely absorbed after intracavitary administration. After injection, mechlorethamine is rapidly (within minutes) inactivated. Contraindications/Precautions/Warnings Mechlorethamine is contraindicated in patients with a known in-fection or have had a prior anaphylactic reaction to the drug. Mechlorethamine should be used only when its potential ben-eﬁts outweigh its risks with the following conditions: anemia, bone marrow depression, tumor cell inﬁltration into bone marrow, sen-sitivity to mechlorethamine, or patients who have received previous chemotherapy or radiotherapy. Adverse Effects Bone marrow depression (leukopenia, thrombocytopenia) and GI effects (vomiting, nausea) are quite common and can be serious enough to halt therapy. Ototoxicity may occur with either high dos-ages or regional perfusions. Other potential effects include alope-cia, hyperuricemia, hepatotoxicity, peripheral neuropathy, and GI ulcers. Because severe tissue sloughing may occur, avoid extravasation. Reproductive/Nursing Safety Mechlorethamine is a teratogen in lab animals. Use only during pregnancy when the beneﬁts to the mother outweigh the risks to the offspring. Mechlorethamine can suppress gonadal function. 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. ) While it is not known whether mechlorethamine enters mater-nal milk, nursing puppies or kittens should receive milk replacer when the dam is receiving mechlorethamine. Overdosage/Acute Toxicity Because of the toxic potential of this agent, overdoses must be avoided. Determine dosages carefully. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving mechlorethamine and may be of signiﬁcance in veterinary patients: T ! IMMUNOSUPPRESSANT DRUGS (e. g., azathioprine, cyclophosphamide, corticosteroids ): Use with other immunosuppressant drugs may increase the risk of infection. T ! MYELOSUPPRESSIVE DRUGS (e. g., chloramphenicol, ﬂucytosine, ampho-tericin B, or colchicine ): Use extreme caution when used concur-rently with other drugs that are also myelosuppressive, including many of the other antineoplastics and other bone marrow de-pressant drugs. Bone marrow depression may be additive. T ! VACCINES, LIVE : Live virus vaccines should be used with caution, if at all, during therapy.	pppbs.pdf
MECLIZINE HCL 561 Laboratory Considerations T ! Mechlorethamine may raise serum uric acid levels. Drugs such as allopurinol may be required to control hyperuricemia. Doses For more information on using mechlorethamine as part of che-motherapy protocols, 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). T ! DOGS: For the adjunctive treatment of lymphoreticular neoplasms or with intracavitary administration for treating pleural and peri-toneal effusions: a) 5 mg/m2 IV or intracavitary; repeat as needed (Jacobs, Lums-den et al. 1992) For MOPP lymphoma rescue: a) Mechlorethamine: 3 mg/m2 IV days 1 and 7; Vincristine: 0. 7 mg/m2 IV days 1 and 7; Procarbazine: 50 mg/m2 PO daily days 1-14; Prednisone: 30 mg/m2 PO daily day 1-14. No treatment given days 15-28 and then protocol is repeated at 4 weeks. Protocol may be severely myelosuppressive. (Meleo 2003) T ! CATS: For MOPP lymphoma rescue: a) Mechlorethamine: 3 mg/m2 IV days 1 and 7; Vincristine: 0. 5 mg/m2 IV days 1 and 7; Procarbazine: 50 mg/m2 PO daily days 1-14; Prednisone: 30 mg/m2 PO daily day 1-14. No treatment given days 15-28 and then protocol is repeated at 4 weeks. Cats may require 5-week cycle due to myelosuppres-sion. (Meleo 2003) b) Mechlorethamine: 3 mg/m2 IV days 0 and 7; Vincristine: 0. 025 mg/kg IV days 0 and 7; Procarbazine: 10 mg (total dose) PO daily days 0-14; Prednisone: 5 mg (total dose) PO twice daily continuously. May also be considered for inducing ﬁrst remission in cats. Anorexia may be reduced if procarbazine is given every other day or given with metoclopramide. (Frim-berger 2002) Monitoring T ! CBC with platelets at least every 1-2 weeks until stable; then ev-ery 3 months T ! Liver function tests; initially before starting treatment and then every 3-4 months T ! Injection site for signs of extravasation Chemistry/Synonyms A bifunctional alkylating agent, mechlorethamine occurs as a hy-groscopic, white, crystalline powder that is very soluble in water. After reconstitution with sterile water or sterile saline, the resultant solution is clear and has a p H of 3-5. Mechlorethamine may also be known as: nitrogen mustard, mustine, HN 2, chlormethine hydrochloride, chlorethazine hydro-chloride, HN2 (mustine [chlormethine]), mechlorethamine hy-drochloride, mustine hydrochloride, nitrogen mustard (mustine [chlormethine]), NSC-762, WR-147650, Caryolysine®, Mustargen® and Onco-Cloramin®. Storage/Stability Store the powder for injection at room temperature. Mechloretha-mine is highly unstable in neutral or alkaline aqueous solutions and rapidly degrades. While more stable in an acidic environment, the drug should be administered immediately after preparation. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Mechlorethamine Powder for Injection: 10 mg; Mustargen® (Ova-tion); (Rx) MECLIZINE HCL (mek-li-zeen) Antivert® ANTIHISTAMINE, ANTIEMETIC Prescriber Highlights TT Antihistamine with sedative & antiemetic effects, used primarily for motion sickness TT Contraindications: Known hypersensitivity TT Caution: Prostatic hypertrophy, bladder neck obstruction, severe cardiac failure, angle-closure glaucoma, or pyelo-duodenal obstruction TT Adverse Effects: Sedation; less frequently anticholinergic effects may be noted (dry mucous membranes, eyes, tachycardia, etc. ); contradictory CNS stimulation possible Uses/Indications Meclizine is principally used in small animals as an antiemetic and for the treatment and prevention of motion sickness. Pharmacology/Actions Meclizine is a piperazine antihistamine and, beside its antihista-mine activity, it also possesses antiemetic, CNS depressant, anti-spasmodic, and local anesthetic effects. The exact mechanisms of action for its antiemetic and anti-motion-sickness effects are not completely understood, but it is thought they are as a result of the drug's central anticholinergic and CNS depressant activity. The an-tiemetic effect is probably mediated through the chemoreceptor trigger zone (CTZ). Pharmacokinetics Very little information is available. Meclizine is metabolized in the liver and has a serum half-life of about 6 hours. Contraindications/Precautions/Warnings Meclizine is contraindicated in patients hypersensitive to it. It should be used with caution in patients with prostatic hypertrophy, bladder neck obstruction, severe cardiac failure, angle-closure glau-coma, or pyeloduodenal obstruction. Adverse Effects The usual adverse effect noted with meclizine is sedation; less fre-quently anticholinergic effects may be noted (dry mucous mem-branes, eyes, tachycardia, etc. ). Contradictory CNS stimulation has also been reported. Cats may develop inappetance while receiving this medication.	pppbs.pdf
562 MEDETOMIDINE HCL Reproductive/Nursing Safety Meclizine is considered teratogenic at high dosages in laboratory animals and cleft palates have been noted in rats at 25-50 times higher than labeled dosages. However, in humans, it has been sug-gested that meclizine possesses the lowest risk for teratogenicity for antiemetic drugs and that it is the drug of ﬁrst choice to treat nau-sea/vomiting associated with pregnancy. In humans, the FDA cat-egorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) It is unknown if meclizine enters milk; its anticholinergic activ-ity may, potentially, inhibit lactation. Overdosage/Acute Toxicity Moderate overdosage may result in drowsiness alternating with hy-perexcitability. Massive overdosages may result in profound CNS depression, hallucinations, seizures and other anticholinergic ef-fects (tachycardia, urinary retention, etc. ). Treatment is consid-ered symptomatic and supportive. Consider gut emptying when patients present soon after ingestion. Avoid respiratory depressant medications. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving meclizine and may be of signiﬁcance in veterinary patients: T ! CNS DEPRESSANTS : Use with other CNS depressants may cause ad-ditive sedation T ! ANTICHOLINERGIC DRUGS : Other anticholinergic drugs may cause additive anticholinergic effects Laboratory Considerations T ! Because these drugs are antihistamines, they may affect the re-sults of skin tests using allergen extracts. Do not use within 3-7 days before testing. Doses T ! DOGS: a) For supportive treatment of peripheral vestibular disease: 25 mg per dog PO once daily. Treatment is usually unnecessary after 72-96 hours. (Hoskins 2005c) b) 25 mg per dog PO once daily. For motion sickness, give one hour before traveling (Papich 1992) c) As an antihistamine: 25 mg PO once daily (Bevier 1990) d) As anti-emetic: 4 mg/kg PO once a day (Dowling 2003a) e) For palliative treatment of vertigo: 25 mg per dog PO once daily. (Schubert 2007) T ! CATS: a) 12. 5 mg per cat PO once daily (Pearce 2006a) b) 6. 25 mg/5 kg of body weight PO (Day 1993) c) As anti-emetic: 4 mg/kg PO once a day (Dowling 2003a) d) For palliative treatment of vertigo: 12. 5 mg per cat PO once daily. (Schubert 2007) T ! RABBITS, RODENTS, SMALL MAMMALS: a) Rabbits: For Rolling, torticollis, motion sickness: 2-12 mg/ kg PO once daily (Ivey and Morrisey 2000) b) Rabbits: For adjunctive treatment of torticollis, head tilt (“wry neck”): 12. 5 mg (total dose) PO q12-24h. (Johnson 2006e) Monitoring T ! Efﬁcacy T ! Adverse effects Client Information T ! When using for motion sickness prevention, instruct client to give medication 30-60 minutes before travel. Chemistry/Synonyms Meclizine HCl is a piperazine derivative antiemetic antihistamine. Meclizine may also be known as: meclozine hydrochloride, mecl-izine hydrochloride; meclizinium chloride; meclozini hydro-chloridum; parachloramine hydrochloride, Agyrax®, Ancolan®, Antivert®, Antrizine®, Bonamine®, Bonine®, Calmonal®, Chiclida®, D-Vert 30®, Dizmiss®, Dramamine II®, Dramine®, Duremesan®, Emetostop®, Marevit®, Meni-D®, Navicalm®, Neo-Istafene®, Nico-Vert®, Peremesin®, Peremesin N®, Peremesine®, Postadoxin N®, Postafen®, Postafene®, Ru-Vert-M®, Sea-Legs®, Suprimal®, Vergon ®, and Vertin®. Storage/Stability/Compatibility Meclizine products should be stored at room temperature in well-closed containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Meclizine HCl Tablets: 12. 5 mg, 25 mg (plain and chewable), 50 mg; Antivert® (Pﬁzer); (Rx); Antrizine® (Major); (Rx); Antivert/25® (Pﬁzer US); (Rx); Dramamine® Less Drowsy Formula (Pﬁzer); (OTC); Bonine® (Pﬁzer Consumer); (OTC); Antivert/50® (Pﬁzer); (Rx); ge-neric; (Rx and OTC). Meclizine Oral Caps: 25 mg; Meni-D® (Seatrace); (Rx) MEDETOMIDINE HCL (mee-de-toe-mi-deen) Domitor® ALPHA-2 ADRENERGIC AGONIST Prescriber Highlights TT Alpha 2-adrenergic sedative analgesic used primarily in dogs & cats, but also may be useful in small mammals, exotics, etc. TT Contraindications: Cardiac disease, respiratory disorders, liver or kidney diseases, shock, severe debilitation, or animals stressed due to heat, cold or fatigue. Caution in very old or young animals TT NOT recommended for use during pregnancy TT Adverse Effects: Bradycardia, occasional AV blocks, de-creased respiration, hypothermia, urination, vomiting, hy-perglycemia, & pain on injection (IM). Rarely: prolonged sedation, paradoxical excitation, hypersensitivity, apnea & death from circulatory failure TT Drug interactions	pppbs.pdf
MEDETOMIDINE HCL 563 Uses/Indications Medetomidine is labeled for use as a sedative and analgesic in dogs over 12 weeks of age to facilitate clinical examinations and proce-dures, minor surgical procedures not requiring muscle relaxation, and minor dental procedures not requiring intubation. The man-ufacturer recommends the IV route of administration for dental procedures. Medetomidine has also been used in cats, primarily in Europe. But there is apparently much less data available to evaluate its use; caution is advised. Pharmacology/Actions An alpha adrenergic receptor, medetomidine has an alpha 2:alpha 1 selectivity factor of 1620, and when compared to xylazine is report-edly 10X more speciﬁc for alpha 2 receptors versus alpha 1 receptors. The pharmacologic effects of medetomidine include: depression of CNS (sedation, anxiolysis), GI (decreased secretions, varying affects on intestinal muscle tone) and endocrine functions, peripheral and cardiac vasoconstriction, bradycardia, respiratory depression, di-uresis, hypothermia, analgesia (somatic and visceral), muscle relax-ation (but not enough for intubation), and blanched or cyanotic mucous membranes. Effects on blood pressure are variable, but medetomidine can cause hypertension longer than does xylazine. Medetomidine also induces sedation for a longer period than does xylazine. Pharmacokinetics After IV or IM injection, onset of effect is rapid (5 min. for IV; 10-15 min. for IM). After SC injection, responses are unreliable and this method of administration cannot be recommended. The drug is absorbed via the oral mucosa when administered sublingually in dogs, but efﬁcacy at a given dose may be less than IM dosing. Contraindications/Precautions/Warnings The label states that medetomidine is contraindicated in dogs hav-ing the following conditions: cardiac disease, respiratory disorders, liver or kidney diseases, shock, severe debilitation, or dogs stressed due to heat, cold, or fatigue. Dogs that are extremely agitated or excited may have a decreased response to medetomidine; the manufacturer suggests allowing these dogs to rest quietly before administration of the drug. Dogs not responding to medetomidine should not be re-dosed. Use in very young or older dogs should be done with caution. Adverse Effects The adverse effects reported with medetomidine are essentially exten-sions of its pharmacologic effects including bradycardia, occasional AV bl o ck s, de c re a s e d re s p i r a t i on, hy p o t h er m i a, u r i n a t i on, vom i t i n g, hyperglycemia, and pain on injection (IM). Rare effects have also been reported, including prolonged sedation, paradoxical excitation, hypersensitivity, apnea, and death from circulatory failure. Reproductive/Nursing Safety The drug is not recommended for use in pregnant dogs or those used for breeding purposes because safety data for use during preg-nancy is insufﬁcient; therefore, use only when the beneﬁts clearly outweigh the drug's risks. Overdosage/Acute Toxicity Single doses of up to 5X (IV) and 10X (IM) were tolerated in dogs, but adverse effects can occur (see above). Death has occurred rarely in dogs (1 in 40,000) receiving 2X doses. Because of the potential of additional adverse effects occurring (heart block, PVC's, or tachycardia), treatment of medetomidine-induced bradycardia with anticholinergic agents (atropine or gly-copyrrolate) is usually not recommended. Atipamezole is probably a safer choice to treat any medetomidine-induced effect. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving medetomidine and may be of signiﬁcance in veterinary patients: Note : Before attempting combination therapy with medetomidine, it is strongly advised to access references from veterinary anesthesi-ologists familiar with the use of this product. !TATROPINE, GLYCOPYRROLATE : The use of atropine or glycopyrrolate to prevent or treat medetomidine-caused bradycardia is contro-versial as tachycardia and hypertension may result. This is more important when using higher doses of medetomidine (>20 mcg/ kg) and concomitant use is discouraged. !TOPIATES : Enhancement of sedation and analgesia may occur when medetomidine is used concurrently with fentanyl, butorphanol, or meperidine, but adverse effects may be pronounced as well. Reduced dosages and monitoring is advised if contemplating combination therapy. !TPROPOFOL : When propofol is used after medetomidine, hypox-emia may occur. Dosage adjustments may be required along with adequate monitoring. !TYOHIMBINE : May reverse the effects of medetomidine; but atipam-ezole is preferred for clinical use to reverse the drug's effects Laboratory Considerations !TMedetomidine can inhibit ADP-induced platelet aggregation in cats. Doses !TDOGS: For sedation/analgesia: a) 750 mcg (0. 75 mg)/m2 body surface area IV or 1000 mcg (1 mg)/m2 body surface area IM. Allow to rest quietly for 15 minutes after injection. Practically, the following dosing table may used: IV DOSING WEIGHT INJECTION VOLUME IM DOSING WEIGHT IN LBS. IN ML IN LBS. 3-4 0. 1-5-7 0. 15 4-5 8-11 0. 2 6-7 12-15 0. 25 8-9 16-21 0. 3 10-14 22-31 0. 4 51-20 32-43 0. 5 21-27 44-55 0. 6 28-35 56-68 0. 7 36-44 69-82 0. 8 45-53 83-97 0. 9 54-63 98-121 1 64-78 122-156 1. 2 79-101 157-194 1. 4 102-126 195+ 1. 6 127-165 -2 166+ (Package Insert; Domitor®—Pﬁzer)	pppbs.pdf
564 MEDIUM CHAIN TRIGLYCERIDES Tb) 10-40 mcg/kg IM; higher doses do not cause greater seda-tion, but increase the duration of effect (Mc Grath and Ko 1997) c) For use with an IM opioid: 5-10 mcg/kg (Hardie 2000) d) 0. 001-0. 01 mg/kg (1-10 mcg/kg) IV, IM or SC (Carroll 1999) T ! CATS: For sedation/analgesia: a) 40-80 mcg/kg IM; higher doses do not cause greater seda-tion, but increase the duration of effect (Mc Grath and Ko 1997) b) For use with an IM opioid: 5-10 mcg/kg (Hardie 2000) c) 0. 001-0. 01 mg/kg (1-10 mcg/kg) IV, IM or SC (Carroll 1999) d) For large, exotic cat (tigers, etc. ) immobilization: Midazo-lam (0. 1 mg/kg) plus medetomidine (0. 05-0. 07 mg/kg) IM followed by ketamine (4-10 mg/kg) IM, if needed. May an-tagonize with atipamezole (0. 25-0. 35 mg/kg) IV, SC. (Curro 2002) T ! SMALL MAMMALS/RODENTS: For chemical restraint: a) Rats: 0. 25-0. 5 mg/kg IM; Guinea pig: 0. 5 mg/kg IM; Rabbits: 0. 25-0. 5 mg/kg IM (Burke 1999) T ! FERRETS: As a sedative/analgesic: a) 15 minutes prior to medetomidine, give atropine (0. 05 mg/ kg or glycopyrrolate (0. 01 mg/kg) then give medetomidine at 60-80 mcg/kg IM or SC. Sedation lasts for up to 3 hours. May be reversed with atipamezole (400 mcg/kg IM); For injectable anesthesia: Butorphanol 0. 1 mg/kg, Ketamine 5 mg/kg, Medetomidine 80 mcg/kg. Combine in one sy-ringe and give IM. May need to supplement with isoﬂurane (0. 5-1. 5%) for abdominal surgery. (Finkler 1999) T ! BIRDS: For sedation/analgesia: a) 0. 1 mg/kg IM; limited data available on duration of effect, adverse effects, etc. (Clyde and Paul-Murphy 2000) T ! REPTILES: a) Medium to small land T ortoises: Medetomidine 100-150 mcg/kg with ketamine 5-10 mg/kg IV or IM; Freshwater Turtles: Medetomidine 150-300 mcg/kg with ketamine 10-20 mg/kg IV or IM; Giant Land T ortoises : 200 kg Aldabra tortoise: Medetomi-dine 40 mcg/kg with ketamine 4 mg/kg IV or IM; Smaller Aldabra tortoises: Medetomidine 40-80 mcg/kg with ketamine 4-8 mg/kg IV or IM. Wait 30-40 minutes for peak effect. Iguanas: Medetomidine 100-150 mcg/kg with ketamine 5-10 mg/kg IV or IM; Reversal of all dosages with atipamezole is 4-5 times the me-detomidine dose. (Heard 1999) Monitoring T ! Level of sedation and analgesia; heart rate; body temperature T ! Heart rhythm, blood pressure, respiration rate, and pulse oxim-etry should be considered, particularly in higher risk patients if the drug is to be used Client Information T ! his drug should be administered and monitored by veterinary professionals only T ! Clients should be made aware of the potential adverse effects as-sociated with its use, particularly in dogs at risk (older, preexist-ing conditions) Chemistry/Synonyms An alpha 2-adrenergic agonist, medetomidine occurs as a white or almost white crystalline substance. It is soluble in water. While the compound exists as two stereoisomers, only the d-isomer is active. Medetomidine HCl may also be known as MPV-785 and Domitor®. Storage/Stability/Compatibility The commercially available injection should be stored at room temperature (15-30°C) and protected from freezing. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Medetomidine HCl for Injection: 1 mg/m L in 10 m L multidose vials; Domitor® (Pﬁzer); (Rx). Approved for use in dogs over 12 weeks of age. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None MEDIUM CHAIN TRIGLYCERIDES (MCT OIL) NUTRITIONAL Prescriber Highlights TT Lipid used to provide calories & fatty acids to animals with restricted fat intake due to chronic inﬁltrative dis-ease of small intestine or fat malabsorption syndromes present TT Cautions: Signiﬁcant hepatic disease ( e. g., portacaval shunts, cirrhosis, etc. ) TT Adverse Effects: Unpalatability, bloating, ﬂatulence, & diarrhea TT Unpalatable if given alone, mix with food Uses/Indications MCT oil is sometimes used to offset the caloric reduction when long-chain triglycerides found in dietary fat are restricted, usually in chronic inﬁltrative diseases of the small intestine or when there is fat malabsorption of any cause. Because of expense and unpalat-ability, many clinicians are bypassing MCT oil and having their cli-ents prepare homemade, highly digestible, ultra-low fat diets (e. g., white turkey meat plus rice/potato) or using very low fat prescrip-tion diets. Pharmacology/Actions Medium chain triglycerides (MCT) are more readily hydrolyzed than conventional food fat. They also require less bile acids for di-gestion, are not dependent for chylomicron formation or lymphatic transport, and are transported by the portal vein. Medium chain triglycerides are not a source for essential fatty acids.	pppbs.pdf
MEDROXYPROGESTERONE 565 Pharmacokinetics No speciﬁc information located, see Pharmacology above. Contraindications/Precautions/Warnings MCT oil should be used with caution in patients with signiﬁcant hepatic disease (e. g., portacaval shunts, cirrhosis, etc. ). Medium chain triglycerides are rapidly absorbed via the portal vein and if their hepatic clearance is impaired, signiﬁcantly high systemic blood and CSF levels of medium chain fatty acids can occur. This may precipitate or exacerbate hepatic coma. Adverse Effects Adverse effects seen with MCT oil in small animals include unpal-atability, bloating, ﬂatulence, and diarrhea. These may be transient and minimized by starting doses at the low end of the spectrum and then gradually increasing the dose. Fat-soluble vitamin supplemen-tation (Vitamins A, D, E, and K) by using a commercial feline or canine vitamin-mineral supplement has been recommended. Reproductive/Nursing Safety Although, no reproductive safety data was located, MCT oil would likely not cause problems. Overdosage/Acute Toxicity Overdosage would likely exacerbate the GI adverse effects noted above. Treat severe diarrhea supportively if necessary. Drug Interactions None listed, but MCT oil could, theoretically, affect absorption of drugs that are dependent on fat for oral absorption (e. g., griseoful-vin, fat soluble vitamins, etc. ). Doses T ! DOGS: T o offset the caloric reduction when long-chain triglycerides found in dietary fat are restricted: a) Orally H-4 teaspoons divided per day with food (Williams 2000) b) Begin with one teaspoonful per meal added to food and slowly increase to a maximal tolerated dose, not to exceed 30 m L per lb of food (Zimmer 1986) c) 1-2 m L/kg per day (Steiner 2003) Monitoring T ! Adverse Effects T ! Efﬁcacy (weight, stool consistency) Client Information T ! Because of the unpalatability of the oil, it should be mixed with small quantities of food before offering to the patient. Chemistry/Synonyms MCT Oil is a lipid fraction of coconut oil consisting principally of the triglycerides C 8 (approx. 67%) and C 10 (approx. 23%) satu-rated fatty acids. Each 15 m L contains 115 k Cal (7. 67 k Cal/m L). Medium chain triglycerides may also be known as: triglycerida saturata media, Alembicol D®, Liprocil®, Liquigen®, MCT®, Mytic 810®, Structolipid®, and Teceeme®. Storage/Stability Unless otherwise noted by the manufacturer, store at room tem-perature in glass bottles. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Medium Chain Triglycerides Oil: in quart bottles; MCT® (Mead Johnson Nutritionals); (OTC) MEDROXYPROGESTERONE ACETATE (me-drox-ee-proe-jess-te-rone) Provera® PROG ESTIN Prescriber Highlights TT Synthetic progestin used primarily to treat sexually di-morphic behavior problems such as roaming, inter-male aggressive behaviors, spraying, mounting, etc. ; some-times used to treat feline psychogenic dermatitis & alopecia TT Because of serious adverse effect proﬁle, consider safer alternatives ﬁrst TT Contraindications: Do not use in pre-pubescent cats or dogs, diabetics, pregnancy, pseudopregnant bitches, fe-males in diestrus or with prolonged heat, uterine hemor-rhage or discharge TT Adverse Effects: Increased appetite &/or thirst, depres-sion, lethargy, personality changes, adrenocortical de-pression, mammary changes (including enlargement, milk production, & neoplasms), diabetes mellitus, pyo-metra, & temporary inhibition of spermatogenesis TT SC injection may cause permanent local alopecia, atro-phy & depigmentation may occur TT Drug-lab (including pathology) interactions Uses/Indications In cats, MPA has been used when either castration is ineffective or undesirable to treat sexually dimorphic behavior problems such as roaming, inter-male aggressive behaviors, spraying, mounting, etc. MPA has also been used as a tranquilizing agent to treat syndromes such as feline psychogenic dermatitis and alopecia, but treatment with “true” tranquilizing agents may be preferable. In humans, parenteral MPA has been used as a long-acting contraceptive in females, to decrease sexually deviant behavior in males, and as an antineoplastic agent for some carcinomas (see Pharmacology section above). Oral MPA is used in human females to treat secondary amenorrhea and to treat abnormal uterine bleed-ing secondary to hormone imbalances. Pharmacology/Actions Progestins are primarily produced endogenously by the corpus lu-teum. They transform proliferative endometrium to secretory en-dometrium, enhance myometrium hypertrophy and inhibit spon-taneous uterine contraction. Progestins have a dose-dependent inhibitory effect on the secretion of pituitary gonadotropins and can have an anti-insulin effect. Medroxyprogesterone has exhibited a pronounced adrenocorticoid effect in animals (species not listed) and can suppress ACTH and cortisol release. MPA is anti-estrogen-ic and will also decrease plasma testosterone levels in male humans and dogs.	pppbs.pdf
566 MEDROXYPROGESTERONE TMPA has antineoplastic activity against endometrial carcinoma and renal carcinoma (efﬁcacy in doubt) in human patients. The mechanism for this activity is not known. Pharmacokinetics No speciﬁc pharmacokinetic parameters in veterinary species were located for this drug. It has been reported (Beaver 1989) that inject-able MPA has an approximate duration of action of 30 days when used to treat behavior disorders in cats. When administered IM to women, MPA has contraceptive activity for at least 3 months. Contraindications/Precautions/Warnings Progestagen therapy can cause serious adverse effects (see below). Safer alternative treatments should be considered when possible, otherwise, weigh the potential risks versus beneﬁts before institut-ing therapy. Many clinicians believe that progestogens are grossly overused. Do not use MPA prior to puberty in cats, as chronic, severe, mammary hypertrophy may result. Use in dogs before puberty may precipitate subclinical uterine or endocrine conditions (e. g., cystic endometrial hyperplasia-pyometra; diabetes). This agent should not be used during pregnancy or to treat bitches with pseudo-pregnancy. Females should not be treated dur-ing diestrus, or with uterine hemorrhage. Do not use in females with prolonged heat unless cystic ovarian disease is conﬁrmed and surgery or GNRH or h CG are not viable options. Animals with dia-betes should not receive medroxyprogesterone. Because this drug can suppress adrenal function, exogenous ste-roids may need to be administered if the patient is stressed (e. g., surgery, trauma). When used for reproductive control, patients should 1) undergo a thorough reproductive history to rule out occurrence of estrus within the last 1-2 months (female in diestrus); 2) complete physi-cal exam; 3) palpation of mammary glands to rule out mammary nodules; 4) vaginal smear to rule out presence of estrus (Romagnoli 2002b) Adverse Effects If MPA is administered subcutaneously, permanent local alope-cia, atrophy, and depigmentation may occur. If injecting SC, it is recommended to use the inguinal area to avoid these manifesta-tions. Adverse reactions that are possible in dogs and cats include: increased appetite and/or thirst, depression, lethargy, personality changes, adrenocortical depression, mammary changes (including enlargement, milk production, and neoplasms), diabetes mellitus, pyometra, and temporary inhibition of spermatogenesis. In dogs, acromegaly and increased growth hormone levels have been seen when used in patients with diabetes mellitus. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category X for use dur-ing pregnancy—especially the ﬁrst 4 months: (Studies in animals or humans demonstrate fetal abnormalities or adverse reaction; re-ports indicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible beneﬁt. ) Medroxyprogesterone can be detected in maternal milk, but in humans, no adverse effects in nursing infants have been noted. Overdosage/Acute Toxicity No reports or information was located on inadvertent overdosage with this agent. 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 medroxyprogesterone and may be of signiﬁcance in veterinary patients: !TAMINOGLUTETHIMIDE : May decrease medroxyprogesterone effects !TFELBAMATE : May increase medroxyprogesterone metabolism !TRIFAMPIN : A potential interaction exists with rifampin, which may decrease progestin activity if administered concomitantly. This is presumably due to microsomal enzyme induction with resultant increase in progestin metabolism. The clinical signiﬁcance of this potential interaction is unknown. Laboratory Considerations !TIn humans, progestins in combination with estrogens ( e. g., oral contraceptives) have been demonstrated to increase thyroxine-binding globulin (TBG) with resultant increases in total circu-lating thyroid hormone. Decreased T 3 resin uptake also occurs, but free T 4 levels are unaltered. Liver function tests may also be altered. !The manufacturer recommends notifying the pathologist of pa-tient medroxyprogesterone exposure when submitting relevant specimens. Doses !TDOGS: a) For progestin-responsive dermatitis: 20 mg/kg IM; May re-peat in 3-6 months if needed (Kunkle 1986) b) For adjunctive treatment of aggressive behaviors: 10 mg/kg IM or SC (see Adverse Effects above) as necessary; works best when combined with behavior modiﬁcation. T o treat inter-male aggression: as above, but do not exceed 3 treatments per year. (Voith and Marder 1988a) c) For long-term reproductive control: 2. 5-3 mg/kg IM q5 months (Romagnoli 2002b), (Romagnoli 2006a) d) For treatment of young German shepherd dwarfs: medroxy-progesterone acetate at 2. 5-5 mg/kg initially at 3 week in-tervals and subsequently at 6 week intervals has resulted in some increase in body size and development of an adult hair coat. (Kooistra 2006) e) For treatment of benign prostatic hypertrophy; best used to maintain breeding potential for short time prior to castra-tion; use with caution: MPA at 0. 3 mg/kg SC once; effects last approximately 10 months. (Lane 2006b) !TCATS: a) T o treat behavioral disorders: T o reduce marking in neutered male cats when all other drugs have been unsuccessful: Me-droxyprogesterone acetate at 5-20 mg/kg SC or IM three to four times yearly. (Landsberg 2007) b) For feline psychogenic alopecia and dermatitis: 75-150 mg IM or SC (see Adverse Effects above); repeat as necessary, but never more often than every 2-3 months (Walton 1986) c) For progestagen-responsive dermatitis: 50-100 mg IM; may repeat in 3-6 months if needed (Kunkle 1986) d) T o treat recurrent abortion secondary to progesterone-de-ﬁciency: 1-2 mg/kg IM once weekly, stop treatment 7-10 days prior to parturition (Barton and Wolf 1988) For long-term reproductive control: a) 2. 5-5 mg PO once weekly; 25 mg injected every 6 months to postpone estrus (Henik, Olson, and Rosychuk 1985) b) 2 mg/kg IM q5 months (Romagnoli 2002b), (Romagnoli 2006a)	pppbs.pdf
MEGESTROL ACETATE 567 T ! BIRDS: a) As an antipruritic and to suppress ovulation: 0. 025-1 m L (3 mg/100 grams body weight) IM once every 4-6 weeks. May cause obesity, fatty liver, polydipsia/polyuria and lethargy if used repeatedly. (Clubb 1986) Monitoring T ! Weight T ! Blood glucose (draw baseline before therapy) T ! Mammary gland development T ! Adrenocortical function T ! Efﬁcacy Chemistry/Synonyms A synthetic progestin, medroxyprogesterone acetate (MPA) occurs as an odorless, white to off-white, crystalline powder. It is insoluble in water and sparingly soluble in alcohol. It has a melting range of 200°-210°C. Medroxyprogesterone acetate may also be known as: MPA, MAP, acetoxymethylprogesterone, medroxyprogesteroni acetas, methy-lacetoxyprogesterone, metipregnone, and NSC-26386; many trade names are available. Storage/Stability Medroxyprogesterone acetate suspensions for injection should be stored at room temperature (15-30°C); avoid freezing and tem-peratures above 40°C. MPA tablets should be stored in well-closed containers at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Medroxyprogesterone Acetate Tablets (scored): 2. 5 mg, 5 mg & 10 mg; Provera ® (Pharmacia & Upjohn); generic; (Rx) Medroxyprogesterone Acetate Injection: 104 mg (160 mg/m L) in 0. 65 m L preﬁlled syringes & 1 m L vials; 150 mg/m L in 1 m L; 400 mg/m L in 2. 5 m L and 10 m L vials and 1 m L U-ject; Depo-Sub Q Provera 104® (Pﬁzer); Depo-Provera® (Pharmacia); (Rx) MEGESTROL ACETATE (me-jess-trole) Ovaban®, Megace® PROGESTIN Prescriber Highlights TT Synthetic progestin used in DOGS (FEMALE): for post-ponement of estrus & the alleviation of false pregnancy; DOGS (MALE): benign prostatic hypertrophy. CAT S: Many dermatologic & behavior-related conditions TT Contraindications: Pregnant animals or with uterine disease, diabetes mellitus, or mammary neoplasias; should not be used treat bitches with pseudo-pregnancy; females should not be treated during diestrus, or with uterine hemorrhage TT Caution: Thrombophlebitis TT Adverse Effects: CAT S: Profound adrenocortical suppres-sion, adrenal atrophy, transient diabetes mellitus, poly-dipsia/polyuria, personality changes, increased weight, endometritis, cystic endometrial hyperplasia, mammary hypertrophy, neoplasias, & hepatotoxicity possible. DOGS: Increased appetite & weight gain, lethargy, change in behavior or hair color, mucometra, endometritis, cystic endometrial hyperplasia, mammary enlargement & neo-plasia, acromegaly, adrenocortical suppression, or lacta-tion (rare) Uses/Indications Megestrol acetate (Ovaban®—Schering) is approved by FDA for use in dogs only for the postponement of estrus and the alleviation of false pregnancy. In male dogs, it has been used for benign prostatic hypertrophy. It is used clinically for many dermatologic and behav-ior-related conditions, primarily in the cat. See the Dosage section for speciﬁc indications and dosages for both dogs and cats. Megestrol acetate is indicated in humans for the palliative treat-ment of advanced carcinoma of the breast or endometrium. Pharmacology/Actions Megestrol acetate possesses the pharmacologic actions expected of the other progestationals discussed (e. g., medroxyprogesterone ac-etate). It has signiﬁcant anti-estrogen and glucocorticoid activity (with resultant adrenal suppression). It does not have anabolic or masculinizing effects on the developing fetus. Pharmacokinetics Megestrol acetate is well absorbed from the GI tract and appears to be metabolized completely in the liver to conjugates and free steroids. The half-life of megestrol acetate is reported to be 8 days in the dog. Contraindications/Precautions/Warnings Megestrol acetate is contraindicated in pregnant animals or in ani-mals with uterine disease, diabetes mellitus, or mammary neopla-sias. It has been recommended that MA not be used in dogs prior to their ﬁrst estrous cycle or for anestrus therapy in dogs with abnor-mal cycles. The manufacturer (Schering) recommends that mating be prevented should estrus occur within 30 days of cessation of MA therapy.	pppbs.pdf
568 MEGESTROL ACETATE This agent should not be used during pregnancy or to treat bitches with pseudo-pregnancy. Females should not be treated dur-ing diestrus, or with uterine hemorrhage. Do not use in females with prolonged heat unless cystic ovarian disease is conﬁrmed and surgery or GNRH or h CG are not viable options. Animals with dia-betes should not receive megestrol. Because this drug can suppress adrenal function, exogenous ste-roids may need to be administered if the patient is stressed (e. g., surgery, trauma). For estrus control,the manufacturer recommends that drug must be given for the full treatment regimen to be effective. The package insert states that “Ovaban® should not be given for more than two consecutive treatments,” but the reasons for this are unclear; some theriogenologists question the need for this precaution. In humans, megestrol acetate is to be used with caution in pa-tients with thrombophlebitis and is contraindicated as a test for pregnancy. Adverse Effects In cats, megestrol acetate can induce a profound adrenocortical suppression, adrenal atrophy, and an iatrogenic “Addison's” syn-drome can develop at “standard” dosages (2. 5-5 mg every other day) within 1-2 weeks. Once the drug has been discontinued, se-rum cortisol levels (both resting and ACTH-stimulated) will return to normal levels within a few weeks. Clinical signs of adrenocortical insufﬁciency (e. g., vomiting, lethargy) are uncommon, but exog-enous steroid support should be considered if the animal is stressed (surgery, trauma, etc. ). Cats may develop a transient diabetes mel-litus while receiving MA. Polydipsia/polyuria, personality changes, increased weight, endometritis, cystic endometrial hyperplasia, mammary hypertrophy and neoplasias may also occur. Increased appetite and weight gain is not consistently seen, but MA is occa-sionally used as an appetite stimulant. Rarely, megestrol acetate can cause hepatotoxicity (increased alkaline phosphatase) in cats. Limited clinical studies have suggested that megestrol acetate may cause less cystic endometrial hyperplasia than other proges-tational agents, but cautious use and vigilant monitoring is still warranted. In dogs, increased appetite and weight gain, lethargy, change in behavior or hair color, mucometra, endometritis, cystic endometri-al hyperplasia, mammary enlargement and neoplasia, acromegaly, adrenocortical suppression or lactation (rare) may occur. One dog reportedly developed diabetes mellitus after use. Reproductive/Nursing Safety No effects were noted in either the bitch or litter when pregnant dogs received 0. 25 mg/kg/day for 32 days during the ﬁrst half of pregnancy; reduced litter sizes and puppy survival were detected when the dose was given during the last half of pregnancy. Fetal hypospadias are possible if progestational agents are administered during pregnancy. During the ﬁrst 4 months of pregnancy in humans, the FDA cat-egorizes this drug as category X for use during pregnancy (Studies in animals or humans demonstrate fetal abnormalities or adverse re-action; reports indicate evidence of fetal risk. The risk of use in preg-nant women clearly outweighs any possible beneﬁt. ) During the last 5 months of pregnancy in humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fe-tal risk, but the potential beneﬁts from the use of the drug in pregnant women may be acceptable despite its potential risks. ) Detectable amounts of progestins enter the milk of mothers re-ceiving these agents. Effects on nursing infants have not been es-tablished. Overdosage/Acute Toxicity No information was located regarding acute overdosage of mege-strol acetate. In humans, dosages of up to 800 mg/day caused no observable adverse reactions. T oxicity studies performed in dogs at dosages of 0. 1-0. 25 mg/ kg/day PO for 36 months yielded no gross abnormalities in the study population. Histologically, cystic endometrial hyperplasia was noted at 36 months, but resolved when therapy was discon-tinued. At dosages of 0. 5 mg/kg/day PO for 5 months, a reversible uterine hyperplasia was seen in treated dogs. Dosages of 2 mg/kg/ day demonstrated early cystic endometritis in biopsies done on dogs at 64 days. Drug Interactions !TCORTICOSTEROIDS : Megestrol used with corticosteroids (long-term) may exacerbate adrenocortical suppression and diabetes mellitus. !TRIFAMPIN : May decrease progestin activity if administered con-comitantly. This is presumably due to microsomal enzyme in-duction with resultant increase in progestin metabolism. The clinical signiﬁcance of this potential interaction is unknown. Doses !TDOGS: For estrus control: a) T o halt cycle in proestrus: 2. 2 mg/kg once daily for 8 days starting during the ﬁrst 3 days of proestrus. While the timing of the next cycle is variable, it may be prolonged with 2. 2 mg/ kg/day for 4 days, then 0. 55 mg/kg/day for 16-20 days. T o postpone an anticipated cycle : 0. 55 mg/kg/day for 32 days, beginning at least 7 days prior to proestrus (Burke 1985) b) For suppression during proestrus (ﬁrst 3 days): 2. 2 mg/kg once daily for 8 days (92% efﬁcacy). Bitch must be controlled until behavioral signs of estrus disappear. If mating occurs during ﬁrst 3 days of therapy, stop treatment and consider mismating therapy. There is an increased likelihood of pyo-metra developing if progestins are used concomitantly with estrogens. If mating occurs after 3 or more days of therapy continue at a dosage rate of 3-4 mg/kg PO. T o delay an anticipated heat during anestrus: 0. 55 mg/kg PO for 32 days initiated 7 days prior to proestrus. Recommend doing vaginal cytology prior to therapy. If no erythrocytes are seen, initiate therapy if cycle time frame is appropriate. If erythrocytes are seen, delay therapy until proestrus therapy can be instituted. Do not repeat therapy more often than once every 6 months. (Woody 1988) c) 2 mg/kg (or less) administered for ≤2 weeks in proestrus, or ≤2 mg/kg administered for a longer duration in anestrus. A typical dose for estrus suppression is 2 mg/kg PO once daily for 8 consecutive days, while a typical dose for temporary postponement is 0. 5 mg/kg PO once daily in late anestrus. (Romagnoli 2002b), (Romagnoli 2006a) For benign prostatic hypertrophy: a) 0. 5 mg/kg PO daily for 4-8 weeks (Root Kustritz and Klaus-ner 2000) b) 0. 55 mg/kg PO daily (Purswell 1999) c) 0. 1-0. 5 mg/kg per day for 3-8 weeks; best used to maintain breeding potential for short time prior to castration; use with caution. (Lane 2006b) For pseudocyesis (false pregnancy): a) 0. 5 mg/kg PO once daily for 8 days (Barton and Wolf 1988) T o prevent vaginal hyperplasia development: a) 2. 2 mg/kg PO for 7 days early in proestrus (Wykes 1986)	pppbs.pdf
MEGESTROL ACETATE 569 TFor treatment of severe galactorrhea: a) 0. 55 mg/kg PO once daily for 7 days (Olson and Olson 1986) For behavior disorders: a) For adjunctive treatment of aggressive or unacceptable mas-culine behavior: 1. 1-2. 2 mg/kg PO once daily for 2 weeks, then 0. 5-1. 1 mg/kg once daily for 2 weeks. Should be used with behavior modiﬁcation. (Voith and Marder 1988a) !TCATS: For suppression of estrus: a) In anestrus: 5 mg/cat PO every 2 weeks or 2. 5 mg/cat per week (better if divided into 2 doses given every 3. 5 days); In proestrus: 5 mg/cat per day for 4 days, then 5 mg PO every 2 weeks. (Romagnoli 2006a) b) If in behavioral estrus, signs may be inhibited by giving 5 mg/ day PO until estrus stops (generally within 3-5 days), then 2. 5-5 mg PO once weekly for 10 weeks Postponement of estrus (if started during diestrus): 2. 5 mg PO daily for 8 weeks Postponement of estrus (if started during anestrus): 2. 5 mg PO once weekly for up to 18 months. Recommend allowing cat to have a cycle (unmedicated) before beginning another treatment cycle. (Woody 1988) c) If started in diestrus: 2. 5 mg per day PO for up to 2 months If started in anestrus: 2. 5 mg per week for up to 18 months For prevention of estrus: 5 mg daily PO for 3 days as soon as behavioral signs of estrus are seen; next estrus period will oc-cur in approximately 4 weeks (Romatowski 1989) (informa-tion from package insert; Ovarid®—Glaxovet) For treatment of idiopathic feline miliary dermatitis: a) 2. 5-5 mg once every other day, followed by weekly main-tenance dosages. May be necessary to treat for animal's life-time. Reserve use for severe cases; explain risks to owner and do not exceed 2. 5 mg per week during maintenance phase. (Kwochka 1986) As appetite stimulant: a) 0. 25-0. 5 mg/kg q24h for 3-5 days, then q48-72h (Smith 2003a) As an alternative treatment for immune-mediated skin diseases: a) 2. 5-5 mg PO once daily for 10 days, then every other day (Giger and Werner 1988) For adjunctive therapy of eosinophilic granulomas: a) 0. 5 mg/kg PO once daily for 2 weeks, then twice weekly as needed (Coppoc 1988) For eosinophilic ulcers: a) Alone or in combination with methylprednisolone acetate (Depo-Medrol®): 5-10 mg PO every other day for 10-14 doses, then every 2 weeks as needed (De Novo, Potter, and Woolfson 1988) For eosinophilic keratitis (feline proliferative keratitis): a) 0. 5 mg/kg PO daily until a response is noted, then reduce dose to 1. 25 mg PO 2-3 times weekly as required (Nelson 1986) For feline plasma cell gingivitis: a) 2. 5 mg PO once daily for 10 days, then once every other day for 5 treatments, then as needed (Morgan 1988) As a secondary therapy (thyroid hormone replacement ﬁrst choice) for treatment of feline endocrine alopecia (FEA): a) 5 mg PO every second to third day initially, then 2. 5 mg PO once to twice weekly (Thoday 1986) For feline psychogenic alopecia and dermatitis: a) 2. 5-5 mg every other day initially, then taper to the lowest maintenance dosage possible, given weekly as needed (Wal-ton 1986) For adjunctive therapy (with urine acidiﬁcation, increased urine crystalloid solubility, and antispasmodics if required) for persis-tent hematuria and urethritis in a non-obstructed cat: a) 2. 5-5 mg PO once daily to every other day (with prednisone: 2. 5-5 mg PO daily) (Lage, Polzin, and Zenoble 1988) For urine marking, intraspecies aggression, anxiety: a) 2 mg/kg/day for 5 days, then 1 mg/kg/day for 5 days, then 0. 5 mg/kg/day for 5 days (Romatowski 1989) (information from package inserts; Ovarid®—Glaxovet) b) T o reduce marking in neutered male cats when all other drugs have been unsuccessful: megestrol acetate at 2. 5-10 mg (total dose) per cat PO once daily for one week, then re-duce to once or twice weekly. (Landsberg 2007) Monitoring !TWeight !TBlood glucose (draw baseline before therapy) !TMammary gland development and appearance !TAdrenocortical function !TLiver enzymes if long-term treatment !TEfﬁcacy Client Information !The client should fully understand the potential risks of therapy (see Adverse Effects above) before starting therapy and should report changes in mammary glands or other signs associated with adverse reactions (e. g., PU/PD, extreme lethargy, behavior changes, etc. ) to the veterinarian. Chemistry/Synonyms A synthetic progestin, megestrol acetate (MA) occurs as an essen-tially odorless, tasteless, white to creamy white, crystalline powder that is insoluble in water, sparingly soluble in alcohol, and slightly soluble in ﬁxed oils. It has a melting range of 213°-219°C over a 3° range and a speciﬁc rotation of +8° to +12°. Megestrol acetate may also be known as: BDH-1298, compound 5071, megestroli acetas, NSC-71423, SC-10363, Acestrol®, Borea®, Endace®, Gynodal®, Maygace®, Megace®, Megastrol®, Megefren®, Megestat®, Megestil®, Megestin®, Megostat®, Meltonar®, Meprogest®, Mestrel®, Nia ®, Niagestin®, Niagestine®, Ovaban®, Prazoken®, and Varigestrol®. Storage/Stability Megestrol acetate tablets should be stored in well-closed containers at a temperature of less than 40°C. The tablets may be crushed and administered with food. The veterinary manufacturer recommends storing the tablets from 2°-30°C (36°-86°F). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Megestrol Acetate Oral Tablets: 5 mg, 20 mg; available in bottles of 250 and 500 tablets, and in 30 foil strips of 8 and packaged in cartons of 240 tablets; Ovaban® (Schering-Plough); (Rx). Approved for use in dogs only. HUMAN-LABELED PRODUCTS: Megestrol Acetate Tablets: 20 mg & 40 mg; Megace® (Bristol-Meyers Oncology); generic; (Rx) Megestrol Acetate Suspension: 40 mg/m L in 240 m L; 125 mg/m L in 150 m L; Megace® (Bristol-Meyers Oncology); Megace ES® (Par Phar-maceutical Inc); (Rx)	pppbs.pdf
570 MEGLUMINE ANTIMONIATE MEGLUMINE ANTIMONIATE (meg-loo-meen an-tih-mohne-ee-ate) Glucantime®, Gulcantim® PENTA V ALENT A NTIMONY ANTILEISHMANIAL Prescriber Highlights TT Pentavalent antimony compound used for treating leish-maniasis (with or without allopurinol) in dogs TT Not available in USA TT Extreme caution (relatively contraindicated) in patients with cardiac, hepatic or renal insufﬁciency TT Primary adverse effects noted in dogs with meglumine antimoniate are injection site reactions, lethargy & gas-trointestinal effects (inappetance, vomiting) TT Treatment is prolonged & cost may be substantial Uses/Indications Meglumine antimoniate is used alone or in combination with al-lopurinol to treat leishmaniasis in dogs. It is available commercially in some Mediterranean and South American countries but not in the USA. Pharmacology/Actions Pentavalent antimony compounds such as meglumine antimoniate and sodium stibogluconate selectively inhibit the leishmanial en-zymes required for glycolytic and fatty acid oxidation. Pentavalent antimony compounds rarely are successful in eradicating Leishmania organisms completely in infected dogs. Pharmacokinetics After subcutaneous or intramuscular injections in dogs systemic bioavailability is about 92%; highest tissue concentrations are found in the liver, spleen, and skin. Within 9 hours of dosing, 80% of the antimony is excreted in the urine. Contraindications/Precautions/Warnings Patients with renal, hepatic or cardiac failure are more likely to develop serious adverse effects with this agent; weigh the potential risks versus beneﬁts carefully before treating. Hypersensitivity re-actions have been reported in people, and any patient with previ-ous hypersensitivity to meglumine antimoniate should not receive the drug. Adverse Effects Primary adverse effects noted in dogs are injection site reactions, lethargy, and gastrointestinal effects (inappetance, vomiting). Transient increases in liver enzymes have been reported. In humans, increased serum lipase, amylase, creatinine, urea nitrogen, and increased QT interval on ECG, have been reported. Occasionally, decreases in white blood cell counts and hemoglobin have been reported in humans. Reproductive/Nursing Safety There is limited information available. Pregnant rats given up to 300 mg/kg on days 6-15 caused increased fetal resorptions and in-creased rates of abnormalities of the atlas bone. Weigh the risks ver-sus beneﬁts when deciding to treat during pregnancy. It is unknown if the drug enters maternal milk. Overdosage/Acute Toxicity No speciﬁc overdose information was located. Depending on the dosage, a single overdose could potentially cause renal, hepatic, pancreatic, and hematologic effects, but gastrointestinal effects (vomiting) and lethargy would be the most likely outcomes. It is recommended to observe the patient and contact an animal poison control center for further guidance with an overdose situation. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving meglumine antimoniate and may be of signiﬁcance in veterinary patients (dogs): T ! AGENTS T HAT CAN PROLONG QT INTERV AL (e. g., tricyclic antidepres-sants, disopyramide, quinidine, procainamide, etc. ): meglumine an-timoniate may prolong QT interval further with increased risk for arrhythmias Laboratory Considerations No speciﬁc laboratory interactions or considerations noted Doses T ! DOGS: For leishmaniasis: a) Meglumine antimoniate at a minimum dosage of 100 mg/ kg SC daily for 3-4 weeks; better results are obtained with longer durations (4-6 weeks) of treatment. Protocol with allopurinol may reduce relapse rates: meglumine antimoni-ate as above with allopurinol at 20-40 mg/kg PO daily for a minimum of 3 weeks. Followed with long-term treatment with allopurinol (alone) at 20-40 mg/kg PO daily or inter-mittently (one week treatment per month). (Noli and Auxilia 2005) b) Meglumine antimoniate (100 mg/kg/day SC) until resolu-tion; with allopurinol at 20 mg/kg PO q12h for 9 months. (Brosey 2005) Monitoring T ! Efﬁcacy (PCR preferred) T ! CBC (baseline and periodic) T ! Liver enzymes; renal function tests (serum creatinine, BUN); se-rum lipase and amylase (baseline and periodic) T ! Urinalysis (baseline and periodic) Client Information T ! Clients should understand that treatment with this drug can be prolonged and expensive, and that a “cure” (complete eradica-tion) is unlikely Chemistry/Synonyms Meglumine antimoniate is 1-Deoxy-1-methylamino-D-glucitol antimoniate. It has a molecular weight of 366. One gram contains approximately 272 mg of antimony. Meglumine antimoniate may also be known as: meglumine an-timonate, N-methylglucamine antimoniate, RP-2168, antimony meglumine, Protostib, 1-Deoxy-1-methylamino-D-glucitol anti-moniate, Glucantime® and Glucantim®. Storage/Stability Unless otherwise speciﬁed by the manufacturer, commercially available ampules should be stored below 40°C, preferably between 15°-30°C; protect from freezing.	pppbs.pdf
MELARSOMINE 571 Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None in the USA. HUMAN-LABELED PRODUCTS: None in the USA Meglumine antimoniate may be available in several countries, in-cluding Brazil, France, Italy, Spain and Venezuela; trade names in-clude: Glucantime® and Glucantim®. Commercially it is available as a solution containing 1. 5 grams of meglumine antimoniate (425 mg pentavalent antimony) per 5 m L. The FDA may allow legal importation of this medication for compas-sionate use in animals; for more information, see the Instructions for Legally Importing Drugs for Compassionate Use in the USA found in the appendix. MELARSOMINE (mee-lar-soe-meen) Immiticide® ARSENICAL ANTIPARASITIC Prescriber Highlights TT Organic arsenical for heartworm disease TT Contraindications: Class IV (very severe) heartworm dis-ease; weigh risk vs. potential beneﬁts in pregnant, lactat-ing, or breeding dogs TT Reportedly very toxic to cats; not currently recommended TT Adverse Effects: Many possible, most common are: Injec-tion site reactions coughing/gagging, depression/lethar-gy, anorexia/inappetence, excessive salivation, fever, lung congestion, vomiting, pulmonary thromboembolism TT Special IM injection technique; do not give IV or SC TT Avoid human exposure TT Calculate dosages very carefully Uses/Indications Melarsomine is indicated for the treatment of stabilized class I, II, and III heartworm disease caused by immature (4 month old, stage L5) to mature adult infections of D. immitis in dogs. When com-pared with thiacetarsamide, melarsomine appears to be more efﬁca-cious, less irritating to tissues, and does not cause hepatic necrosis. Melarsomine may also be useful for treating ferrets; it has been suggested to contact the manufacturer before using the drug in this species. Pharmacology/Actions While melarsomine is an arsenical compound, its exact mechanism of action is not known. Both laboratory and ﬁeld studies have dem-onstrated that melarsomine is 90-99% effective in killing adult and L5 larvae of D. immitis in dogs at recommended dosages. Pharmacokinetics Melarsomine is reportedly rapidly absorbed after IM injection in dogs; time to peak plasma concentration is about 11 minutes. The apparent volume of distribution is about 0. 7 L/kg; terminal half-life is approximately 3 hours. Contraindications/Precautions/Warnings Melarsomine is contraindicated in dogs with class IV (very severe) heartworm disease. Class IV is having caval syndrome (heartworms present in venae cavae and right atrium). Melarsomine is report-edly very toxic to cats and its use cannot be recommended for this species at this time. Older dogs (>8 years) may be more susceptible to adverse effects than younger dogs. Do NOT give IV or SC; signiﬁcant toxicity or tissue damage may occur. Administer only deep IM as directed (lumbar epaxial mus-cles (L3-L5). Do not administer at any other site. While all dogs with heartworm disease are at risk for post-treat-ment pulmonary thromboembolism, those with severe pulmonary artery disease are at increased risk for post treatment morbidity and mortality. Dogs should be exercise restricted after treatment. Wash hands after use or wear gloves. Avoid drug contact with an-imal's eyes; if exposed wash with copious amounts of water. Avoid human exposure. If human exposure occurs, contact a physician. Adverse Effects Approximately N of dogs show signs of injection site reactions (pain, swelling, tenderness, reluctance to move) after receiving melarsomine. Most of these signs resolve within weeks, but, rarely, severe injection reactions can occur. Firm nodules at the injection site can persist indeﬁnitely. SC or IV injections must be avoided. The most severe local reactions are usually seen if the drug leaks back from the injection site into subcutaneous tissues. Applying ﬁrm pressure to the injection site after administration may reduce the risk for this problem. Other reactions reported in 5% or more dogs treated include: coughing/gagging (22% incidence; average day of onset after treat-ment = 10); depression/lethargy (15% incidence; average day of onset after treatment = 5); anorexia/inappetence (13% incidence; average day of onset after treatment = 5); fever (7%); lung conges-tion (6%); vomiting (5%). There is signiﬁcant interpatient variance in both the date of onset and duration for the above effects. Dogs may also exhibit excessive salivation after dosing. There are a plethora of other adverse effects in dogs with report-ed incidences less than 3%, including paresis and paralysis. Refer to the package insert for speciﬁcs. Animals not exhibiting adverse effects after the ﬁrst dose or course of therapy may demonstrate them after the second dose or course of therapy. Reproductive/Nursing Safety Safety has not been established for use in pregnant, lactating, or breeding dogs. Risks versus potential beneﬁts of therapy should be weighed before use. Overdosage/Acute Toxicity There is low margin of safety with melarsomine dosages. A 3X dose (7. 5 mg/kg) in healthy dogs have demonstrated respiratory inﬂam-mation and distress, excessive salivation, restlessness, panting, vom-iting, edema, tremors, lethargy, ataxia, cyanosis, stupor, and death. Signs of diarrhea, excessive salivation, restlessness, panting, vomit-ing, and fever have been noted in infected dogs that have received inadvertent overdoses (2X). Treatment with dimercaprol (BAL in Oil) may be considered to treat melarsomine overdoses. Clinical efﬁcacy of melarsomine may be reduced, however.	pppbs.pdf
572 MELATONIN Drug Interactions The manufacturer reports that during clinical ﬁeld trials, melar-somine was given to dogs receiving antiinﬂammatory agents, an-tibiotics, insecticides, heartworm prophylactic medications, and various other drugs commonly used to stabilize and support dogs with heartworm disease and that no adverse drug interactions were noted. T ! ASPIRIN : Has been shown not to reduce adverse effects and may complicate therapy; use is not recommended T ! CNS DEPRESSANT DRUGS : Drugs that have similar adverse effects (e. g., depression caused by CNS depressants, etc. ) may cause ad-ditive adverse effects or increase their incidence when used with melarsomine Doses CAUTION : Because of the low margin of safety; calculate dosages very carefully. Do not confuse mg/lb with mg/kg! T ! DOGS: For treatment of diroﬁlariasis it is suggested to review the guide-lines published by the American Heartworm Society at www. heartworm society. org for more information. Immiticide® (Merial) product support phone number: 888-637-4251 For treatment of heartworm disease: a) After diagnosis, determine the class (stage) of the disease. Note : The manufacturer provides worksheets that assist in the classiﬁcation and treatment regime determination. It is highly recommended to use these treatment records to avoid confusion and document therapy. Class I, & II: 2. 5 mg/kg deep IM as directed (lumbar epaxial muscles (L3-L5) twice 24 hours apart and rest. Use alternat-ing sides with each administration. In 4 months, the regimen may be repeated. Class III: 2. 5 mg/kg deep IM as directed (lumbar epaxial mus-cles (L3-L5). Strict rest and give all necessary systemic treat-ment. One month later, give 2. 5 mg/kg deep IM as directed (lumbar epaxial muscles (L3-L5) twice 24 hours apart. Note : Recommended needle size for dogs 10 kg or less = 23 gauge 1 inch; 10 kg or more body weight = 22 gauge 1. 5 inch. (Package Insert; Immiticide®—Merial) b) The three-injection alternative protocol [2. 5 mg/kg deep IM as directed (lumbar epaxial muscles; L3-L5). Strict rest and give all necessary systemic treatment. One month later, give 2. 5 mg/kg deep IM as directed (lumbar epaxial muscles; L3-L5) twice 24 hours apart] is the treatment of choice of the American Heartworm Society and several university teaching hospitals, regardless of stage of disease, due to the increased safety and efﬁcacy beneﬁts and subsequently fewer dogs that require further treatment with melarsomine. (American Heartworm Society; www. heartwormsociety. org ; accessed 2007) Monitoring/Client Information T ! Clinical efﬁcacy T ! Adverse effects; dogs should be observed for 24 hours after the last injection T ! Because of the seriousness of the disease and the potential for morbidity and mortality associated with the treatment, clients should give informed consent before electing to treat. Chemistry/Synonyms An organic arsenical compound, melarsomine dihydrochloride has a molecular weight of 501 and is freely soluble in water. Melarsomine may also be known as Immiticide®. Its CAS regis-try is 128470-15-5. Storage/Stability/Preparation The unreconstituted powder should be stored upright at room temperature. Once reconstituted, the solution should be kept in the original container and kept refrigerated for up to 24 hours. Do not freeze. Do not mix with any other drug. Reconstitute with 2 m L of the diluent provided (sterile water for injection) with a resultant concentration of 25 mg/m L. Once reconstituted, the solution should be kept in the original container and kept refrigerated for up to 24 hours. Do not freeze. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Melarsomine Dihydrochloride Powder for Injection: 50 mg/vial; Im-miticide® (Merial); (Rx). Approved for use in dogs. HUMAN-LABELED PRODUCTS: None MELATONIN (mel-a-tone-in) Regulin® HORMONE Prescriber Highlights TT Oral & implantable pineal gland hormone TT Potential uses include: Alopecia in dogs, sleep & behav-ior disorders in cats & dogs, adjust seasonally controlled fertility in sheep, goats, & horses, & adjunctive treatment for adrenal disease in ferrets TT Adverse effects appear to be minimal, but little experi-ence TT Potential contraindications include: Pregnancy, sexually immature animals, & liver dysfunction Uses/Indications Melatonin may be useful to treat Alopecia-X in Nordic breeds, ca-nine pattern baldness, or canine recurrent ﬂank alopecia in dogs. It has been used anecdotally for the treatment of sleep cycle disor-ders in cats and geriatric dogs and to treat phobias and separation anxiety in dogs. Melatonin implants are used in the mink and fox pelt industries to promote the development of luxurious hair coats. Implants are also used to improve early breeding and ovulation rates in sheep and goats. Preliminary research is being done for this purpose in horses also. In pigs, one study (Bubenik, Ayles et al. 1998) demonstrated that 5 mg/kg in feed reduced the incidence of gastric ulcers in young pigs. Pharmacology/Actions Melatonin is involved with the neuroendocrine control of photope-riod dependent molting, hair growth and pelage color. Melatonin stimulates winter coat growth and spring shedding occurs when melatonin decreases. The mechanism of how melatonin induces these effects is not well understood. It may have direct effects on the hair follicle or alter the secretion of prolactin and/or melanocyte stimulating hormone.	pppbs.pdf
MELATONIN 573 Melatonin also increases serum prolactin levels, growth hor-mone, and increases response to growth hormone releasing hor-mone. Long-term use may decrease luteinizing hormone. Melatonin is also ostensibly a free radical scavenger. Pharmacokinetics No speciﬁc information was located. Contraindications/Precautions/Warnings Melatonin implants are considered contraindicated in pregnant or sexually immature animals. There are very speciﬁc times for administration depending on latitude, hemisphere, and breed. Animals that are nursing young may not beneﬁt from implant therapy. In humans, melatonin is considered contraindicated in patients with hepatic insufﬁciency as it is cleared hepatically. It is also con-traindicated in patients with a history of cerebrovascular disease, depression or neurological disorders. Use caution in patients with renal impairment. Adverse Effects Melatonin appears to be quite safe in dogs. Side effects in dogs when given orally are rare but the hormone may cause sedation, and af-fect sex hormone secretion and fertility. Subcutaneous implants in dogs have been associated with sterile abscesses. Adverse effects in ferrets have not been reported. Adverse effects reported in humans include altered sleep pat-terns, hypothermia, sedation, tachycardia, confusion, headache, and pruritus. Reproductive/Nursing Safety No information was located; use with caution. Overdosage/Acute Toxicity Little information is available; unlikely to cause signiﬁcant morbid-ity after a single overdose. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving melatonin and may be of signiﬁcance in veterinary patients: !!BENZODIAZEPINES : Melatonin may potentiate effects !!SUCCINYLCHOLINE : Melatonin may potentiate effects Doses !TDOGS: For dermatologic conditions: a) For experimental treatment of Alopecia-X in Nordic breeds, canine pattern baldness, or canine recurrent ﬂank alopecia: Empirical dose of one to four 12 mg implants SC. Retreat-ment may be necessary once or twice a year. If implants are unavailable, oral melatonin at 3-6 mg every 8-12 hours may be tried. Although appears to be safe, recommend hav-ing owners sign a release form noting the “experimental” na-ture of treatment. (Paradis 2000) b) For treatment of canine recurrent ﬂank alopecia or seasonal ﬂank alopecia: 2-3 mg per dog PO once daily for 3-5 days weekly or monthly or this as a daily dose. Doses of up to 10 mg per dog have used. Improvement is usually seen in one month with maximal improvement in 3 months. (Merchant 2000) c) For treatment of Alopecia-X in Nordic breeds, Canine pat-tern baldness, or canine recurrent ﬂank alopecia: 3 mg for dogs under 10 kg and 6 mg for dogs 10 kg or greater PO q8-12 hrs for 6 to 8 weeks. (Campbell 1999) d) For treatment of Alopecia-X: Empirical dose is 3 mg-12 mg (depending on the dog's size) PO 2 to 3 times a day. Perform a trial for at least 4 months before evaluating response; only reported side effect is drowsiness. (T orres 2007a) For sleep disorders (nocturnal activity): a) 3-6 mg (total dose) PO q12-24h (Virga 2002) !TCATS: For sleep disorders (nocturnal activity): a) 3-12 mg (total dose) PO q12-24h (Virga 2002) !TFERRETS: For adjunctive treatment of adrenal disease: a) 0. 5-1 mg per ferret PO once daily 7-9 hours after sunrise has been anecdotally effective in alleviating alopecia, aggres-sive behavior, vulvar swelling and prostatomegaly. Improve-ment more likely in patients with adrenal hyperplasia or ad-enoma; less likely if adenocarcinoma. Has no effect on tumor growth or metastasis. The implant form (5. 4 mg) releases melatonin over a 3-4 month period. Response to melatonin, in general, is better in fall and winter. Can be used with other treatments (e. g., leuprolide, anastrozole, bicalutamide, ﬁnas-teride). (Johnson 2006b) Monitoring !TClinical efﬁcacy Client Information !TFor use in small animals, must be administered as directed to be effective. !TRelatively “experimental”; safety and efﬁcacy are not clearly established. Chemistry/Synonyms A naturally occurring hormone produced in the pineal gland, me-latonin occurs as a pale yellow, crystalline solid and has a molecular weight of 232. It can be derived from natural sources or by synthetic means. Melatonin may also be known as: n-acetyl-5-methoxytryptam-ine, MEL, MLT, pineal hormone, Benedorm®, Buenas Noches®, Cronocaps®, Dermatonin®, Ferretonin®, HT90®, Melapure®, Melatol®, Regulin®, Repentil®, Revenox®, and Transzone®. Storage/Stability Unless otherwise labeled, store at room temperature in tight containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Melatonin 5. 4 mg implant product marketed for ferrets; Ferretonin® (Melatek); 1-877-635-2835; www. melatek. Approval status is not known Melatonin 8 mg, 12 mg, 18 mg implant product marketed for dogs; Dermatonin® (Melatek); Approval status not known An 18 mg implant for sustained subcutaneous release is available in a variety of countries. One trade name is Regulin®. It is labeled for use in sheep (UK and NZ) and goats (NZ) to improve early breeding and ovulation rates. There reportedly are mink implants available in the United States from Neo-Dynamics (800-206-7227).	pppbs.pdf
574 MELOXICAM HUMAN-LABELED PRODUCTS: Melatonin tablets are available in a variety of strengths from a variety of sources. Common strengths available range from 0. 5 mg to 3 mg tablets. Sustained release capsules (3 mg) and oral liquid (500 mcg/ m L) may also be available. Because melatonin is considered a “nutri-ent” there is no ofﬁcial labeling or central quality control systems for it in the USA. Purchase from reputable sources. MELOXICAM (mel-ox-i-kam) Metacam® NONSTEROIDAL A NTIINFLA MMATORY AGENT Prescriber Highlights TT NSAID used in dogs & cats; COX-2 preferential TT Available as both an injectable & oral product TT GI adverse effects can occur Uses/Indications Meloxicam is principally used for the symptomatic treatment of os-teoarthritis in dogs. Short-term (single dose injectable) use is also approved (in the USA) for cats for the control of postoperative pain and inﬂammation associated with orthopedic surgery, ovariohys-terectomy and castration when administered prior to surgery. Pharmacology/Actions Meloxicam has antiinﬂammatory, analgesic, and antipyretic activ-ity similar to other NSAIDs. Like other NSAIDs, meloxicam exhib-its analgesic, antiinﬂammatory, and antipyretic activity probably through its inhibition of cyclooxygenase, phospholipase A 2, and inhibition of prostaglandin synthesis. It is considered COX-2 pref-erential (not COX-2 speciﬁc) as at higher dosages its COX-2 speci-ﬁcity is diminished. Acute dosing studies in dogs have not demonstrated any untow-ard renal or hepatic toxicity. Pharmacokinetics In dogs, meloxicam is well absorbed after oral administration. Food does not alter absorption. Peak blood levels occur in about 7-8 hours after administration. The volume of distribution in dogs is 0. 3 L/kg and about 97% is bound to plasma proteins. Meloxicam is extensively biotransformed to several different metabolites in the liver; none of these appear to have pharmacologic activity. The majority of these (and unchanged drug) are eliminated in the fe-ces. A signiﬁcant amount of enterohepatic recirculation occurs. Elimination half-life is species speciﬁc. The elimination half-life in dogs averages 24 hours (range: 12-36 hours); other species: pigs: 4 hours; horses: 3 hours; cattle: 13 hours. In cats, subcutaneous injection is nearly completely absorbed. Peak levels occur about 1. 5 hours after injection. Meloxicam is rela-tively highly bound to feline plasma proteins (97%) and volume of distribution is about 0. 27 L/kg. After a single dose, total systemic clearance is approximately 130 m L/hr/kg and elimination half life is approximately 15 hours. Contraindications/Precautions/Warnings Meloxicam is contraindicated in dogs hypersensitive to it. Safe use has not been evaluated in dogs less than 6 months old. The European label states that safe use has not been evaluated in dogs less than 6 weeks old. Although not part of the label, it should prob-ably not be used in dogs with active GI ulceration or bleeding. It should be used with caution in patients with impaired hepatic, car-diac or renal function and hemorrhagic disorders. Meloxicam is contraindicated in cats with known hypersen-sitivity to meloxicam or other NSAIDs. The manufacturer warns that additional doses of meloxicam or other NSAIDs are contrain-dicated as no safe dosage for repeated NSAID administration has been established. Use in cats less than 4 months of age has not been established. Use preoperatively for cats undergoing major surgery where hypotensive episodes are possible; may be at higher risk for renal damage. The human label states that no dosage adjustment is necessary in patients with mild to moderate hepatic or renal impairment. Use extreme caution in dehydrated, hypovolemic, or hypoten-sive animals as there is a potential increased risk of renal toxicity developing. Adverse Effects Experience in Europe and Canada has demonstrated a relatively safe adverse effect proﬁle for meloxicam in dogs. GI distress is the most commonly reported adverse effect, and in US ﬁeld trials vomiting, soft stools, diarrhea, and inappetance were the most common ad-verse effects reported. Renal toxicity appears to be quite low. Post-approval adverse effects reported have included GI effects (vomit-ing, anorexia, diarrhea, melena, ulceration), elevated liver enzymes, pruritus, azotemia, elevated creatinine, and renal failure. In cats, single doses of meloxicam appear relatively safe. In ﬁeld trials some cats developed elevated BUN, post-treatment anemia and, rarely, residual pain at the injection site. In other studies, meloxicam has caused GI effects (vomiting, diarrhea, inappetance), behavior changes, and lethargy. Repeated use of meloxicam in cats had been associated with renal failure and death. Reproductive/Nursing Safety Safe use has not been established in dogs or cats used for breeding, or in pregnant or lactating animals. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Most NSAIDs are excreted in milk; use cautiously. Overdosage/Acute Toxicity The manufacturer warns to prevent accidental overdosing in small dogs, and to administer drops on food and not directly into the mouth. Treat symptomatically and supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving meloxicam and may be of signiﬁcance in veterinary patients: T ! ACE INHIBITORS (e. g., enalapril, benazepril ): Some NSAIDs can re-duce effects on blood pressure T ! ANTICOAGULANTS (e. g., heparin, warfarin, etc. ): Increased chance for bleeding T ! ASPIRIN : May increase the risk of gastrointestinal toxicity (e. g., ul-ceration, bleeding, vomiting, diarrhea) T ! CORTICOSTEROIDS (e. g., prednisone ): May increase the risk of gastrointestinal toxicity (e. g., ulceration, bleeding, vomiting, diarrhea) T ! DIGOXIN : NSAIDS may increase serum levels T ! FLUCONAZOLE : Administration has increased plasma levels of cele-coxib in humans and potentially could also affect meloxicam lev-els in dogs	pppbs.pdf
MELPHALAN 575 T ! FUROSEMIDE : NSAIDs may reduce saluretic and diuretic effects T ! METHOTREXATE : Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate; use together with extreme caution T ! NEPHROTOXIC DRUGS (e. g., furosemide, aminoglycosides, amphotericin B, etc. ): May enhance the risk of nephrotoxicity T ! NSAIDS, OTHER : May increase the risk of gastrointestinal toxicity (e. g., ulceration, bleeding, vomiting, diarrhea) Doses When doses are listed in “drops” use with caution, as drug concen-tration per drop may be different in products marketed in various countries. T ! DOGS: For approved indications (osteoarthritis, analgesia, inﬂamma-tory conditions): a) Initially 0. 2 mg/kg PO, IV or SC on the ﬁrst day of treat-ment, subsequent doses of 0. 1 mg/kg PO once daily in food or placed directly into mouth (not when dosing by the drop). (Package Insert; Metacam® Injection/Oral Suspension) T ! CATS: For pain: a) For labeled indications: 0. 3 mg/kg SC once (Label informa-tion; Metacam® Injection for Cats—BI) Note : The following dosages are extra-label in cats: b) 0. 2 mg/kg PO initially, followed by 0. 1 mg/kg PO (in food) once daily for 2 days and then 0. 025 mg/kg 2-3 times a week (Mc Laughlin 2000) c) 0. 1 mg/kg PO once daily (limit to 4 days use); 0. 3 mg/kg IV or SC (one time use only) (Hardie 1997) d) For surgical pain: 0. 2 mg/kg (or less) PO or SC once; 0. 1 mg/ kg (or less) SC, PO daily for 3-4 days For chronic pain: 0. 2 mg/kg (or less) PO, SC once; 0. 1 mg/ kg (or less) PO for 3-4 days; 0. 025 mg/kg PO (0. 1 mg maxi-mum dose per cat) 2-3 times weekly (Mathews 2000) T ! RABBITS, RODENTS: For musculoskeletal and mild visceral pain: a) 0. 2 mg/kg PO or SC once daily. Has a duration of action for 24-48 hours in most species; may be used for prolonged pe-riods of time; also very effective when used in combination with opioids. (Mayer 2007) Monitoring T ! Clinical efﬁcacy T ! Adverse effects T ! Renal function and hepatic function if used chronically Client Information T ! Shake oral liquid well before using. T ! Carefully measure dose (oral liquid); do not confuse the mark-ings on the syringe (provided by the manufacturer) with m L or kgs. If using drops to measure dose in small dogs, do not place drops directly into dog's mouth; mix with food. Otherwise, may place oral syringe into dogs mouth or mix with food. T ! If animal develops adverse effects, contact the veterinarian T ! If dispensed for outpatient use, obtain client information sheet for this medication Chemistry/Synonyms A COX-2 receptor preferential NSAID, meloxicam occurs as a pale yellow powder. It is in the oxicam class, related to piroxicam. Meloxicam may also be known as: UH-AC-62, and UH-AC-62XX; many trade names are available. Storage/Stability Unless otherwise labeled, store the injection and oral liquid at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Meloxicam Oral Suspension: 1. 5 mg/m L (0. 05 mg per drop in the USA product) in a honey-ﬂavored base: 10 m L, 32 m L, 100 m L drop-per bottles with measuring syringe (marked in 5 lb body weight in-crements); Metacam® (Boehringer Ingelheim Vetmedica); (Rx). Ap-proved for use in dogs. Meloxicam 5 mg/m L for Injection: 10 m L vial; Metacam® Injection for Dogs (Boehringer Ingelheim Vetmedica); (Rx). Approved for use in dogs. Meloxicam 5 mg/m L for Injection: 10 m L vial; Metacam® Injection for Cats (Boehringer Ingelheim Vetmedica); (Rx). Approved for use in cats. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Meloxicam Tablets: 7. 5 mg & 15 mg; Mobic® (Boehringer Ingelheim/ Abbott); generic; (Rx) Meloxicam Oral Solution: 7. 5 mg/5 m L in 100 m L; Mobic® (Boeh-ringer Ingelheim/Abbott); Meloxicam (Roxane); (Rx) In Canada, Mobicox® (Boehringer Ingelheim); (Rx) MELPHALAN (mel-fa-lan) Alkeran® ANTINEOPLASTIC Prescriber Highlights TT Alkylating agent antineoplastic used for ovarian carci-noma, lymphoreticular neoplasms, osteosarcoma, mam-mary or pulmonary neoplasms, & multiple myeloma TT Contraindications (relative; risk vs. beneﬁt): Anemia, bone marrow depression, current infection, impaired re-nal function, tumor cell inﬁltration of bone marrow, sen-sitivity to drug, or patients who have received previous chemotherapy or radiotherapy TT Adverse Effects: GI effects (anorexia, vomiting, diarrhea), pulmonary inﬁltrates or ﬁbrosis, bone marrow depression (anemia, thrombocytopenia, leukopenia) TT Potential teratogen TT Determine dosages carefully	pppbs.pdf
576 MELPHALAN Uses/Indications Melphalan may be useful in the treatment of a variety of neoplastic diseases, including ovarian carcinoma, lymphoreticular neoplasms, osteosarcoma, and mammary or pulmonary neoplasms. When combined with prednisone, it is considered the drug of choice for treating multiple myeloma. It has been used successfully in a rescue protocol combining dexamethasone, melphalan, dactinomycin and cytarabine to treat relapsed multicentric lymphoma in dogs. Pharmacology/Actions Melphalan is a bifunctional alkylating agent and interferes with RNA transcription and DNA replication, thereby disrupting nu-cleic acid function. Because it is bifunctional, it has affect on both dividing and resting cells. Melphalan does not require activation by the liver (unlike cyclophosphamide). Pharmacokinetics Melphalan absorption is variable and often incomplete. It is dis-tributed throughout the body water, but it is unknown whether it crosses the placenta, blood brain barrier or enters maternal milk. Melphalan is eliminated principally by hydrolysis in plasma. In hu-mans, terminal half-lives average about 90 minutes. Contraindications/Precautions/Warnings Melphalan should be used with the following conditions only when its potential beneﬁts outweigh its risks: anemia, bone marrow depression, current infection, impaired renal function, tumor cell inﬁltration of bone marrow, sensitivity to melphalan or patients who have received previous chemotherapy or radiotherapy. Adverse Effects Potential adverse effects include GI effects (anorexia, vomiting, diarrhea), and pulmonary inﬁltrates or ﬁbrosis. The most serious adverse effect likely with melphalan is bone marrow depression (anemia, thrombocytopenia, leukopenia). Reproductive/Nursing Safety Safe use of melphalan during pregnancy has not been established; other alkylating agents are known teratogens. Use only during preg-nancy when the beneﬁts to the mother outweigh the risks to the offspring. Melphalan can suppress gonadal function. While it is unknown whether melphalan enters maternal milk, nursing puppies or kittens should receive milk replacer when the bitch or queen is receiving melphalan. Overdosage/Acute Toxicity Because of the toxic potential of this agent, overdoses must be avoided. Determine dosages carefully. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving melphalan and may be of signiﬁcance in veterinary patients: !TCYCLOSPORINE : There are anecdotal reports of melphalan causing increased nephrotoxicity associated with systemic cyclosporine use in humans. !TIMMUNOSUPPRESSANT DRUGS (e. g., azathioprine, cyclophosphamide, corticosteroids ): Use with other immunosuppressant drugs may increase the risk of infection. !TMYELOSUPPRESSIVE DRUGS (e. g., chloramphenicol, ﬂucytosine, ampho-tericin B, or colchicine ): Use extreme caution when used concur-rently with other drugs that are also myelosuppressive, including many of the other antineoplastics and other bone marrow de-pressant drugs. Bone marrow depression may be additive. !TVACCINES, LIVE : Live virus vaccines should be used with caution, if at all, during therapy. Laboratory Considerations !TMelphalan may raise serum uric acid levels. Drugs such as allo-purinol may be required to control hyperuricemia. Doses For more information on using melphalan as part of chemotherapy protocols, refer to the protocols found in the appendix or other dos-ages/protocols found in numerous references, including: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). !TDOGS: As part of a rescue protocol (DMAC) to treat relapsed multi-centric lymphoma: a) Dactinomycin (0. 75 mg/m2 IV), Cytarabine (300 mg/m2 IV over 4 hours or SC) and dexamethasone (1 mg/kg PO) on day 0 and melphalan (20 mg/m2 PO) and dexamethasone (1 mg/kg PO) on day 7. The cycle is repeated continuously every 2 weeks as long as a complete or partial remission is achieved. After four cycles, chlorambucil was substituted for melphalan at the same dose. If complete remission achieved, protocol was discontinued after 5-8 cycles and maintenance therapy with the LMP (chlorambucil, methotrexate, pred-nisone) or lomustine/prednisone protocols were instituted. If dogs developed grades 3 or 4 toxicosis, DMAC was dis-continued and maintenance protocol was started. (Alvarez, Kisseberth et al. 2006), (Rassnick 2006) For adjunctive treatment of ovarian carcinoma, multiply myelo-ma, lymphoreticular neoplasms, osteosarcoma, and mammary or pulmonary neoplasms: a) 2-4 mg/m2 PO every 48 hours (every other day). 1. 5 mg/ m2 PO every 24 hours (once daily) for 7-10 days (Jacobs, Lumsden et al. 1992) For multiple myeloma (usually in combination with predni-sone): a) 2 mg/m2 once daily for 7-10 days, then 2-4 mg/m2 PO every other day. Alternatively give 6-8 mg/m2 PO for 4-5 days, repeated every 21 days. Used in combination with pred-nisone. (Kitchell and Dhaliwal 2000) b) 0. 05-0. 1 mg/kg PO once daily until remission, then every other day (Lana 2002) For anal sac or apocrine gland adenocarcinomas: a) 2 mg/m2 PO once daily for one week, then every other day (Peterson and Couto 1994) !TCATS: For adjunctive treatment of FIP: a) Predniso(lo)ne 4 mg/kg PO once daily with melphalan 2 mg/ m2 (or about G of a 2 mg tablet) once every 48 hours (Weiss 1994) For chronic lymphocytic leukemia: a) 2 mg/m2 PO every other day with or without prednisone at 20 mg/m2 PO every other day (Peterson and Couto 1994) Monitoring !TCBC with platelets at least every 1-2 weeks until stable	pppbs.pdf
MEPERIDINE HCL 577 Client Information T ! Clients must understand the importance of both administering melphalan as directed and immediately reporting any signs asso-ciated with toxicity (e. g., abnormal bleeding, bruising, urination, depression, infection, shortness of breath, etc. ). Chemistry/Synonyms A nitrogen mustard derivative, melphalan occurs as an off-white to buff-colored powder that is practically insoluble in water. Melphalan may also be known as: CB-3025, NSC-8806, PAM, L-PAM, L-phenylalanine mustard, phenylalanine mustard, pheny-lalanine nitrogen mustard, L-sarcolysine, WR-19813, Alkeran® or Alkerana®. Storage/Stability/Compatibility Store melphalan tablets in well-closed, light-resistant, glass con-tainers in the refrigerator (2-8°C). It is recommended to dispense the tablets in glass containers. Once reconstituted, the injectable product should not be refrig-erated or a precipitate may form. It is stable at room temperature for 90 minutes after reconstitution. For administration, the recon-stituted solution should be further diluted with sterile 0. 9% sodium chloride to a concentration of not more than 0. 45 mg/m L. This di-luted solution is stable for 60 minutes at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Melphalan Tablets: 2 mg; Alkeran® (Celgene); (Rx) Melphalan Powder for Injection (lyophilized): 50 mg in single use vi-als with 10 m L vial of sterile diluent; Alkeran® (Celegene); (Rx) MEPERIDINE HCL (me-per-i-deen) Demerol®, Pethidine OPIATE AGONIST Prescriber Highlights TT Opiate analgesic; infrequently used as it has a short du-ration of analgesia & may cause more adverse effects than other commonly used injectable opiates TT Contraindications: Hypersensitivity to it, diarrhea caused by a toxic ingestion TT Extreme Caution: Respiratory disease or acute respira-tory dysfunction TT Caution: Hypothyroidism, severe renal insufﬁciency, adre-nocortical insufﬁciency, geriatric or severely debilitated patients, head injuries or increased intracranial pressure, & acute abdominal conditions (e. g., colic) TT Adverse Effects: Respiratory depression, histamine re-lease, bronchoconstriction, CNS depression, GI (nausea, vomiting, & decreased intestinal peristalsis), mydriasis (dogs), salivation (esp. cats); physical dependence (chron-ic use). HORSES (in addition): Tachycardia with PVC's, profuse sweating, & hyperpnea TT Give very slowly if using IV (many state not to use IV), may be irritating if given SC TT C-II controlled substance Uses/Indications Although no product is licensed in the United States for veterinary use, this agent has been used as an analgesic in several different spe-cies. It has been used as sedative/analgesic in small animals for both post-operative pain and for medical conditions such as acute pan-creatitis and thermal burns, but usually other opiates are preferred as the drug has a short analgesic duration of activity and can cause signiﬁcant histamine release. It is occasionally used in equine medi-cine in the treatment of colic and in other large animal species for pain control. Pharmacology/Actions Receptors for opiate analgesics are found in high concentrations in the limbic system, spinal cord, thalamus, hypothalamus, striatum, and midbrain. They are also found in tissues such as the gastroin-testinal tract, urinary tract, and in other smooth muscle. The morphine-like agonists (morphine, meperidine, oxymor-phone) have primary activity at the mu receptors, with some ac-tivity possible at the delta receptor. The primary pharmacologic effects of these agents include: analgesia, antitussive activity, re-spiratory depression, sedation, emesis, physical dependence, and intestinal effects (constipation/defecation). Secondary pharma-cologic effects include: CNS: euphoria, sedation, and confusion. Cardiovascular: bradycardia due to central vagal stimulation, al-pha-adrenergic receptors may be depressed resulting in peripheral vasodilation, decreased peripheral resistance, and baroreceptor in-hibition. Orthostatic hypotension and syncope may occur. Urinary: Increased bladder sphincter tone can induce urinary retention. Meperidine is primarily a Mu agonist. It is approximately Jth as potent as morphine, but produces equivalent respiratory de-pression at equi-analgesic doses as morphine. Like morphine, it can cause histamine release. It does not have antitussive activity at doses lower than those causing analgesia. Meperidine is the only used opioid that has vagolytic and negative inotropic properties at clinically used doses. One study in ponies demonstrated changes in jejunal activity after meperidine administration, but no effects on transit time or colonic electrical activity were noted. Refer to the monograph: Narcotic (opiate) Analgesic Agonists, Pharmacology of, for more information. Pharmacokinetics Although generally well absorbed orally, a marked ﬁrst-pass effect limits the oral effectiveness of meperidine. After injection by IM or subcutaneous routes the peak analgesic effects occur between 30-60 minutes, with the IM route having a slightly faster onset. Duration of action is variable with effects generally lasting from 1-6 hours in most species. In dogs and cats, analgesic duration of only 1-2 hours is generally seen at clinically used doses. The drug is metabolized primarily in the liver (mostly hydrolysis with some conjugation) and approximately 5% is excreted unchanged in the urine. Contraindications/Precautions/Warnings Meperidine is contraindicated in cases where the patient is hypersensitive to narcotic analgesics, or in patients receiving monamine oxidase inhibitors (MAOIs). It is also contraindicated in patients with diarrhea caused by a toxic ingestion until the toxin is eliminated from the GI tract. All opiates should be used with cau-tion in patients with hypothyroidism, severe renal insufﬁciency, adrenocortical insufﬁciency (Addison's disease), and in geriatric or severely debilitated patients. Many clinicians state that meperidine should not be adminis-tered intravenously. If given IV, it must be given very slowly or se-vere hypotension can result.	pppbs.pdf
578 MEPERIDINE HCL Meperidine should be used with caution in patients with head injuries or increased intracranial pressure and acute abdominal conditions (e. g., colic) as it may obscure the diagnosis or clinical course of these conditions. It should be used with extreme caution in patients suffering from respiratory disease or from acute respi-ratory dysfunction (e. g., pulmonary edema secondary to smoke inhalation). Opiate analgesics are also contraindicated in patients who have been stung by the scorpion species Centruroides sculpturatus Ewing and C. gertschi Stahnke as they may potentiate these venoms. Adverse Effects Meperidine may be irritating when administered subcutaneously and must be given very slowly IV or it may cause severe hypoten-sion. It can cause pronounced histamine release, particularly with IV administration. At usual doses, the primary concern is the ef-fect the opioids have on respiratory function. Decreased tidal vol-ume, depressed cough reﬂex, and the drying of respiratory secre-tions may all have a detrimental effect on a susceptible patient. Bronchoconstriction following IV doses has been noted in dogs. Gastrointestinal effects may include: nausea, vomiting, and de-creased intestinal peristalsis. In dogs, meperidine causes mydriasis (unlike morphine). If given orally, the drug may be irritating to the buccal mucosa and cause salivation; this is of particular concern in cats. Chronic administration can lead to physical dependence. In horses undergoing general anesthesia, meperidine has been associated with a reaction that manifests as tachycardia with PVC's, profuse sweating, and hyperpnea. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as class: B (Safe for use if used cautiously. Studies in laboratory animals may have un-covered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term. ) Most opiates are excreted into milk. Meperidine enters human breast milk at concentrations slightly higher than those found in serum, but effects on nursing offspring may not be signiﬁcant. Overdosage/Acute Toxicity In most species, overdosage may produce profound respiratory and/or CNS depression. Other effects can include cardiovascular collapse, hypothermia, and skeletal muscle hypotonia. Some species (especially cats) may demonstrate CNS excitability (hyperreﬂexia, tremors) and seizures at doses greater than 20 mg/kg. Naloxone is the agent of choice in treating respiratory depression. In massive overdoses, naloxone doses may need to be repeated, and animals should be closely observed as naloxone's effects can diminish before subtoxic levels of meperidine are attained. Mechanical respiratory support should also be considered in cases of severe respiratory depression. Pentobarbital has been suggested as a treatment for CNS excite-ment and seizures in cats. Caution must be used as barbiturates and narcotics can have additive effects on respiratory depression. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving meperidine and may be of signiﬁcance in veterinary patients: !TCNS DEPRESSANTS, OTHER (e. g., anesthetic agents, antihistamines, phenothiazines, barbiturates, tranquilizers, alcohol, etc. ): May cause increased CNS or respiratory depression when used with meperidine !TDIURETICS : Opiates may decrease efﬁcacy in CHF patients !TISONIAZID : Meperidine may enhance INH adverse effects !TMONAMINE OXIDASE (MAO) INHIBITORS (e. g., amitraz, possibly sele-giline ): Meperidine is contraindicated in patients receiving monamine oxidase (MAO) inhibitors for at least 14 days after receiving MAO inhibitors in humans. Some human patients have exhibited signs of opiate overdose after receiving therapeutic doses of meperidine while taking MAOIs. !TMUSCLE RELAXANTS, SKELETAL : Meperidine may enhance neuro-muscular blockade !TTRICYCLIC ANTIDEPRESSANTS (clomipramine, amitriptyline, etc. ): Me-peridine may exacerbate the effects of tricyclic antidepressants !TWARFARIN : Opiates may potentiate anticoagulant activity Laboratory Considerations !TAs they may increase biliary tract pressure, opiates can increase plasma amylase and lipase values up to 24 hours following their administration. Doses !TDOGS: Analgesic duration in dogs usually lasts 45 minutes to 1 hour. Drug may also be given IV, but SLOWLY. a) Analgesic for acute pancreatitis: 5-10 mg/kg IM (Morgan 1988) b) 5-10 mg/kg IM, SC. Duration of effect is short (30-60 min-utes) (Mama 2002b) c) For perioperative pain: 3-5 mg/kg IM or SC. Duration of action 1-2 hours (Pascoe 2000) d) Preanesthetic: 2. 5-6. 5 mg/kg (Booth 1988a) !TCATS: For perioperative pain: a) 3-5 mg/kg IM or SC. Duration of action 1-2 hours (Pascoe 2000) b) 2-5 mg/kg IM, SC. Duration of effect is short (30 minutes to an hour) (Mama 2002b) As a preanesthetic: a) 2. 2-4. 4 mg/kg (Booth 1988a) Not recommended for cats. (Scherk 2003a) !TFERRETS: a) 5-10 mg/kg SC or IM every 2-3 hours (Williams 2000) !TRABBITS, RODENTS, SMALL MAMMALS: a) Rabbits: For moderate pain: 5-10 mg/kg SC, IM q2-3h. Us-ing Banana ﬂavored oral syrup: 0. 2 mg/m L in drinking water (Ivey and Morrisey 2000) a) Analgesic (patient administered moderate pain relief): 0. 2 mg/m L in drinking water (Huerkamp 1995) !TCATTLE: As an analgesic: a) 3. 3-4. 4 mg/kg SC or IM (Jenkins 1987) b) 500 mg IM (Booth 1988a) c) 150-200 mg/100 lbs IM or SC (or slow IV) (Mc Connell and Hughey 1987) !THORSES: Note : Narcotics (meperidine included) may cause CNS excite-ment in the horse. Some recommend pretreatment with acepro-	pppbs.pdf
MERCAPTOPURINE 579 mazine (0. 02-0. 04 mg/kg IV), or xylazine (0. 3-0. 5 mg/kg IV) to reduce the behavioral changes caused by these drugs. WARN-ING: Narcotic analgesics can mask the behavioral and cardiovas-cular signs associated with mild colic. As an analgesic: a) 2. 2-4 mg/kg IM or 0. 2-0. 4 mg/kg IV (may cause excite-ment) (Robinson 1987) b) 2-4 mg/kg IM or IV (may cause excitement and hypoten-sion with IV use) (Jenkins 1987) c) 500 mg (total dose) IV (slowly, CNS excitement may occur) or 1000 mg (total dose) IM (Booth 1988a) d) 0. 2-0. 4 mg/kg IV (Muir 1987) T ! SWINE: As a restraining agent: a) Given alone the drug does not give much restraint in large animals. Has been used in combination with promazine (2 mg/kg IM) and atropine (0. 07-0. 09 mg/kg IM) at a dose of 1-2 mg/kg IM as a preanesthetic 45-60 minutes before bar-biturate/inhalant anesthesia. All the above should be given in separate sites (Booth 1988a) As an analgesic: a) 2 mg/kg IM q4h IM as needed (Jenkins 1987) T ! SHEEP & GOATS: As an analgesic: a) Up to 200 mg total dose IM (Jenkins 1987) Monitoring T ! Respiratory rate/depth T ! CNS level of depression/excitation T ! Blood pressure (especially with IV use) T ! Analgesic activity Client Information T ! Oral dosage forms may cause mouth irritation. T ! When given parenterally, this agent should be used in an inpa-tient setting or with direct professional supervision. Chemistry/Synonyms A synthetic opiate analgesic, meperidine HCl is a ﬁne, white, crys-talline, odorless powder that is very soluble in water, sparingly sol-uble in ether and soluble in alcohol. It has a p K a of 7. 7-8. 15 and a melting range of 186-189°C. The p H of the commercially available injectable preparation is between 3. 5 and 6. Meperidine HCl may also be known as: pethidine HCl, isonipecaine, meperidine hydrochloride, pethidini hydrochlo-ridum; Alodan®, Centralgine®, Demerol ®, Dolantin®, Dolantina®, Dolantine®, Dolestine®, or Dolosal®. Storage/Stability/Compatibility Meperidine is stable at room temperature. Avoid freezing the in-jectable solution and protect from light during storage. Meperidine has not exhibited signiﬁcant adsorption to PVC IV bags or tubing in studies to date. Meperidine is reported to be physically compatible with the fol-lowing ﬂuids and drugs: sodium chloride 0. 45 and 0. 9%, Ringer's injection, lactated Ringer's injection, dextrose 2. 5, 5 and 10% for injection, dextrose/saline combinations, dextrose/Ringers lactated solutions, atropine, benzquinamide, butorphanol, chlorpromazine, dimenhydrinate, diphenhydramine HCl, dobutamine, droperidol, fentanyl citrate, glycopyrrolate, metoclopramide, pentazocine lac-tate, promazine HCl, succinylcholine, and verapamil HCl. Meperidine is reported to be physically incompatible when mixed with the following agents: aminophylline, amobarbital sodium, heparin sodium, hydrocortisone sodium succinate, methicillin, methylprednisolone sodium succinate, morphine sulfate, nitro-furantoin sodium, oxytetracycline HCl, pentobarbital sodium, phe-nobarbital sodium, phenytoin sodium, sodium iodide, tetracycline HCl, thiopental sodium, and thiamylal sodium. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Meperidine HCl Injection: 25 mg/m L in 1 m L vials, amps & 1m L Carpuject syringes; 50 mg/m L in 1 m L vials, 0. 5 m L, 1 m L, 1. 5 m L and 2 m L amps, 30 m L multi-dose vials and 1 m L Carpuject syringes; 75 mg/m L in 1 m L vials & 1 m L Carpuject syringes; 100 mg/m L in 1m L amps, 20 m L multidose vials and 1 m L Carpuject syringes; Demerol® (Abbott); generic, (Rx, C-II) Meperidine HCl Tablets: 50 mg & 100 mg tablets; generic; (Rx, C-II) Meperidine HCl Syrup/Oral Solution: 50 mg/5 m L in 473 m L & 500 m L, Demerol® (Sanoﬁ-Synthelabo); generic (Roxane); (Rx, C-II) Note : Meperidine is listed as a Class-II controlled substance and all products require a prescription. Very accurate record keeping is re-quired as to use and disposition of stock. MERCAPTOPURINE (mer-kap-toe-pyoor-een) Purinethol® ANTINEOPLASTIC; IMMUNOSUPPRESSANT Prescriber Highlights TT Oral antineoplastic/immunosuppressant used for adjunc-tive treatment of lymphosarcoma, acute leukemias, & severe rheumatoid arthritis or other autoimmune condi-tions (e. g., unresponsive ulcerative colitis) TT Contraindications: Hypersensitivity to it TT Caution (risk versus beneﬁt): In patients with hepatic dysfunction, bone marrow depression, infection, renal function impairment (adjust dosage), or with a history of urate urinary stones TT Adverse Effects: GI effects (nausea, anorexia, vomiting, diarrhea) most likely; bone marrow suppression, hepa-totoxicity, pancreatitis, GI (including oral) ulceration &, potentially, dermatologic reactions. TT Teratogenic; use milk replacer in nursing animals TT Drug interactions Uses/Indications Veterinary uses of mercaptopurine include adjunctive therapy of lymphosarcoma, acute leukemias, and severe rheumatoid arthritis. It may have potential beneﬁt in treating other autoimmune condi-tions (e. g., unresponsive ulcerative colitis) as well. Pharmacology/Actions Intracellularly, mercaptopurine is converted into a ribonucleotide that acts as a purine antagonist, thereby inhibiting RNA and DNA synthesis. Mercaptopurine acts as an immunosuppressant, primar-ily inhibiting humoral immunity.	pppbs.pdf
580 MERCAPTOPURINE Pharmacokinetics Absorption after oral dosing is variable and incomplete. Absorbed drug and its metabolites are distributed throughout the total body water. The drug crosses the blood-brain barrier, but not in levels signiﬁcant enough to treat CNS neoplasms. It is unknown whether mercaptopurine enters milk. Via the enzyme, xanthine oxidase, mercaptopurine is rapidly metabolized in the liver to 6-thiouric acid, which along with the parent compound and other metabolites are principally excreted in the urine. Contraindications/Precautions/Warnings Mercaptopurine is contraindicated in patients hypersensitive to it. The drug should be used cautiously (risk versus beneﬁt) in patients with hepatic dysfunction, bone marrow depression, infection, renal function impairment (adjust dosage), or a history of urate urinary stones. Adverse Effects At usual doses, GI effects (nausea, anorexia, vomiting, diarrhea) are most likely seen in small animals. However, bone marrow suppres-sion, hepatotoxicity, pancreatitis, GI (including oral) ulceration, and dermatologic reactions are, potentially, possible. Reproductive/Nursing Safety Mercaptopurine is mutagenic and teratogenic and is not recom-mended for use during pregnancy. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential beneﬁts from the use of the drug in pregnant women may be acceptable despite its potential risks. ) It is not known whether mercaptopurine is excreted in milk, but use of milk replacer is recommended for nursing bitches or queens. Overdosage/Acute Toxicity T oxicity may present acutely (GI effects) or be delayed (bone mar-row depression, hepatotoxicity, gastroenteritis). It is suggested to use standard protocols to empty the GI tract if ingestion was recent and to treat supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving mercaptopurine and may be of signiﬁcance in veterinary patients: !TALLOPURINOL : The hepatic metabolism of mercaptopurine may be decreased by concomitant administration of allopurinol. In hu-mans, it is recommended to reduce the mercaptopurine dose to G-N usual if both drugs are to be used together. !TAMINOSALICYLATES (mesalamine, sulfasalazine ): May increase risk for mercaptopurine toxicity !THEPATOTOXIC DRUGS (e. g., halothane, ketoconazole, valproic acid, phenobarbital, primidone, etc. ): Mercaptopurine should be used cautiously with other drugs that can cause hepatotoxicity. In hu-mans, one study demonstrated increased hepatotoxicity when mercaptopurine was used in conjunction with doxorubicin. !TIMMUNOSUPPRESSIVE DRUGS (e. g., azathioprine, cyclophosphamide, corticosteroids ): Use with other immunosuppressant drugs may increase the risk of infection. !TMYELOSUPPRESSIVE DRUGS (e. g., antineoplastics, chloramphenicol, ﬂucytosine, amphotericin B, colchicine, etc. ): Use extreme caution when used concurrently with other drugs that are also myelosup-pressive, including many of the other antineoplastics and other bone marrow depressant drugs; bone marrow depression may be additive. In humans, enhanced bone marrow depression has oc-curred when used concomitantly with trimethoprim/sulfa. !TVACCINES, LIVE : Live virus vaccines should be used with caution, if at all, during therapy !TWARFARIN : Mercaptopurine may reduce anticoagulant effect Laboratory Considerations !TMercaptopurine may give falsely elevated serum glucose and uric acid values when using a SMA (sequential multiple analyzer) 12/60. Doses !TDOGS: a) As an immunosuppressant in combination with corticoster-oids for treating bullous pemphigoid: 2. 2 mg/kg once daily (q24h), then q48h. (Swartout 2004) b) For erosive, immune-mediated polyarthritis in combina-tion with corticosteroids: 2 mg/kg PO once daily (q24h) for 14-21 days, then q48h (every other day). (Beale and Worley 2004) c) For treatment of immune-mediated diseases or acute lym-phocytic and granulocytic leukemias: 50 mg/m2 PO once daily (q24h) to effect, then every other day (q48h) or as needed. (Jacobs, Lumsden et al. 1992) Monitoring !THemograms (including platelets) should be monitored closely; initially every 1-2 weeks and every 1-2 months once on main-tenance therapy. It is recommended by some clinicians that if the WBC count drops to between 5,000-7,000 cells/mm3 the dose be reduced by 25%. If WBC count drops below 5,000 cells/mm3 treatment should be discontinued until leukopenia resolves !TLiver function tests; serum amylase, if indicated !TEfﬁcacy Client Information !TClients must be briefed on the possibilities of severe toxicity de-veloping from this drug, including drug-related neoplasms or mortality. !TClients should contact veterinarian should the animal exhibit signs of abnormal bleeding, bruising, anorexia, vomiting, or in-fection. !TAlthough, no special precautions are necessary with handling in-tact tablets, it is recommended to wash hands after administering the drug. Chemistry/Synonyms A purine analog, mercaptopurine occurs as a slightly yellow, crys-talline powder. It is insoluble in water and has a p Ka of 7. 6. Mercaptopurine may also be known as: 6-mercaptopurine,6-MP, 6MP, mercaptopurinum, NSC-755, purinethiol,WR-2785, Flocoﬁl®, Ismipur®, Mercap®, Mercaptina®, Puri-Nethol®, Purinethol®, and Varimer®. Storage/Stability Mercaptopurine tablets should be stored at room temperature in well-closed containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Mercaptopurine Tablets: 50 mg; Purinethol® (Gate Pharmaceuticals); generic (Par); (Rx)	pppbs.pdf
MEROPENEM 581 TMEROPENEM (mare-oh-pen-ehm) Merrem I. V. ® CARBAPENEM ANTIBIOTIC Prescriber Highlights TT Carbapenem antibiotic similar to imipenem, but does not cause seizures & may be more effective against some resistant gram-negative infections TT Use should be reserved for documented resistant infec-tions &/or when aminoglycosides not indicated (renal dysfunction, CNS infections) TT Seems well-tolerated in animal patients TT Must be given IV or SC TT Expense an issue Uses/Indications Meropenem may be useful in treating resistant gram-negative bacterial infections, particularly when aminoglycoside use would be risky (i. e., renal failure) or not effective (i. e., resistance or CNS infections). While meropenem has a very broad spectrum, less ex-pensive or easier to administer antibiotics are usually effective for other infections. Pharmacology/Actions Meropenem has a broad antibacterial spectrum similar to that of im-ipenem, but meropenem is more active against Enterobacteriaceae and less so against gram-positive bacteria. Oxacillin-resistant Staphylococcus are usually resistant to meropenem. Because mero-penem is more stable to renal dehydropeptidase-I than is imipen-em, it does not require the addition of cilastatin to inhibit that en-zyme. Meropenem may also have less potential to induce seizures than imipenem. Pharmacokinetics Meropenem must be administered via parenteral means. After SC injection in dogs, bioavailability is 84%. After IV injection in dogs, meropenem's volume of distribution is approximately 0. 37 L/kg and protein binding about 12%; half-life ≈ 40 minutes, and clear-ance ≈ 6. 5 m L/min/kg. Concentrations of unbound drug in tissue ﬂuid and plasma are similar. In ewes, after IM injection meropenem was rapidly absorbed and had a bioavailability equal to that of intravenous dosing. Volume of distribution at steady state was 0. 06 L/kg and protein binding about 43%; elimination half-life was about 43 minutes. 91% of the drug was recovered in the urine over 24 hours after IM injection. Pharmacokinetic data for humans include: wide distribution in body tissues and ﬂuids, including into the CSF and bile; very low protein binding ≈ 2%; in patients with normal renal function, elimination half-life is about an hour. One inactive metabolite has been identiﬁed, but the majority of the drug is eliminated via re-nal mechanisms (tubular secretions and glomerular ﬁltration) and 70% of a dose is recovered unchanged in the urine over 12 hours. Contraindications/Precautions/Warnings Meropenem is contraindicated in patients hypersensitive to it or other carbapenems, and those that have developed anaphylaxis af-ter receiving any beta-lactam antibiotic. Adverse Effects Meropenem is usually very well tolerated. Animals given the drug SC may show slight hair loss over injection sites. In human patients receiving meropenem, only GI effects (nausea, vomiting, diarrhea) have been reported to occur in greater than 1% of patients treated. Reproductive/Nursing Safety In humans, meropenem 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. ) Meropenem is likely safe to use during lactation. Overdosage/Acute Toxicity Overdoses of meropenem are unlikely to occur in patients with nor-mal renal function. In human trials, doses of 2 grams every 8 hours failed to demonstrate any signiﬁcant adversity. Should an overdose occur, the drug can be discontinued if necessary or the next dose could be delayed by a few hours. Meropenem can be removed via hemodialysis when necessary. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving meropenem and may be of signiﬁcance in veterinary patients: T ! AMINOGLYCOSIDES : In vitro evidence of synergy against Pseudomo-nas aeruginosa T ! PROBENECID : May increase serum concentrations and elimination half-life of meropenem Laboratory Considerations No speciﬁc laboratory interactions were noted for meropenem. Doses T ! DOGS & CAT S: For treatment of susceptible infections: a) For bacteremia/sepsis: 24 mg/kg IV q24h (once daily) or 12 mg/kg SC q8h; For UTI: 12 mg/kg SC q12h; For CNS infections: 40 mg/kg IV or SC q8h. This dose is ex-trapolated from children and maximum dose per adminis-tration is 2 grams. T o help prevent development of resistant strains that might infect humans, use should be limited or avoided unless ultimately necessary. (Greene, Hartmannn et al. 2006) b) For systemic infections: 12 mg/kg q8h SC or 24 mg/kg IV q24h (once daily); for urinary tract infections 12 mg/kg q12h SC (Papich 2002a) c) 125 mg (total dose) for small dogs and cats q8h IV or SC; 250 mg q8h IV or SC for medium dogs; 500 mg q8h IV or SC for large (>100 lbs. ) dogs. Note : If serum creatinine greater than 4, may be given q12h. (Aucoin 2002b) Plumb's Note: The recommended dose for treating meningitis with meropenem in humans is 40 mg/kg IV q8h. Until more information becomes available for veterinary patients, consider using a similar dose if treating dogs or cats (with normal renal function) for CNS bacterial infections. Monitoring T ! here are no speciﬁc monitoring requirements for meropenem except to monitor for clinical efﬁcacy.	pppbs.pdf
582 METFORMIN HCL TClient Information T ! his drug is generally used on an inpatient basis usually because of the seriousness of the infections treated, but clients could give SC injections at home, particularly when treating urinary tract infections. Chemistry/Synonyms A synthetic carbapenem antibiotic, meropenem occurs as a clear to white to pale yellow powder or crystals. It is very slightly soluble in water or hydrated alcohol and practically insoluble in acetone or ether. When the commercially available injection is reconstituted the resulting p H is between 7. 3 and 8. 3. Meropenem may also be known as: ICI-194660, SM-7338, Meronem®, Meropen®, Merrem®, Optinem®, or Zeropenem ®. Storage/Stability/Compatibility The powder for injection should be stored at controlled room tem-perature (20-25°C; 69-77°F). When the commercially available powder for injection is reconstituted with sterile water for injection (up to a concentration of 50 mg/m L), it is stable (per the manufac-turer) for up to 2 hours at room temperature; up to 12 hours when refrigerated. The package insert lists several options for dilution with several different solutions in plastic IV bags, syringes, mini-bags, etc. The longest time the drug the manufacturer states the drug is stable, is 48 hours when diluted in normal saline or sterile water for injection at concentrations from 1-20 mg/m L in plastic METFORMIN HCL (met-fore-min) Glucophage® ANTIHYPERGLYCEMIC Prescriber Highlights TT Oral anti-hyperglycemic agent that potentially could be useful in the adjunctive treatment of non-insulin dependent diabetes mellitus (NIDDM) in cats; use is controversial TT Limited experience, but efﬁcacy has been disappointing TT Contraindicated in patients hypersensitive to it; with re-nal dysfunction, metabolic acidosis, or temporarily when iodinated contrast agents are to be used (see Drug Interactions) TT Adverse effects may include lethargy, inappetence, vomit-ing, & weight loss TT Potentially signiﬁcant drug interactions TT Human dosage forms may be difﬁcult to accurately dose in cats syringes and kept refrigerated. For subcutaneous administration in veterinary patients, mero-penem has been diluted to a concentration of 20 mg/m L in sterile sodium chloride 0. 9%. The solution should be protected from light and is reportedly stable if kept refrigerated for up to 96 hours. Once the refrigerated solution is brought back to room temperature it should be used within 6 hours. (Jordan 2004) Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Meropenem Powder for Injection: 500 mg and 1 g in 20 m L, & 30 m L vials; Merrem ® I. V. (Astra Zeneca); (Rx) Uses/Indications Metformin may be useful in the adjunctive treatment of non-in-sulin dependent diabetes mellitus in cats. Only limited trials of the drug have been performed in cats, with only very limited success when the drug is used alone. Studies comparing its safety and ef-ﬁcacy with other oral antihyperglycemics (e. g., glipizide or insulin) were not located. Pharmacology/Actions Metformin's actions are multifaceted. At usual dosages, it increas-es insulin's ability to transport glucose across cell membranes in skeletal muscle without increasing lactate production and inhib-its formation of advanced glycosylation end-products. Metformin decreases hepatic glucose production, and may decrease intestinal absorption of glucose. It does not stimulate insulin production or release from the pancreas and, therefore, does not cause hypogly-cemia. Pharmacokinetics A pharmacokinetic study done in cats (Chastain, Panciera et al. 1999) showed that metformin is variably absorbed after oral ad-ministration 35-67%. In cats, steady-state volume of distribution was 0. 55 L/kg; elimination half-life about 12 hours and total clear-ance was 0. 15 L/hr/kg. Metformin is primarily eliminated via the kidneys. The authors concluded that the drug's pharmacokinetics are similar to that seen in humans, and that a dosage of 2 mg/kg twice daily would give plasma concentrations known to be effective in humans. Contraindications/Precautions/Warnings In humans (and presumably cats), metformin is contraindicated in patients hypersensitive to it, with renal dysfunction or metabolic acidosis. It is also temporarily contraindicated when iodinated con-trast agents are to be used (see Drug Interactions).	pppbs.pdf
METFORMIN HCL 583 Adverse Effects In cats, metformin may cause lethargy, inappetence, vomiting, and weight loss. In a study evaluating metformin in diabetic cats (Nelson, Spann et al. 2004), 1 of 5 diabetic cats studied died 11 days after receiving metformin. As the cause of death was unde-termined, metformin could not be ruled out as a causative factor. Hypoglycemia would not be an expected adverse effect when met-formin is used as a single agent. Reproductive/Nursing Safety In pregnant humans, metformin is designated by the FDA as a cat-egory B drug (Animal studies have not demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal 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. ) Metformin is excreted in maternal milk in levels equivalent to those found in plasma. While adverse effects in nursing kittens would be unlikely, use with caution in lactating queens. Overdosage/Acute Toxicity There is limited information available. Massive overdoses in hu-mans (100 grams) caused hypoglycemia only 10% of the time, but lactic acidosis occurred. There were 26 exposures to metformin reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org ) dur-ing 2005-2006. In these cases 24 were dogs with 5 showing clinical signs and the remaining 2 cases were 1 bird and 1 cat neither of which showed clinical signs. Common ﬁndings in dogs recorded in decreasing frequency included vomiting and depression. Treatment is symptomatic and supportive. Hemodialysis can enhance the removal of drug from the body. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving metformin and may be of signiﬁcance in veterinary patients: !TACE INHIBITORS : May increase risk for hypoglycemia !TCIMETIDINE : In humans, cimetidine can cause a 60% increase in peak metformin plasma levels and a 40% increase in AUC !TCORTICOSTEROIDS : May reduce efﬁcacy !TDIURETICS, THIAZIDE : May reduce hypoglycemic efﬁcacy !TFUROSEMIDE : Can increase the AUC and plasma levels of met-formin by 22% in humans; metformin can decrease the peak plasma concentrations and AUC of furosemide !TIODINATED CONTRAST AGENTS, PARENTERAL : May cause acute renal failure and lactic acidosis if used within 48 hours of a metformin dose !TISONIAZID : May reduce hypoglycemic efﬁcacy !TSYMPATHOMIMETIC AGENTS : May reduce hypoglycemic efﬁcacy Laboratory Considerations No speciﬁc laboratory interactions or considerations noted. Doses !TCATS: a) For cats with non-insulin dependent diabetes mellitus: 5 mg/ kg PO twice daily. (Greco 2002a) Note : In a more recent refer-ence the author states that “metformin has been shown toxic to cats and should not be used. It is also ineffective. ” (Greco 2007c) b) For cats with non-insulin dependent diabetes mellitus (pa-tients with detectable concentrations of insulin): 50 mg (total dose) per cat PO twice daily; may be efﬁcacious only in cats with detectable concentrations of insulin at time of treatment (Nelson, Spann et al. 2004) c) For early NIDDM: 2 mg/kg PO q12h (Melendez and Lorenz 2002) Monitoring !TEfﬁcacy: Standard methods of monitoring efﬁcacy for diabetes treatment should be followed (e. g., fasting blood glucose, appe-tite, attitude, body condition, PU/PD resolution, and perhaps se-rum fructosamine and/or glycosylated hemoglobin levels) !TRenal function (baseline and annually) !TAdverse effects Client Information !TClients should understand the relative “investigational” nature of using this compound in cats and report any untoward effects to the veterinarian. Chemistry/Synonyms A biguanide oral anti-hyperglycemic agent, metformin HCl occurs as white to off-white crystals that are slightly soluble in alcohol and freely soluble in water. It is a weak base; a 1% aqueous solution of metformin HCl has a p Ka of 6. 68 and metformin base has a p Ka of 12. 4. Metformin HCl may also be known as dimethylbiguanide HCl or metforimini hydrochloridium. There are many proprietary names outside of the USA for this drug. Storage/Stability Metformin HCl oral products (oral tablets, sustained-release tab-lets, and ﬁxed dose combination products with glipizide or rosigli-tazone) should be stored protected from light at a controlled room temperature of 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F). The combination product containing met-formin HCL and glyburide should be stored at temperatures up to 25°C (77°F) and protected from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Metformin HCl Tablets: 500 mg, 850 mg, 1000 mg; Glucophage® (Bristol-Myers Squibb); generic; (Rx) Metformin HCl Extended-Release Tablets: 500 mg, 750 mg & 1000 mg; Glucophage XR® (Bristol-Myers Squibb); Glumetza® (Depomed); Fortamet® (First Horizon); (Rx) Metformin HCl Oral Solution: 500 mg/5 m L in 120 m L & 480 m L; Riomet® (Ranbaxy); (Rx) The following ﬁxed-dose oral tablet combination products are available: Glyburide/Metformin Hydrochloride Film-coated Tablets: 1. 25 mg/250 mg, 2. 5 mg/500 mg, 5 mg/500 mg; Glucovance® (Bristol-My-ers Squibb); generic; (PAR); (Rx) Rosiglitazone Maleate/Metformin HCl Film-coated Tablets: 2 mg/500 mg, 2 mg/1000 mg, 4 mg/500 mg or 4 mg/1000 mg; Avandamet® (Glaxo Smith Kline); (Rx) Glipizide/Metformin HCL Film-coated Tablets: 2. 5 mg/250 mg, 2. 5 mg/500 mg and 5 mg/500 mg; Metaglip® (Bristol-Myers Squibb); ge-neric; (Rx) Pioglitazone HCl and Metformin HCl Film-coated Tablets: 15 mg/500 mg, 15 mg/850 mg; Acto Plus Met® (Takeda); (Rx)	pppbs.pdf
584 METHADONE HCL METHADONE HCL (meth-a-done) Dolophine® OPIATE AGONIST Prescriber Highlights TT Narcotic agonist that may be used as an alternative to morphine in dogs, cats TT Causes less histamine-release (with IV), sedation & vom-iting than morphine TT Depending on country, may be signiﬁcantly more expen-sive than morphine TT C-II controlled substance in USA Uses/Indications Methadone may be used as an alternative opioid preanesthetic or analgesic in dogs or cats. It is also being investigated for epidural use for horses. Pharmacology/Actions In small animals methadone acts similarly to morphine with re-gard to its degree of analgesia and duration of action. Methadone is a mu-receptor agonist that also is a non-competitive inhibitor of NMDA (n-methyl-d-aspartate) receptors. Methadone is more lipid-soluble than is morphine and approximately 1-1. 5 times as potent. It does not cause signiﬁcant histamine release when admin-istered intravenously. Refer to the monograph: Narcotic (opiate) Analgesic Agonists, Pharmacology of, for more information. Pharmacokinetics Limited information is available on the pharmacokinetics of meth-adone in domestic animals. One study in dogs showed a terminal elimination half-life of 2-3 hours. In humans, methadone is well absorbed from the GI tract (PO), and after subcutaneous or intra-muscular injection. It is widely distributed and extensively bound to plasma proteins (60-90%). Methadone is metabolized in the liver primarily by the cytochrome P450 CYP3A isoenzyme, but other isoenzymes also play a role. Metabolites do not have activity. Methadone half-life is widely variable in humans (15-60 hours); elimination half-lives may be extended if giving multiple doses. Contraindications/Precautions/Warnings All opiates should be used with caution in patients with head inju-ries, elevated CSF pressures, and in geriatric or severely debilitated patients. Adverse Effects Adverse effects from methadone can include sedation, vomiting, defecation, constipation, bradycardia, and respiratory depres-sion. Methadone tends to cause less sedation or vomiting than morphine. Reproductive/Nursing Safety Methadone is relatively safe to use at low dosages for short periods during the ﬁrst two trimesters of pregnancy, but it should be avoid-ed late in term as signiﬁcant respiratory depression and increased rates of stillbirths have been noted in humans. Infants of humans who have been taking methadone for opiate addiction, have shown high rates of moderate to severe opiate withdrawal signs during the neonatal period, and long-term developmental problems. Although methadone enters maternal milk, the American Academy of Pediatrics considers methadone compatible with breast-feeding in women. Overdosage/Acute Toxicity Overdosage may produce profound respiratory and/or CNS de-pression in most species. Newborns may be more susceptible to these effects than adult animals. Other toxic effects can include cardiovascular collapse, hypothermia, and skeletal muscle hypo-tonia. Naloxone is the agent of choice in treating respiratory de-pression. In massive overdoses, naloxone doses may need to be re-peated. Animals should be closely observed since naloxone's effects might diminish before sub-toxic levels of methadone are attained. Mechanical respiratory support should be considered in cases of severe respiratory depression. Dialysis, charcoal hemoperfusion, or forced diuresis do not appear to be beneﬁcial in treating methadone overdoses. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methadone and may be of signiﬁcance in veterinary patients: T ! ANTIARRHYTHMICS, CLASS I & III (e. g., lidocaine, procainamide, quini-dine, amiodarone ): Use with methadone may increase risks for arrhythmias T ! AZOLE ANTIFUNGALS (ﬂuconazole, itraconazole, ketoconazole ): May increase methadone levels T ! CALCIUM CHANNEL BLOCKERS : Use with methadone may increase risks for arrhythmias T ! CNS DEPRESSANTS, OTHER (e. g., anesthetic agents, antihistamines, phenothiazines, barbiturates, tranquilizers, alcohol, etc. ): May cause increased CNS or respiratory depression when used with methadone T ! CORTICOSTEROIDS (MINERALOCORTICOIDS ): Use with methadone may increase potential for electrolyte abnormalities T ! DIURETICS : Opiates may decrease efﬁcacy in CHF patients T ! MACROLIDE ANTIBIOTICS (erythromycin, clarithromycin ): May inhibit metabolism of methadone and increase levels T ! MONAMINE OXIDASE (MAO) INHIBITORS (e. g., amitraz, possibly sele-giline ): Meperidine with MAOIs in humans has caused severe CNS/behavior reactions and potentially could do the same with methadone; avoid concomitant use T ! MUSCLE RELAXANTS, SKELETAL : Methadone may enhance neuro-muscular blockade T ! PHENOBARBITAL, PHENYTOIN : May decrease methadone levels T ! RIFAMPIN : May decrease methadone levels T ! SSRI ANTIDEPRESSANTS (ﬂuoxetine, sertraline, etc. ): May increase methadone levels T ! St JOHN'S WORT : May decrease methadone levels T ! TRICYCLIC ANTID EPRE SSANTS (clomipramine, amitriptyline, etc. ): Methadone may exacerbate the effects of tricyclic antidepressants T ! WARFARIN : Opiates may potentiate anticoagulant activity T ! ZIDOVUDINE : Methadone may increase zidovudine levels Laboratory Considerations T ! As they may increase biliary tract pressure, opiates can increase plasma amylase and lipase values up to 24 hours following their administration.	pppbs.pdf
METHAZOLAMIDE 585 Doses T ! DOGS: a) As a pre-anesthetic: 0. 2-0. 5 mg/kg SC, IM; or a combination of methadone 0. 1-0. 3 mg/kg with acepromazine 0. 02-0. 05 mg/kg SC, IM (Cornell 2004) b) For pain: 0. 1-0. 25 mg/kg IM, SC, IV. Duration of effect 4-6 hours. (Otero 2006a) c) For perioperative pain control: 0. 1-0. 5 mg/kg IM or SQ; du-ration of effect is 2-4 hours. (Pascoe 2006) T ! CATS: a) For perioperative pain control: 0. 05-0. 5 mg/kg IV, IM or SC q4-6h (Tranquilli 2003) b) As a pre-anesthetic: 0. 1-0. 2 mg/kg SC, IM; or a combination of methadone 0. 1-0. 3 mg/kg with acepromazine 0. 02-0. 05 mg/kg SC, IM (Cornell 2004) c) For moderate to severe pain: 0. 1-0. 2+ mg/kg IM or SQ; du-ration of effect is 2-6 hours. For IV dosing use H the low end dose, titrate over 3-5 minutes; duration of effect is 1-4 hours. (Mathews 2006) d) For pain: 0. 1-0. 2 mg/kg SC, IV. Duration of effect 2-3 hours. (Otero 2006a) Monitoring T ! Analgesic or preanesthetic efﬁcacy T ! At higher dosages, monitor for respiratory depression Client Information T ! When given parenterally, this agent should be used in an inpa-tient setting or with direct professional supervision. T ! If being used orally for pain control, be sure to keep out of reach of children and pets. Chemistry/Synonyms A synthetic diphenylheptane-derivative narcotic agonist, metha-done HCl occurs as an odorless, colorless or white crystalline pow-der. It is freely soluble in water, chloroform, or alcohol and prac-tically insoluble in ether or glycerol. The p H of a 1% solution in water is between 4. 5 and 6. 5. The commercially available injection has a p H from 3-6. 5. The dispersible tablet formulation (Diskets®) contains insoluble ingredients that deter their use for injection. Methadone may also be known as: Amidine HCl, amidone HCl, methadoni hydrochloridum, Phenadone, Adolan®, Biodone®, Cloro Nona®, Dolmed®, Eptadone®, Gobbidona®, Heptadon®, Ketalgine®, Metadol®, Metasedin®, Methaddict®, Methadose®, Methatabs®, Methex®, Pallidone®, Phymet ®, Physeptone®, Pinadone®, Sedo®, Symoron®, or Synastone®. Storage/Stability/Compatibility Unless otherwise labeled, methadone products should be stored at room temperature and protected from light. Methadone injection is reportedly stable when mixed in a sy-ringe with acepromazine. The injection is reportedly not compatible with pentobarbital, phenobarbital, amobarbital, or thiopental. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 1 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Methadone HCl Injection: 10 mg/m L in 20 m L multidose vials; Methadone Hydrochloride (aai Pharma); (Rx, C-II) Methadone HCl Tablets: 5 mg & 10 mg; Dispersible Tablets 40 mg; Dolophine® Hydrochloride (Roxane); Methadose® (Mallinckrodt); ge-neric; (Rx, C-II) Methadone HCl Oral Solution/Concentrate: 1 mg/m L, & 10 mg/m L (also in sugar & dye free) in 30 m L, 500 m L, 946 m L & 1 L; Methadone Hydrochloride (Roxane); Methadose® (Mallinckrodt); (Rx, C-II) All methadone-containing products are C-II controlled substances in the USA. When used as an analgesic, methadone may be dispensed by any pharmacy or practitioner registered with the DEA for Class-II narcotics. When methadone is used to treat narcotic addiction, spe-cialized approval must be obtained from the FDA and, usually, state regulators. METHAZOLAMIDE (meth-a-zoe-la-mide) Neptazane® CARBONIC ANHYDRASE INHIBITOR Prescriber Highlights TT Oral carbonic anhydrase inhibitor used primarily for open angle glaucoma TT Contraindicated in patients with signiﬁcant hepatic, renal, pulmonary or adrenocortical insufﬁciency, hyponatremia, hypokalemia, hyperchloremic acidosis or electrolyte im-balance TT Give oral doses with food if GI upset occurs TT Monitor with tonometry for glaucoma; check electrolytes Uses/Indications Orally administered methazolamide is used for the medical treat-ment of glaucoma. Pharmacology/Actions The carbonic anhydrase inhibitors act by a noncompetitive, revers-ible inhibition of the enzyme carbonic anhydrase. This reduces the formation of hydrogen and bicarbonate ions from carbon dioxide and reduces the availability of these ions for active transport into body secretions. Pharmacologic effects of the carbonic anhydrase inhibitors in-clude decreased formation of aqueous humor, thereby reducing in-traocular pressure; increased renal tubular secretion of sodium and potassium and, to a greater extent, bicarbonate, leading to increased urine alkalinity and volume; anticonvulsant activity, which is inde-pendent of its diuretic effects (mechanism not fully understood, but may be due to carbonic anhydrase or a metabolic acidosis effect). Pharmacokinetics Little information is available. Methazolamide is absorbed from the GI tract albeit more slowly than acetazolamide. It is distrib-uted throughout the body, including the CSF and aqueous humor. Methazolamide is at least partially metabolized in the liver. Contraindications/Precautions/Warnings Carbonic anhydrase inhibitors are contraindicated in patients with signiﬁcant hepatic disease (may precipitate hepatic coma), renal or adrenocortical insufﬁciency, hyponatremia, hypokalemia, hyper-chloremic acidosis or electrolyte imbalance. They should not be used in patients with severe pulmonary obstruction unable to in-crease alveolar ventilation or those who are hypersensitive to them.	pppbs.pdf
586 METHAZOLAMIDE Long-term use of carbonic anhydrase inhibitors is contraindicated in patients with chronic, noncongestive, angle-closure glaucoma as angle closure may occur and the drug may mask the condition by lowering intra-ocular pressures. Adverse Effects Potential adverse effects that may be encountered include GI distur-bances (vomiting, diarrhea, inappetance), metabolic acidosis, CNS effects (sedation, depression, excitement, etc. ), hematologic effects (bone marrow depression, thrombocytopenia), renal effects (crys-talluria, dysuria, renal colic, polyuria, polydipsia), hypokalemia, hy-perglycemia, hyponatremia, hyperuricemia, hepatic insufﬁciency, dermatologic effects (rash, etc. ), and hypersensitivity reactions. Combining methazolamide (oral dosing) with topical (ophthal-mic) dorzolamide does not apparently yield additive reductions in intraocular pressure and may cause increased adverse effects. 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. ) Safety for use during nursing has not been established. But a related compound, acetazolamide, is excreted in the milk in con-centrations unlikely to have pharmacologic effect. Overdosage/Acute Toxicity Information regarding overdosage of this drug is not readily avail-able. It is suggested to monitor serum electrolytes, blood gases, vol-ume status, and CNS status during an acute overdose. Treat symp-tomatically and supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methazolamide and may be of signiﬁcance in veterinary patients: !TANTIDEPRESSANTS, TRICYCLIC : Alkaline urine caused by meth-azolamide may decrease excretion !TASPIRIN (or other salicylates ): Increased risk of methazolamide accumulation and toxicity; increased risk for metabolic acidosis; methazolamide increases salicylate excretion !TDIGOXIN : As methazolamide may cause hypokalemia, increased risk for toxicity !TINSULIN : Rarely, carbonic anhydrase inhibitors interfere with the hypoglycemic effects of insulin !TMETHENAMINE COMPOUNDS : Methazolamide may negate effects in the urine !TPOTASSIUM, DRUGS A FFECTING (corticosteroids, amphotericin B, corti-cotropin, or other diuretics ): Concomitant use may exacerbate po-tassium depletion !TPHENOBARBITAL : Increased urinary excretion, may reduce pheno-barbital levels !TPRIMIDONE : Decreased primidone concentrations !TQUINIDINE : Alkaline urine caused by methazolamide may de-crease excretion Laboratory Considerations !TBy alkalinizing the urine, carbonic anhydrase inhibitors may cause false positive results in determining urine protein using bro-mphenol blue reagent (Albustix®, Al butest®, Labstix®), sulfos-alicylic acid (Bumintest®, Exton's ® Test Reagent), nitric acid ring test, or heat and acetic acid test methods. !TCarbonic anhydrase inhibitors may decrease iodine uptake by the thyroid gland in hyperthyroid or euthyroid patients. Doses !TDOGS: For medical treatment of glaucoma: a) 2-5 mg/kg PO q8-12h (Wilkie 2003) b) 2-4 mg/kg PO two to three times a day (Diehl 2007a) c) 3-5 mg/kg divided q12h PO (Millichamp 2006) d) 2 mg/kg PO two to three times a day (Collins 2006) !TCATS: For medical treatment of glaucoma: a) 3-4 mg/kg PO twice a day. Cats may not tolerate oral car-bonic anhydrase inhibitors (CAIs) as well as dogs. Reported side effects include lethargy, inappetence, vomiting. T opical CAIs may be better tolerated. (Powell 2003) Monitoring !TIntraocular pressure/tonometry !TSerum electrolytes, p H !TBaseline CBC with differential and periodic retests if using chronically !TOther adverse effects Client Information !TIf GI upset occurs, give with food. !TNotify veterinarian if abnormal bleeding or bruising occurs or if animal develops tremors or a rash. Chemistry/Synonyms A carbonic anhydrase inhibitor similar to dichlorphenamide, met-hazolamide occurs as a white to slightly yellow crystalline powder. It is very slightly soluble in water. Methazolamide may also be known as: Glauc Tabs®, Glaumetax®, MZM®, and Neptazane®. Storage/Stability Methazolamide tablets should be stored at room temperature in well-closed containers. Methazolamide tablets have an expiration date of 5 years after manufacture. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Methazolamide Tablets: 25 mg & 50 mg; generic; (Rx)	pppbs.pdf
METHENAMINE 587 METHENAMINE MANDELATE METHENAMINE HIPPURATE (meth-en-a-meen) Mandelamine®, Hiprex®, Urex® URINARY ANTISEPTIC Prescriber Highlights TT Theoretically, converted into an urinary antiseptic; efﬁ-cacy somewhat questionable in small animals TT Contraindications: Hypersensitivity to it, renal insufﬁcien-cy, severe hepatic impairment (due to ammonia produc-tion), or severe dehydration TT Adverse Effects: GI irritation; dysuria possible if used long-term TT Urine p H must be below 6. 5 to be effective Uses/Indications Methenamine is used as an antimicrobial agent for the treatment and prophylaxis of recurrent urinary tract infection. Pharmacology/Actions In an acidic urinary environment (p H <6. 5), methenamine is con-verted to formaldehyde. Formaldehyde is a non-speciﬁc antibacte-rial agent that exerts a bactericidal effect. It has activity on a variety of bacteria, including both gram-positive (Staphylococcus aureus, S. epidermidis, Enterococcus) and gram-negative organisms (E. Coli, Enterobacter, Klebsiella, Proteus, and Pseudomonas aeruginosa). Reportedly, methenamine has activity against fungal urinary tract infections. Mandelic acid or hippuric acid are added primarily to help acidify the urine, but they also have some non-speciﬁc antibacterial activity. Bacterial resistance to formaldehyde, mandelic acid, or hip-puric acid does not usually occur. Pharmacokinetics Human data: While methenamine and its salts are well absorbed from the GI tract, up to 30% of a dose may be hydrolyzed by gas-tric acid to ammonia and formaldehyde. With enteric-coated tab-lets, the amount hydrolyzed in the gut is reduced. While absorbed, plasma concentrations of both formaldehyde and methenamine are very low and have negligible systemic antibacterial activity. Methenamine does cross the placenta and is distributed into milk. Within 24 hours, 70-90% of a dose is excreted unchanged into the urine. In acidic urine, conversion to ammonia and formalde-hyde takes place, maximal hydrolysis occurs at urine p H's of 5. 5 or less, but at p H's below 6. 5 some conversion occurs. Peak formalde-hyde concentrations occur in the urine at about 2 hours post-dose (3-8 hours with enteric-coated tablets). Contraindications/Precautions/Warnings Methenamine and its salts are contraindicated in patients known to be hypersensitive to it, with renal insufﬁciency, severe hepatic im-pairment (due to ammonia production), or severe dehydration. Adverse Effects The most likely adverse effect noted is gastrointestinal upset, with nausea, vomiting, and anorexia predominant. Some patients may develop dysuria, probably secondary to irritation due to high form-aldehyde concentrations. Lipoid pneumonitis has been reported in some humans receiving prolonged therapy with the suspension. Potentially, systemic acidosis could occur. Because methenamine requires acid urine to be beneﬁcial, urine p H should ideally be kept at or below 5. 5. Some urea-splitting bac-teria (e. g., Proteus and some strains of staphylococci, Enterobacter and Pseudomonas) may increase urine p H. Addition of a urinary acidiﬁcation program may be required using dietary modiﬁcation and acidifying drugs (e. g., ascorbic acid, methionine, sodium bi-phosphate, ammonium chloride). Reproductive/Nursing Safety While methenamine crosses the placenta and lab animal studies have not demonstrated any teratogenic effects, it should be used with caution during pregnancy. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Methenamine enters milk but no adverse effects have not been reported in nursing children of mothers taking methenamine. Overdosage/Acute Toxicity Dogs have received single IV dosages of up to 600 mg/kg of meth-enamine hippurate without overt toxic effects. Large oral overdoses should be handled using established gut emptying protocols, main-taining hydration status and supporting as required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methenamine and may be of signiﬁcance in veterinary patients: T ! SULFAMETHIAZOLE : Use of methenamine with sulfamethiazole is not recommended. An insoluble precipitate may form. T ! URINE ALKALINIZING DRUGS (e. g., calcium or magnesium containing antacids, carbonic anhydrase inhibitors, citrates, sodium bicarbonate, thiazide diuretics ): Use of urinary alkalinizing drugs may reduce the efﬁcacy of the methenamine Laboratory Considerations T ! Urinary values of the following compounds may be falsely el-evated: catecholamines, vanillylmandelic acid (VMA ), 17-hydrocorti-costeroid T ! Falsely decreased urinary values of estriol or 5-HIAA may occur T ! Methenamine may cause may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict's So-lution, Clinitest®) and false-negative tests utilizing the glucose oxidase (Tes-Tape®, Clinistix®) method Doses T ! DOGS: a) Methenamine mandelate: 10 mg/kg PO q6h; use with am-monium chloride to acidify urine and increase effectiveness (Grauer 2003) b) Methenamine mandelate: 10 mg/kg PO q6h (Bartges 2007) T ! CATS: a) Methenamine hippurate: 250 mg PO q12h (Papich 1992), (Bartges 2007) Monitoring T ! Urine p H T ! Efﬁcacy Client Information T ! Give after meals if GI distress occurs T ! Encourage compliance	pppbs.pdf
588 METHIMAZOLE Chemistry/Synonyms Methenamine is chemically unrelated to other anti-infective agents. It is commercially available in two salts, methenamine mandelate and methenamine hippurate. Methenamine mandelate occurs as a white, crystalline powder and contains approximately 48% methenamine and 52% mandelic acid. It is very soluble in water. Methenamine hippurate occurs as a white, crystalline powder with a sour taste and contains approximately 44% methenamine and 56% hippuric acid. It is freely soluble in water. Methenamine may also be known as: hexamine amygdalate, hex-amine mandelate, mandelato de metenamina, Aci-steril®, Hiprex®, Mandelamine®, Reﬂux®, Urocedulamin®, and Urex®. Storage/Stability/Compatibility Commercially available methenamine products should be stored at room temperature. Because acids hydrolyze methenamine to formaldehyde and ammonia, do not mix with acidic vehicles before administering. Methenamine is physically incompatible when mixed with most alkaloids and metallic salts (e. g., ferric, mercuric or silver salts). Ammonium salts or alkalis will darken methenamine. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Methenamine Mandelate Tablets: 0. 5 gram & 1 gram; enteric-coated: 0. 5 g & 1 g; Mandelamine® (Warner Chilcott); generic; (Rx) Methenamine Mandelate Suspension: 0. 5 g/5m L in 480 m L; generic; (Rx) Methenamine Hippurate Tablets: 1 gram; Hiprex® (Hoechst Marion Roussel); Urex ® (3M Pharm); (Rx) METHIMAZOLE (meth-im-a-zole) Tapazole® Prescriber Highlights TT Used for medical treatment of feline hyperthyroidism TT Potentially, transdermal gels with methimazole may have efﬁcacy in cats (or owners) that cannot tolerate oral dosing TT Contraindications: Hypersensitivity to it TT Caution: History of or concurrent hematologic abnormali-ties, liver disease, or autoimmune disease TT Adverse Effects: Most occur within ﬁrst 3 mos. of treat-ment: vomiting, anorexia, & depression most frequent. Eosinophilia, leukopenia, & lymphocytosis are usually transient. Rare, but serious: self-induced excoriations, bleeding, hepatopathy, thrombocytopenia, agranulocyto-sis, positive direct antiglobulin test, & acquired myasthe-nia gravis TT Place kittens on milk replacer if mother receiving drug TT Very bitter taste Uses/Indications Methimazole is considered by most clinicians to be the agent of choice when using drugs to treat feline hyperthyroidism. Propylthiouracil has signiﬁcantly higher incidences of adverse re-actions when compared to methimazole and is rarely used today. Transdermal methimazole (in PLO gel; 2. 5 mg twice daily) has been used with some therapeutic success in cats that do not tolerate oral dosing. Efﬁcacy may require four or more weeks to detect. Studies are ongoing. Methimazole appears to be useful for the prophylactic preven-tion of cisplatin induced nephrotoxicity in dogs. Pharmacology/Actions Methimazole interferes with iodine incorporation into tyrosyl resi-dues of thyroglobulin, thereby inhibiting the synthesis of thyroid hormones. It also inhibits iodinated tyrosyl residues from coupling to form iodothyronine. Methimazole has no effect on the release or activity of thyroid hormones already formed or in the general circulation. Pharmacokinetics Information on the pharmacokinetics of methimazole in cats is available (Trepanier, Peterson, and Aucoin 1989). These researchers reported that in normal cats, the bioavailability of the drug is high-ly variable (45-98%), as is the volume of distribution (0. 12-0. 84 L/kg). 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. In dogs, me-thimazole has a serum half-life of 8-9 hours. Methimazole appar-ently concentrates in thyroid tissue. Contraindications/Precautions/Warnings Methimazole is contraindicated in patients who are hypersensitive to it. It should be used very cautiously in patients with a history of or concurrent hematologic abnormalities, liver disease, or autoim-mune disease. Adverse Effects Most adverse effects associated with methimazole use in cats occur within the ﬁrst three months of therapy, with vomiting, anorexia, and depression/lethargy occurring most frequently. GI effects occur in about 10% of treated cats may be related to the drug's bitter taste or direct gastric irritation and are usually transient. Eosinophilia, leukopenia, thrombocytopenia, and lymphocytosis may be noted in approximately 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 facial 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 adjunc-tive therapy. Up to 50% of cats receiving methimazole chronically (>6 months) will develop a positive ANA, requiring dosage reduc-tion. Rarely cats will develop an acquired myasthenia gravis that requires either withdrawal or concomitant glucocorticoid therapy. Reproductive/Nursing Safety High levels of methimazole cross the placenta and may induce hy-pothyroidism in kittens born of queens receiving the drug. 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 acceptable despite its potential risks. ) Levels higher than those found in plasma are detected in human breast milk. It is suggested that kittens be placed on a milk replacer after receiving colostrum from mothers on methimazole. Overdosage/Acute Toxicity 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	pppbs.pdf
METHIONINE 589 Tthat 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 symptomatically and supportively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methimazole and may be of signiﬁcance in veterinary patients: T ! BUPROPION : Potential for increased risk for hepatotoxicity; in-creased monitoring (LFT's) necessary T ! DIGOXIN : Methimazole may decrease digoxin efﬁcacy T ! WARFARIN : Potential for decreased anticoagulant efﬁcacy if me-thimazole added Doses T ! DOGS: As an investigative method to reduce nephrotoxicity associated with cisplatin therapy: a) 40 mg/kg IV over one minute prior to cisplatin. (Kitchell and Dhaliwal 2000) Note : No commercially available parenteral product in USA at time of writing. T ! CATS: For hyperthyroidism: a) For cats with azotemia or for clients declining radioiodine: 1. 25-5 mg per cat twice daily (start at lower end. (Trepanier 2007) b) Initially, 2. 5 mg (total dose) PO once a day for 2 weeks. If adverse reactions not noted by owner, physical exam reveals no new problems, CBC and platelets are within normal lim-its, and serum T4 concentration is greater than 26 nmol/L after 2 weeks of therapy, the dose is increased to 2. 5 mg PO twice daily and the same parameters are checked in another 2 weeks. The dosage should then be increased every 2 weeks by 2. 5 mg per day until serum T4 is between 13 and 26 nmol/L or adverse effects develop. Serum T4 concentrations decline into the reference range within 1-2 weeks, once the cat is receiving an effective dose. (Nelson 2003b) c) If no signs of renal insufﬁciency/failure, begin at 5 mg (to-tal dose) PO twice daily in cases with severely increased T4 levels. If renal insufﬁciency present (or not sure), start at 2. 5 mg twice daily. If azotemia and overt renal failure, start at 1. 25 mg twice a day. Monitor in 1-2 weeks (T4, CBC with platelet count, renal blood parameters, urinalysis). Monitor for other signs of adverse effects. Based on clinical signs and bloodwork, dose can be increased slowly. Monitor every 2-3 weeks for the ﬁrst 3 months, then every 3-6 months thereaf-ter. (Ward 2003) d) 5 mg two to three times a day. Goal is to maintain T4 in the low or low normal range. Recheck serum T4, CBC with plate-lets and chemistry panel at 2-3 week intervals. After ﬁrst 3 months may recheck less frequently. (Taboada 2000) e) Methimazole (50 mg/m L; 5 mg/0. 1 m L) in PLO for trans-dermal administration: 2. 5 mg to inner pinna q12h. Person applying should wear gloves or ﬁnger cots. Somewhat lower efﬁcacy than PO (67% vs 82% euthyroid at 4 weeks). Lower incidence of GI effects with transdermal (4% vs. 24%). No difference in facial excoriation, neutropenia, hepatotoxicity, or thrombocytopenia. Drawbacks for transdermal include: erythema at application site, increased cost, and stability of compounded med (2 weeks guaranteed stable). (Trepanier 2006) Monitoring During ﬁrst 3 months of therapy (baseline values and every 2-3 weeks): T ! CBC, platelet count T ! Serum T 4 T ! If indicated by symptomatology: liver function tests, ANA After stabilized (at least 3 months of therapy): T ! 4 at 3-6 month intervals T ! Other diagnostic tests as dictated by adverse effects Client Information T ! It must be stressed to owners that this drug will decrease exces-sive thyroid hormones, but does not cure the condition and that compliance with the treatment regimen is necessary for success. Chemistry/Synonyms A thioimidazole-derivative antithyroid drug, methimazole occurs as a white to pale buff crystalline powder, having a faint character-istic odor and a melting point of 144-147°C. It is freely soluble (1 gram in 5 m L) in water or alcohol. Methimazole may also be known as: thiamazole, mercazolylum, methylmercaptoimidazole, thiamazolum; tiamazol, Antitiroide®, Danantizol®, Favistan®, Mercaptizol®, Metibasol®, Strumazol®, Tapazol®, Thacapzol®, Thycapzol®, Thyrozol ®, Tirodril®, and Unimazole®. Storage/Stability Methimazole tablets should be stored in well-closed, light-resistant containers at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Methimazole Tablets (plain & scored): 5 mg & 10 mg; Tapazole® (Monarch); generic; (Par Pharm); (Rx) METHIONINE DL-METHIONINE RACEMETHIONINE (me-thye-oh-neen) Ammonil® URINARY ACIDIFIER; NUTRITIONAL Prescriber Highlights TT Used primarily as a urinary acidiﬁer; questionable efﬁ-cacy in reducing stone formation TT Contraindications: Renal failure, pancreatic disease, he-patic insufﬁciency, preexisting acidosis, or urate calculi; not recommended for kittens TT Adverse Effects: Gastrointestinal distress (food may alle-viate), Heinz-body hemolytic anemia (cats) TT Drug interactions	pppbs.pdf
590 METHIONINE Uses/Indications In small animals, methionine has been used primarily for its urine acidiﬁcation effects in the treatment and prevention of certain types (e. g., struvite) of stone formation and to reduce ammoniacal urine odor. In food animals, it has been used as a nutritional supplement in swine and poultry feed and in the treatment of ketosis in cattle. It has been touted as a treatment for laminitis in horses and cattle (purportedly provides a disulﬁde bond substrate to maintain the hoof-pedal bone bond), but deﬁnitive studies demonstrating its ef-fectiveness for this indication are lacking. The drug is used in humans to reduce urine ammonia (p H) and odor. Pharmacology/Actions Methionine has several pharmacologic effects. It is an essential ami-no acid (l-form) and nutrient, a lipotrope (prevents or corrects fatty liver in choline deﬁciency), and a urine acidiﬁer. Two molecules of methionine can be converted to 1 molecule of cysteine. Methionine supplies both sulfhydryl and methyl groups to the liver for metabol-ic processes. Choline is formed when methionine supplies a methyl group to ethanolamine. After methionine is metabolized, sulfate is excreted in the urine as sulfuric acid, thereby acidifying it. Pharmacokinetics No information is available on the pharmacokinetics of this agent in veterinary species or humans. Contraindications/Precautions/Warnings Methionine (in therapeutic doses) is contraindicated in patients with renal failure or pancreatic disease. If used in patients with frank hepatic insufﬁciency, methionine can cause increased pro-duction of mercaptan-like compounds and intensify the signs of hepatic dementia or coma. Methionine should not be given to animals with preexisting acidosis or urate calculi. It is not recom-mended for use in kittens. Adverse Effects At usual doses, gastrointestinal distress can occur; give with food to alleviate this effect and to enhance efﬁcacy. Methionine may cause Heinz-body hemolytic anemia in cats. See Overdosage (below) for other potential adverse effects. Unmonitored use with an acidifying diet (e. g., s/d, c/d), may lead to signs associated with overdose. Reproductive/Nursing Safety No speciﬁc information was located; methionine could, potentially, cause fetal acidosis. Overdosage/Acute Toxicity Methionine may be toxic to kittens who consume other cats' food in which methionine has been added. When methionine was admin-istered at a dose of 2 grams orally per day to mature cats, anorexia, methemoglobinemia, Heinz body formation (with resultant hemo-lytic anemia), ataxia and cyanosis were noted. Metabolic acidosis, particularly in combination with an acidifying diet may occur with overdoses in any species. No speciﬁc information was located on the treatment of methionine overdosage. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methionine and may be of signiﬁcance in veterinary patients: !TAMINOGLYCOSIDES (gentamicin, amikacin, etc): The aminoglyco-sides are more effective in an alkaline medium; urine acidiﬁca-tion may diminish these drugs effectiveness in treating bacterial urinary tract infections !TERYTHROMYCIN : Is more effective in an alkaline medium; urine acidiﬁcation may diminish erythromycin effectiveness in treat-ing bacterial urinary tract infections !TQUINIDINE : Urine acidiﬁcation may increase the renal excretion of quinidine Doses !TDOGS: For urine acidiﬁcation: a) In struvite dissolution therapy if diet and antimicrobials do not result in acid urine: 0. 2-1 grams PO q8h (Lage, Polzin, and Zenoble 1988), (Kirk 1986) !TCATS: For urine acidiﬁcation: a) 1000-1500 mg per day given in the food once daily (if diet and antimicrobials do not reduce p H) (Lewis, Morris, and Hand 1987) b) 0. 2-1 grams PO once daily (Lage, Polzin, and Zenoble 1988) !TCATTLE: a) 20-30 grams PO (Jenkins 1988) !THORSES: a) 22 mg/kg PO once daily for one week; then 11 mg/kg PO once daily for 1 week; then 5. 5 mg/kg PO once daily for one week (Robinson 1987) b) 12. 5 grams IV in one liter saline/dextrose solution (may be effective in Senecio-induced liver damage (Rossoff 1974) Monitoring !TUrine p H (Urine p H's of ≤6. 5 have been recommended as goal of therapy) !TBlood p H if signs of toxicity are present !TCBC in cats exhibiting signs of toxicity Client Information !TGive with meals or mixed in food, unless otherwise instructed by veterinarian. Chemistry/Synonyms A sulfur-containing amino acid, methionine occurs as a white, crys-talline powder with a characteristic odor. One gram is soluble in about 30 m L of water and it is very slightly soluble in alcohol. 74. 6 mg is equivalent to 1 m Eq of methionine. Methionine may also be known as: dl-methionine, racemethio-nine, M, s-methionine, l-methionine, methioninum, Acimethin®, Acimol®, Ammonil®, DL-Methionine Tablets®, M-Caps®, Methigel®, Methio-Form®, Methiotrans®, Methnine®, Neutrodor®, Pedameth®, Uracid®, and Uromethin®. Storage/Stability Methionine should be stored at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Methionine is labeled for use in dogs, cats, and horses in pharma-ceutical dosage forms. Products labeled as nutritionals may be ap-proved for use in other species. Depending on the product, me-thionine may be available without prescription. Methionine is an ingredient in many other nutritional products. Methionine Tablets: 200 mg and 500 mg; Ammonil® Tablets (Virbac), DL-Methionine Tablets® (V. E. T. ); (Rx). Approved for use in cats and dogs	pppbs.pdf
METHOCARBAMOL 591 Methionine Tablets Chewable: 500 mg; Methio-Form® (Vet-A-Mix); (Rx). Approved for use in dogs and cats. Methionine Powder (concentration varies with product); Trade Names/Products include: d-l-methionine Powder (Butler, First Pri-ority). Labeled for use in dogs and cats. Methionine Gel: 400 mg (8%) in 120. 5 g tubes. Methigel® (Vetoqui-nol); (OTC). Labeled for use in cats and dogs. HUMAN-LABELED PRODUCTS: Methionine Capsules: 200 mg & 500 mg; M-Caps® (Pal-Pak); U ra-cid® (Wesley); generic; (Tyson & Assoc); (Rx) Methionine Tablets: 500 mg; generic; (Rx) T opical Ointments, cream, lotion, pads and powder available. METHOCARBAMOL (meth-oh-kar-ba-mole) Robaxin® MUSCLE RELAXANT Prescriber Highlights TT Oral & injectable centrally acting muscle relaxant TT Contraindications: Food animals, renal disease (inject-able only), hypersensitivity to it TT Adverse Effects: Sedation, salivation, emesis, lethargy, weakness, & ataxia TT Give IV slowly (don't exceed 2 m L/min); avoid extravasa-tion; do not give SC Uses/Indications In dogs and cats, methocarbamol is indicated (FDA approved) “as adjunctive therapy of acute inﬂammatory and traumatic conditions of the skeletal muscle and to reduce muscular spasms. ” In horses, intravenous use is indicated (FDA approved) “as adjunctive thera-py of acute inﬂammatory and traumatic conditions of the skeletal muscle to reduce muscular spasms, and effect striated muscle relax-ation. ” (Package insert; Robaxin®V—Robins) Pharmacology/Actions Methocarbamol's exact mechanism of causing skeletal muscle re-laxation is unknown. It is thought to work centrally, perhaps by general depressant effects. It has no direct relaxant effects on stri-ated muscle, nerve ﬁbers, or the motor endplate. It will not directly relax contracted skeletal muscles. The drug has a secondary sedative effect. Pharmacokinetics Limited pharmacokinetic data is available in veterinary species. In humans, methocarbamol has an onset of action of about 30 min-utes after oral administration. Peak levels occur approximately 2 hours after dosing. Serum half-life is about 1-2 hours. The drug is metabolized and the inactive metabolites are excreted into the urine and the feces (small amounts). In horses, plasma clearances appear to be dose dependent after IV administration (Muir, Sams, and Ashcraft 1984), lower clearanc-es were measured after higher doses were given. The serum half-life of methocarbamol in the horse is approximately 60-70 minutes. Guaifenesin is a minor metabolite of methocarbamol, but because of very low concentrations, it probably has no clinical effect in the horse. Contraindications/Precautions/Warnings Because the injectable product contains polyethylene glycol 300, the manufacturer lists known or suspected renal pathology as a con-traindication to injectable methocarbamol therapy. Polyethylene glycol 300 has been noted to increase preexisting acidosis and urea reten tion in humans with renal impairment. Methocarbamol should not be used in patients hypersensitive to it or in animals to be used for food purpose. Do not administer subcutaneously and avoid extravasation. Do not exceed 2 m L per minute when injecting IV in dogs and cats. Adverse Effects Side effects can include sedation, salivation, emesis, lethargy, weak-ness, and ataxia in dogs and cats. Sedation and ataxia are possible in horses. Because of its CNS depressant effects, methocarbamol may impair the abilities of working animals. Reproductive/Nursing Safety Methocarbamol should be used with caution during pregnancy as studies demonstrating its safety during pregnancy are lacking. In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ). In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the beneﬁt of therapy clearly outweighs the risks. ) It is not known whether methocarbamol is excreted in milk. Exercise caution, but the American Academy of Pediatrics classiﬁes methocarbamol as compatible with women breastfeeding. Overdosage/Acute Toxicity Overdosage is generally characterized by CNS depressant effects (loss of righting reﬂex, prostration). Excessive doses in dogs and cats may be represented by emesis, salivation, weakness, and ataxia. If the overdose is after oral administration, emptying the gut may be indicated if the overdose was recent. Do not induce emesis if the patient's continued consciousness is not assured. Other clinical signs should be treated if severe and in a supportive manner. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methocarbamol and may be of signiﬁcance in veterinary patients: T ! CNS DEPRESSANTS, OTHER : Additive depression may occur when given with other CNS depressant agents T ! PYRIDOSTIGMINE : One human patient, with myasthenia gravis and taking pyridostigmine, developed severe weakness after receiving methocarbamol Laboratory Considerations T ! Urinary values of the following compounds may be falsely elevat-ed: vanillylmandelic acid (VMA ), or 5-HIAA may occur Doses T ! DOGS: a) Injectable: For relief of moderate conditions: 44 mg/kg IV; For controlling severe effects of strychnine and tetanus: 55-220 mg/kg IV, do not exceed 330 mg/kg/day. Administer half the estimated dose rapidly, then wait until animal starts to relax and continue administration to effect.	pppbs.pdf
592 METHOHEXITAL SODIUM Tablets: Initially, 132 mg/kg/day PO divided q8h-q12h, then 61-132 mg/kg divided q8-12h. If no response in 5 days, dis-continue. (Package insert; Robaxin®-V—Fort Dodge) b) For muscle relaxation for intervertebral disk disease: 15-20 mg/kg PO three times daily. For muscle relaxation for certain toxicosis (e. g., strychnine, metaldehyde, tetanus): 150 mg/kg IV (Morgan 1988) c) For strychnine/brucine poisoning: Average ﬁrst dose is 149 mg/kg IV, repeat half dose as needed (Bailey 1986a) d) T o help control severe tremors associated with tremorgenic Mycotoxin intoxication: 55-220 mg/kg IV to effect at a rate no more than 2 m L/minute (Schell 2000) e) T o help control tremors associated with Guarna (Paillinia spp. ; caffeine) toxicity: 50-220 mg/kg IV, administered slowly and to effect; do not exceed 330 mg/kg/day. (Atkins 2006b) T ! CATS: a) Injectable: For relief of moderate conditions: 44 mg/kg IV; For controlling severe effects of strychnine and tetanus: 55-220 mg/kg IV, do not exceed 330 mg/kg/day. Administer half the estimated dose rapidly, then wait until animal starts to relax and continue administration to effect. Tablets: Initially, 132 mg/kg/day PO divided q8h-q12h, then 61-132 mg/kg divided q8-12h. If no response in 5 days, dis-continue. (Package insert, Robaxin®-V—Fort Dodge) T ! CATTLE: a) For treatment of CNS hyperactivity: 110 mg/kg IV (Bailey 1986b) T ! HORSES: (Note : ARCI UCGFS Class 4 Drug) a) For moderate conditions: 4. 4-22 mg/kg IV to effect; for severe conditions: 22-55 mg/kg IV (Package insert, Robaxin®-V— Fort Dodge) b) 15-25 mg/kg IV by slow infusion (Robinson 1987) c) T o give orally: Use 2-3 times the recommended IV dose (Cunningham, Fisher et al. 1992) d) For acute rhabdomyolysis: 15-25 mg/kg slow IV infusion. May repeat up to four times daily if needed to decrease mus-cle cramping. (Hanson 1999) Monitoring T ! Level of muscle relaxation/sedation Client Information T ! Animal's urine color may darken, but need not be a concern. Chemistry/Synonyms A centrally acting muscle relaxant related structurally to guaifene-sin, methocarbamol occurs as a ﬁne, white powder with a charac-teristic odor. In water, it has a solubility of 25 mg/m L. The p H of commercial injection is approximately 4-5. Methocarbamol may also be known as: guaiphenesin car-bamate, Labycarbol®, Laxan®, Lumirelax®, Miowas®, Musxan®, Myocin®, Myomethol®, Ortoton ®, Remisol®, Rexivin ®, Robinax®, and Traumacut®. Storage/Stability/Compatibility Methocarbamol tablets should be stored at room temperature in tight containers; the injection should be stored at room tempera-ture and not frozen. Solutions prepared for IV infusion should not be refrigerated as a precipitate may form. Because a haze or precipi-tate may form, all diluted intravenous solutions should be physi-cally inspected before administration. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Methocarbamol Tablets: 500 mg; Robaxin®V (Fort Dodge); (Rx). Ap-proved for use in dogs and cats. Methocarbamol Injection: 100 mg/m L in vials of 20 m L and 100 m L; Robaxin®-V (Fort Dodge); (Rx). Approved for use in dogs, cats, and horses not intended for food. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Methocarbamol Tablets: 500 mg & 750 mg; Robaxin® & Robaxin-750® (Schwarz Pharma); generic; (Rx) Methocarbamol Injection: 100 mg/m L in 10 m L vials; Robaxin® (Wy-eth-Ayerst); (Rx) METHOHEXITAL SODIUM (meth-oh-hex-i-tal) Brevital® UL TRA-SHORT AC TING BARBITURAT E Prescriber Highlights TT Infrequently used ultra-short acting barbiturate for anes-thesia induction, or for anesthesia for very short proce-dures, especially in sight hounds TT Contraindications: Absolute contraindications: absence of suitable veins for IV administration, history of hyper-sensitivity reactions to barbiturates, status asthmaticus. Relative contraindications: severe cardiovascular disease or preexisting ventricular arrhythmias, shock, increased intracranial pressure, myasthenia gravis, asthma, & conditions where hypnotic effects may be prolonged (e. g., severe hepatic disease, myxedema, severe anemia, ex-cessive premedication, etc. ) TT NOT recommended for use in cattle TT Avoid extravasation TT No analgesic or muscle relaxant properties TT Adverse Effects: Apnea, hypotension. Tremors, seizure during recovery; premed may help reduce/prevent rough recoveries TT C-IV Controlled Substance; relatively expensive Uses/Indications Methohexital is sometimes used in small animals as an ultrashort acting anesthetic agent, but, propofol has largely supplanted meth-ohexital's use in small animals. However, because it is not depen-dent on redistribution to fat to reverse its effect, it may be useful in canine sight hound breeds. Because methohexital can induce an-esthesia very rapidly, it may also be useful when general anesthesia must be administered to a patient with a full stomach, as an ET tube may be placed rapidly before aspiration of vomitus can occur. Pharmacology/Actions Methohexital is an ultra-short acting methylated oxybarbiturate anesthetic agent. It is about twice as potent as thiopental and has a duration of action about H as long. Like all the barbiturates, methohexital acts by depressing the reticular activating center of the brain.	pppbs.pdf
METHOHEXITAL SODIUM 593 Pharmacokinetics After IV injection, methohexital rapidly causes anesthesia (15-60 seconds). Its distribution half-life is 5-6 minutes. When used alone, a single dose will cause surgical anesthesia for 5-15 minutes. Unlike the thiobarbiturates, methohexital is rapidly metabolized by the liver and is not dependent on redistribution to fat to reverse its effects. No drug is detectable in the body 24 hours after administra-tion. Its elimination half-life is reported to be 3-5 hours. Recovery times in small animals average 30 minutes. Contraindications/Precautions/Warnings Contraindicated in patients hypersensitive to barbiturates or who do not have adequate veins for safe IV administration. Relative contraindications include: seizure-prone animals, severe cardio-vascular disease or preexisting ventricular arrhythmias, shock, increased intracranial pressure, myasthenia gravis, asthma, and conditions where hypnotic effects may be prolonged (e. g., severe hepatic disease, myxedema, severe anemia, excessive premedica-tion, etc. ). These relative contraindications do not preclude the use of methohexital, but dosage adjustments must be considered and the drug must be given slowly and cautiously. Because of its unpredictability in cattle, it is not recommended for use in this species. Adverse Effects Methohexital can cause profound respiratory depression. The lethal dose may only be 2-3 times that of the anesthetic dose. Because excitation (including muscle tremors and seizures) can oc-cur upon recovery, methohexital is generally recommended for use with a premed. Postoperative seizures have been reported and can be treated with IV diazepam. In small animals, methohexital may induce rougher recoveries when compared to thiopental. Because of its rapid elimination and very short action, there is a possibility that methohexital's effects may diminish before inhalant anesthesia takes full effect. T oo rapid an injection may lead to apnea and hypotension. Barbiturates do not provide analgesia or any muscle relaxation. Because it can be very irritating to tissues and localized necrosis can occur in soft tissue, methohexital solutions must be only given IV, and perivascular injection must be avoided. Extravasation inju-ries can be treated with multiple inﬁltrates of sterile normal saline. Lidocaine can be injected to reduce pain. Reproductive/Nursing Safety While safety of methohexital has not been established in pregnancy, doses of up to 7 times those of humans given to pregnant rabbits and rats resulted in no overt teratogenicity or fetal harm. 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. ) Small amounts of thiopental have been detected in milk fol-lowing administration of large doses to humans. It is unlikely that methohexital poses much risk to nursing offspring. Overdosage/Acute Toxicity See Adverse Effects above; ﬁgure dosages carefully. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methohexital and may be of signiﬁcance in veterinary patients: !TCNS DEPRESSANT DRUGS : When used with other CNS depressant drugs, methohexital may have additive effects. Doses !TDOGS: a) For induction with premedication: 5 mg/kg; give H-e to e of dose over 10 seconds. In 30 seconds if adequate plane is not reached to allow intubation, give additional drug. De-lay will result in poor induction due to rapid redistribution. (Mc Kelvey and Hollingshead 2000) b) For induction or sole anesthetic in non-premedicated dogs or cats: 11 mg/kg IV, give approximately H the dose rapidly and then titrate to effect. If premedicated, give 5. 5-6. 6 mg/ kg IV, 10-30% is given rapidly IV and then the remainder titrated to effect. (Paddleford 1999) !TCATS: a) For induction or sole anesthetic in non-premedicated dogs or cats: 11 mg/kg IV, give approximately H the dose rapidly and then titrate to effect. If premedicated, give 5. 5-6. 6 mg/ kg IV, 10-30% is given rapidly IV and then the remainder titrated to effect. (Paddleford 1999) Monitoring !TPlane of anesthesia !TRespiratory rate/depth !TCardiac rate, rhythm and blood pressure !TUpon recovery, monitor for CNS stimulation (seizures) Client Information !TMethohexital should be used in a setting only where adequate monitoring and support are available. Chemistry/Synonyms An ultra-short acing barbiturate agent, methohexital occurs as a white, crystalline powder. It is freely soluble in water. Methohexital sodium may also be known as: compound 25398, enallynymalnatrium, methohexitone sodium, Brevimytal®, Brevital®, and Brietal®. Storage/Stability/Compatibility Methohexital sodium powder for injection should be stored at room temperature (less than 25°C). Preferably, reconstitute the powder for injection with sterile water for injection. D 5W or 0. 9% sodium chloride may also be used, particularly when making concentrations of 0. 2% (to avoid extreme hypotonicity). While the manufacturer states not to make concentrations greater than 1%, some veterinary anesthesiologists will make concentrations of up 6% (especially when using in large animals). Do not use solutions with bacteriostatic agents to prepare the solution. After reconstituting with sterile water for injection, solutions are stable for at least 6 weeks at room temperature. As long as the solution remains clear and colorless, the manufacturer states that it is permissible to use. Solutions of D 5W or normal saline are not stable for much more than 24 hours after reconstituting. Methohexital solutions are alkaline. Do not mix with acidic drugs (e. g., atropine or succinylcholine). Refer to specialized refer-ences before attempting to mix methohexital with another drug. Methohexital is incompatible with silicone. Do not allow contact with silicone-treated rubber stoppers or silicone treated parts of disposable syringes.	pppbs.pdf
594 METHOTREXATE Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Methohexital Sodium Powder for Injection: 2. 5 g in 20m L vials; Brevital® Sodium (Monarch); (Rx, C-IV) METHOTREXATE METHOTREXATE SODIUM (meth-oh-trex-ate) MTX, Amethopterin ANTINEOPLASTIC, IMMUNOSUPPRESSIVE Prescriber Highlights TT Antineoplastic/immunosuppressant used primarily for lymphomas & some solid tumors in dogs & cats TT Contraindications: Preexisting bone marrow depression, severe hepatic or renal insufﬁciency, or hypersensitivity to the drug TT Caution: If patient susceptible or has preexisting clinical signs associated with the adverse reactions associated with this drug (see below) TT Adverse Effects: GI (diarrhea, nausea, & vomiting); Higher dosage: listlessness, GI toxicity (ulcers, mucosal sloughing, stomatitis), hematopoietic toxicity (nadir at 4-6 days), hepatopathy, renal tubular necrosis, alopecia, depigmentation, pulmonary inﬁltrates & ﬁbrosis; anaphy-laxis (rare) TT Avoid human exposure TT Teratogenic; may affect spermatogenesis TT Determine dosages accurately TT Drug interactions Uses/Indications Indicated for lymphomas and some solid tumors in dogs and cats (see the Doses section and the recommended treatment protocol references at the end of this section). In human medicine, metho-trexate is also being used to treat refractory rheumatoid arthritis and severe psoriasis. Pharmacology/Actions An S-phase speciﬁc antimetabolite antineoplastic agent, metho-trexate competitively inhibits folic acid reductase, preventing the reduction of dihydrofolate to tetrahydrofolate and affecting pro-duction of purines and pyrimidines. Rapidly proliferating cells (e. g., neoplasms, bone marrow, GI tract epithelium, fetal cells, etc. ) are most sensitive to the drug's effects. Dihydrofolate reductase has a much greater afﬁnity for metho-trexate than either folic acid or dihydrofolic acid and coadministra-tion of folic acid will not reduce methotrexate's effects. Leucovorin calcium, a derivative of tetrahydrofolic acid, can block the effects of methotrexate. Methotrexate also has immunosuppressive activity, possibly due to its effects on lymphocyte replication. Tumor cells have been noted to develop resistance to methotrexate that may be due to de-creased cellular uptake of the drug. Pharmacokinetics Methotrexate is well absorbed from the GI tract after oral adminis-tration of dosages <30 mg/m2 with a bioavailability of about 60%. In humans, peak levels occur within 4 hours after oral dosing, and between 30 minutes and 2 hours after IM injection. Methotrexate is widely distributed in the body and is actively transported across cell membranes. Highest concentrations are found in the kidneys, spleen, gallbladder, liver, and skin. When giv-en orally or parenterally, methotrexate does not reach therapeutic levels in the CSF. When given intrathecally, methotrexate attains therapeutic levels in the CSF and also passes into the systemic cir-culation. Methotrexate is about 50% bound to plasma proteins and crosses the placenta. Methotrexate is excreted almost entirely by the kidneys via both glomerular ﬁltration and active transport. Serum half-life is less than 10 hours and generally between 2-4 hours. Contraindications/Precautions/Warnings Methotrexate is contraindicated in patients with preexisting bone marrow depression, severe hepatic or renal insufﬁciency, or hypersensitivity to the drug. It should be used with caution in pa-tients who are susceptible to, or have preexisting clinical signs as-sociated with, the adverse reactions associated with this drug. When administering MTX, either wear gloves or immediately wash hands after handling. Gloves are particularly important if handling split, broken, or crushed tablets. Preparation of intrave-nous solutions should ideally be performed in a vertical laminar ﬂow hood. Adverse Effects In dogs and cats, gastrointestinal side effects are most prevalent with diarrhea, nausea, inappetance (especially cats) and vomit-ing (especially dogs) seen. Higher dosages may lead to listlessness, GI toxicity (ulcers, mucosal sloughing, stomatitis), hematopoietic toxicity (nadir at 4-6 days), hepatopathy, renal tubular necrosis, alopecia, depigmentation, pulmonary inﬁltrates, and ﬁbrosis. CNS toxicity (encephalopathy) may be noted if methotrexate is given in-trathecally. Rarely, anaphylaxis may be seen. Reproductive/Nursing Safety Methotrexate is teratogenic, embryotoxic, and may affect spermato-genesis in male animals. In humans, the FDA categorizes this drug as category X for use during pregnancy (Studies in animals or hu-mans demonstrate fetal abnormalities or adverse reaction; reports in-dicate evidence of fetal risk. The risk of use in pregnant women clearly outweighs any possible beneﬁt. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as 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. ) Methotrexate is contraindicated in nursing mothers. It is excret-ed in breast milk in low concentrations with a milk:plasma ratio of 0. 08:1. Nursing offspring should be switched to milk replacer if the dam requires methotrexate. Overdosage/Acute Toxicity Acute overdosage in dogs is associated with exacerbations of the adverse effects outlined above, particularly myelosuppression and acute renal failure. Acute tubular necrosis is secondary to drug pre-cipitation in the tubules. In dogs, the maximally tolerated dose is reported to be 0. 12 mg/kg q24h for 5 days. Treatment of acute oral overdoses include emptying the gut and preventing absorption using standard protocols if the ingestion is recent. Additionally, oral neomycin has been suggested to help pre-	pppbs.pdf
METHOTREXATE 595 Tvent absorption of MTX from the intestine. In order to minimize renal damage, forced alkaline diuresis should be considered. Urine p H should be maintained between 7. 5-8 by the addition of 0. 5-1 m Eq/kg of sodium bicarbonate per 500 m L of IV ﬂuid. Leucovorin calcium is speciﬁc therapy for methotrexate over-doses. It should be given as soon as possible, preferably within the ﬁrst hour and, deﬁnitely, within 48 hours. Doses of leucovorin re-quired are dependent on the MTX serum concentration. Humans having serum concentrations greater than 5 x 10-7 M at 48 hours are likely to develop severe toxicity. Leucovorin in doses ranging from 25-200 mg/m2 every 6 hours doses is given until serum levels fall below 1 x 10-8 M. Dogs treated with leucovorin at 15 mg/m2 every 3 hours IV for 8 doses, then IM q6h for 8 doses were able to tolerate MTX doses as high as 3 g/m2 (O'Keefe and Harris 1990). Another dose of 3 mg/m2 for leucovorin in dogs has also been suggested (Coppoc 1988). Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methotrexate (MTX) and may be of signiﬁcance in veterinary patients: !TAMIODARONE : Prolonged PO administration of amiodarone (>2 weeks) may inhibit MTX metabolism !TASPA RAGINASE : Asparaginase given concomitantly with MTX may decrease MTX efﬁcacy !TAZATHIOPRINE : Potential for increased risk for hepatic toxicity !TCHLORAMPHENICOL : May displace MTX from plasma proteins in-creasing risk for toxicity, but also may reduce MTX absorption and enterohepatic recirculation !TCISPLATIN : May have synergistic action with MTX, but alter the renal elimination of MTX !TCYCLOSPORINE : May increase MTX levels !TFOLIC ACID : May reduce MTX efﬁcacy, but folate deﬁciency in-creases MTX toxicity !TNEOMYCIN (oral): Oral neomycin may decrease the absorption of oral methotrexate if given concomitantly !TNSAIDS, SALICYLATES : In humans, severe hematologic and GI toxic-ity has resulted in patients receiving both MTX and non-steroidal antiinﬂammatory agents; use caution in dogs also on MTX !TPENICILLINS : May decrease MTX renal elimination !TPROBENECID : May inhibit the tubular secretion of MTX and in-crease its half-life !TPYRIMETHAMINE : Pyrimethamine, a similar folic acid antagonist, may increase MTX toxicity and should not be given to patients receiving MTX !TRETINOIDS : Potential for increased risk for hepatic toxicity !TSULFASALAZINE : Potential for increased risk for hepatic toxicity !TSULFONAMIDES : May displace MTX from plasma proteins increas-ing risk for toxicity !TTETRACYCLINES : May displace MTX from plasma proteins increas-ing risk for toxicity, but also may reduce MTX absorption and enterohepatic recirculation !TTHEOPHYLLINES : MTX may reduce theophylline elimination !TTRIMETHOPRIM/SULFA : Rarely, may increase myelosuppression of MTX !TVACCINES, LIVE: Live virus vaccines should be used with caution, if at all during therapy Laboratory Considerations !TMethotrexate may interfere with the microbiologic assay for folic acid. Doses Dosages of methotrexate sodium are expressed in terms of meth-otrexate as are the dosage forms. For more information on using MTX as part of chemotherapy protocols, refer to the protocols found in the appendix or other dosages/protocols found in numer-ous references, including: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). !TDOGS: For susceptible neoplastic diseases (usually as part of a multi-drug protocol): a) As part of the LMP protocol for maintenance of canine lym-phoma: Chlorambucil 20 mg/m2 PO every 15 days; Metho-trexate 2. 5-5 mg/m2 PO twice a week; Prednisone 20 mg/ m2 PO every other day. When Vincristine is added it is at a dose of 0. 5-0. 7 mg/m2 and is given every 15 days alternating weeks with the chlorambucil. (Berger 2005) b) 2. 5 mg/m2 PO 2-3 times weekly; 0. 3-0. 8 mg/m2 IV every 7 days (O'Keefe and Harris 1990) c) “High dose therapy”: 5-10 mg/m2 PO, IV, IM or intrathe-cally followed 2-4 hours later with leucovorin at 3 mg/m2 “Normal dose therapy”: 2. 5 mg/m2 once daily. Adjust dos-age/frequency according to toxicity (Thompson 1989a) d) For lymphoma (as part of protocol): 0. 5 mg/kg IV (maxi-mum dose 25 mg) on day 14 (Matus 1989) e) In combination with other antineoplastics (per protocol) 5 mg/m2 PO twice weekly or 0. 8 mg/kg IV every 21 days; alter-natively 2. 5 mg/m2 PO daily (USPC 1990) !TCATS: For susceptible neoplastic diseases (usually as part of a multi-drug protocol): a) 2. 5 mg/m2 PO 2-3 times weekly; 0. 3-0. 8 mg/m2 IV every 7 days (O'Keefe and Harris 1990) b) For lymphoma (as part of protocol—see reference): 0. 8 mg/ kg IV on day 14 with 5 mg prednisone twice daily PO (Matus 1989) c) In combination with other antineoplastics (per protocol) 5 mg/m2 PO twice weekly (USPC 1990) Monitoring !TEfﬁcacy !Toxicity: a) Monitor for clinical signs of GI irritation and ulceration b) Complete blood counts (with platelets) should be performed weekly early in therapy and eventually every 4-6 weeks when stabilized. If WBC is <4000/mm 3 or platelet count is <100,000/mm3 therapy should be discontinued c) Baseline renal function tests. Continue to monitor if abnormal d) Baseline hepatic function tests. Monitor liver enzymes on a regular basis during therapy. Client Information !TClients must be briefed on the possibilities of severe toxicity de-veloping from this drug, including drug-related mortality. !TClients should contact the veterinarian if the patient exhibits clinical signs of profound depression, abnormal bleeding (in-cluding bloody diarrhea) and/or bruising.	pppbs.pdf
596 METHOXYFLURANE T ! Wear gloves when administering tablets (particularly if crushed or split); if gloves are not used, wash hands thoroughly after han-dling tablets. Chemistry/Synonyms A folic acid antagonist, methotrexate is available commercially as the sodium salt. It occurs as a yellow powder that is soluble in water. Methotrexate sodium injection has a p H of 7. 5-9. Methotrexate and methotrexate sodium may also be known as: MTX, amethopterin, 4-Amino-4-deoxy-10-methylpteroyl-L-glu-tamic acid, 4-Amino-10-methylfolic acid, CL-14377, alpha-meth-opterin, methotrexatum, metotrexato, NSC-740, WR-19039; there are many trade names available. Storage/Stability/Compatibility Methotrexate sodium tablets should be stored at room temperature (15-30°C) in well-closed containers and protected from light. The injection and powder for injection should be stored at room tem-perature (15-30°C) and protected from light. Methotrexate sodium is reportedly physically compatible with the following intravenous solutions and drugs: Amino acids 4. 25%/ dextrose 25%, D 5W, sodium bicarbonate 0. 05 M, cephalothin so-dium, cytarabine, 6-mercaptopurine sodium, sodium bicarbon-ate, and vincristine sulfate. In syringes, methotrexate is physically compatible with: bleomycin sulfate, cyclophosphamide, doxorubicin HCl, ﬂuorouracil, furosemide, leucovorin calcium, mitomycin, vin-blastine sulfate, and vincristine sulfate. Methotrexate sodium compatibility information conﬂicts or is dependent on diluent or concentration factors with the follow-ing drugs or solutions: heparin sodium and metoclopramide 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 information. Methotrexate sodium is reportedly physically incompatible when mixed with the following solutions or drugs: bleomycin sulfate (as an IV additive only; compatible in syringes and Y-lines), ﬂuorouracil (as an IV additive only; compatible in syringes and Y-lines), predni-solone sodium phosphate, droperidol, and ranitidine HCl. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Methotrexate Sodium Tablets (plain & scored): 2. 5 mg, 5 mg, 7. 5 mg, 10 mg and 15 mg; Rheumatrex® Dose Pack (STADA); Trexal® (Barr); generic; (Rx) Methotrexate Sodium Injection: 25 mg/m L (as base) in 2 m L & 10 m L vials; preservative-free in 2 m L, 4 m L, 8 m L, 10 m L, 20 m L, and 40 m L single-use vials; Methotrexate LPF® Sodium (Xanodyne); ge-neric; (Rx) Methotrexate Powder for Injection, lyophilized: preservative free in 1 g in single-use vials; generic; (Rx) METHOXYFLURANE (meth-ox-ee-ﬂoo-rane) Penthrane® INHALANT ANESTHETIC Prescriber Highlights TT Infrequently used inhalant general anesthetic agent TT Contraindications: Preexisting renal or hepatic disease TT Caution (beneﬁts vs. risks): Increased CSF or head injury, or myasthenia gravis. TT Adverse Effects: Potential nephrotoxicity TT Drug interactions Uses/Indications Methoxyﬂurane is an inhalant anesthetic, but it is rarely used today primarily due to its potential for causing nephrotoxicity, slow on-set of action (a short-acting barbiturate is often used as an induc-tion agent), and prolonged recovery time. However, it does produce some muscle relaxation and analgesia, even at relatively low con-centrations and can be administered without a precision vaporizer as it will vaporize to a maximum of about 3%. Pharmacology/Actions While the precise mechanism that inhalant anesthetics exert their general anesthetic effects is not precisely known, they may interfere with functioning of nerve cells in the brain by acting at the lipid matrix of the membrane. Some key pharmacologic effects noted with methoxyﬂurane include: CNS depression, depression of body temperature regulating centers, increased cerebral blood ﬂow, re-spiratory depression, hypotension, vasodilatation, and myocardial depression (less so than with halothane) and muscular relaxation. Pharmacokinetics Methoxyﬂurane is rapidly absorbed from the alveoli, but it has a comparatively slow onset of activity. It is rapidly distributed into the CNS and crosses the placenta. Approximately 35% of a dose is eliminated via the lungs and approximately 50% is metabolized in the liver; substantial amounts of inorganic ﬂuoride are formed which are excreted by the kidneys. Minimal Alveolar Concentration (MAC; %) in oxygen report-ed for methoxyﬂurane in various species: Dog = 0. 23; Cat = 0. 23; Horse = 0. 22; Human = 0. 16. Several factors may alter MAC (acid/ base status, temperature, other CNS depressants on board, age, on-going acute disease, etc. ). Contraindications/Precautions/Warnings Methoxyﬂurane should be used cautiously, if at all, in patients with preexisting renal or hepatic disease. It should be used with caution (beneﬁts vs. risks) in patients with increased CSF or head injury, or myasthenia gravis. Adverse Effects The most troublesome adverse effect associated with methoxyﬂu-rane is its potential for causing nephrotoxicity, particularly with prolonged procedures in patients predisposed to nephrotoxicity. Dogs with normal renal function are probably less susceptible to this effect than are humans, unless concomitantly receiving neph-rotoxic agents (NSAIDs, etc. ).	pppbs.pdf
METHYLENE BLUE 597 While methoxyﬂurane, potentially, may cause hepatotoxicity, this apparently occurs rarely and may be associated with hypoxic episodes. Nevertheless, it should be used with caution in patients with preexisting hepatic dysfunction. Reproductive/Nursing Safety Studies are not deﬁnitive, but methoxyﬂurane may cause teratogen-ic effects; other inhalant anesthetic agents may be safer alternatives. If methoxyﬂurane is used during delivery or C-section, oxygen may need to be given to newborns after delivery. In a system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as 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 Overdosage or acute toxicities may cause circulatory depression and hypotension, cardiac arrhythmias, bradycardia, prolonged respira-tory depression, emergence delirium, or malignant hyperthermic crises. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methoxyﬂurane and may be of signiﬁcance in veterinary patients: T ! CLINDAMYCIN, LINCOMYCIN : Should be used with caution with ha-logenated anesthetic agents as additive neuromuscular blockade may occur T ! NEPHROTOXIC DRUGS, OTHER (e. g., aminoglycosides, amphotericin B, cisplatin, NSAIDs, penicillamine ): Because of methoxyﬂurane's po-tential for causing nephrotoxicity, it should not be used concur-rently with other nephrotoxic drugs T ! NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS : Should be used with caution with halogenated anesthetic agents as additive neuromuscular blockade may occur T ! SUCCINYLCHOLINE : Concomitant administration of succinylcholine with inhalation anesthetics may induce increased incidences of cardiac effects (bradycardia, arrhythmias, sinus arrest and apnea) and, in susceptible patients, malignant hyperthermia as well T ! SYMPATHOMIMETICS (dopamine, epinephrine, norepinephrine, ephed-rine, metaraminol, etc. ): While methoxyﬂurane sensitizes the myo-cardium to the effects of sympathomimetics less so than halot-hane, arrhythmias may still result; caution and monitoring are advised Doses T ! DOGS & CAT S: a) 3% (induction); 0. 5-1. 5% (maintenance) (Papich 1992) T ! RUMINANTS & SWINE: a) Induction 1%; maintenance 0. 5% (Howard 1993) Monitoring T ! Respiratory and ventilatory status T ! Cardiac rate/rhythm; blood pressure (particularly with “at risk” patients T ! Level of anesthesia T ! Renal function tests, if patient's post-operative urine output is excessive or markedly reduced Chemistry/Synonyms An inhalant general anesthetic agent, methoxyﬂurane occurs as a clear,mobile liquid. It has a characteristic fruity odor. Methoxyﬂurane is very slightly soluble in water and miscible with al cohol or olive oil. At 20°C, methoxyﬂurane's speciﬁc gravity is 1. 420-1. 425. Methoxyﬂurane may also be known as NSC-110432, Penthrane® and Penthrox®. Storage/Stability/Compatibility Store at room temperature in tight, light-resistant containers. Protect from freezing. Methoxyﬂurane is very soluble in rubber and soda lime. Avoid contact with polyvinyl chloride (PVC) plastics as they can be extracted by methoxyﬂurane. Methoxyﬂurane contains an antioxidant (BHT) that may accu-mulate in the vaporizer causing a yellow to brown discoloration. Do not use discolored solutions. Discolored vaporizer and wick may be cleaned with diethyl ether (all ether must be removed be-fore reuse). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Methoxyﬂurane in 15 m L and 125 m L; Penthrane® (Abbott); (Rx) METHYLENE BLUE (meth-i-leen) ANTIDOTE Prescriber Highlights TT Thiazine dye used to primarily treat methemoglobinemia in ruminants TT Contraindications: Cats (most agree), lactating dairy animals, renal insufﬁciency; hypersensitive to methylene blue; or given as an intraspinal (intrathecal) injection TT Not very effective in horses TT Adverse Effects: Heinz body anemia or other red cell morphological changes, methemoglobinemia, & de-creased red cell life spans. Cats most sensitive, but to a lesser degree, dogs & horses also. TT A 180-day slaughter withdrawal time has been suggested, but 14 days may be sufﬁcient (see doses) Uses/Indications Methylene blue is used primarily for treating methemoglobinemia secondary to oxidative agents (nitrates, chlorates) in ruminants. It is also employed occasionally as adjunctive or alternative therapy for cyanide toxicity. Intra-operative methylene blue is also being used to preferen-tially stain islet-cell tumors of the pancreas in dogs in order to aid in their surgical removal or in determining the animal's prognosis. Pharmacology/Actions Methylene blue is rapidly converted to leucomethylene blue in tis-sues. This compound serves as a reducing agent that helps to con-vert methemoglobin (Fe+++) to hemoglobin (Fe++). Methylene blue is an oxidating agent, and, if high doses (species dependent) are administered, may actually cause methemoglobinemia.	pppbs.pdf
598 METHYLENE BLUE Pharmacokinetics Methylene blue is absorbed from the GI tract, but is usually ad-ministered parenterally in veterinary medicine. It is excreted in the urine and bile, primarily in the colorless form, but some unchanged drug may be also excreted. Contraindications/Precautions/Warnings Methylene blue is contraindicated in patients with renal insufﬁ-ciency, or are hypersensitive to methylene blue. It cannot be given as an intraspinal (intrathecal) injection. Because cats may develop Heinz body anemia and methemoglobinemia secondary to methy-lene blue, it is considered contraindicated in this species by most clinicians. Methylene blue is considered relatively ineffective in re-ducing methemoglobin in horses. Adverse Effects The greatest concern with methylene blue therapy is the develop-ment of Heinz body anemia or other red cell morphological chang-es, methemoglobinemia, and decreased red cell life spans. Cats tend to be very sensitive to these effects; the drug is usually considered contraindicated in them, but dogs and horses can also develop these effects at relatively low dosages. When injected SC or if extravasation occurs during IV adminis-tration, necrotic abscesses may develop. Reproductive/Nursing Safety Safe use of this agent during pregnancy has not been demonstrated. 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. ) No information on lactation safety was found. Overdosage/Acute Toxicity The LD 50 for IV administered 3% methylene blue is approximately 43 mg/kg in sheep. Drug Interactions None reported Laboratory Considerations !TMethylene blue can cause a green-blue color in urine and may affect the accuracy of urinalysis. Doses !TDOGS: T o preferentially stain islet-cell tumors of the pancreas: a) 3 mg/kg in 250 m L sterile normal saline and administered IV over 30-40 minutes intraoperatively. Initial tumor stain-ing requires approximately 20 minutes after infusion has be-gun and is maximal at about 25-35 minutes after infusion is started. Tumors generally appear to be a reddish-violet in color versus a dusky blue (background staining). (Fingeroth and Smeak 1988) T o treat methemoglobinemia: a) Secondary to phenol exposure: A single, slow IV infusion of 4 mg/kg of methylene blue; may use with 20 mg/kg ascorbic acid PO (Dorman and Clark 2000) b) For severe methemoglobinemia: 1 mg/kg as a 1% solution given slowly IV over several minutes. A dramatic response should occur during the ﬁrst 30 minutes after treatment. It may be repeated if necessary, but it should be used cautiously as can cause Heinz body anemia. Measure hematocrit for 3 days after treatment. (Harvey 2006) !TCATS: T o treat methemoglobinemia: a) Secondary to phenol exposure: A single, slow IV infusion of 1. 5 mg/kg of methylene blue, may use with 20 mg/kg ascor-bic acid PO (Dorman and Clark 2000) b) 1-1. 5 mg/kg IV one time only (Christopher 2000) c) For severe methemoglobinemia: 1 mg/kg as a 1% solution given slowly IV over several minutes. A dramatic response should occur during the ﬁrst 30 minutes after treatment. It may be repeated if necessary, but it should be used cautiously as can cause Heinz body anemia. Measure hematocrit for 3 days after treatment. (Harvey 2006) !TRUMINANTS: Note : When used in food animals, FARAD recommends a mini-mum milk withdrawal time of 4 days after the last treatment. Be-cause of concerns of carcinogenicity, an extremely conservative withdrawal time for meat of 180 days has been recommended; however, available data suggest that a much shorter withdrawal time of 14 days would be sufﬁcient. (Haskell, Payne et al. 2005) For methemoglobin-producing toxins (nitrites, nitrates, chlo-rates): a) Cattle: 8. 8 mg/kg by slow IV using a maximum of a 1% so-lution; repeat if necessary. T o prevent hypotension during nitrite poisoning, give a sympathomimetic drug such as epi-nephrine or ephedrine. (Bailey 1986b) b) Food animals: 4-15 mg/kg IV; may be repeated in 6-8 hours (Post and Keller 2000) c) Cattle, sheep: 8. 8 mg/kg slow IV as a 1% solution in normal saline; may repeat carefully in 15-30 minutes if response is not satisfactory. Other species should use 4. 4 mg/kg dosage rate (as above). (Hatch 1988b) d) For nitrate poisoning in cattle: 5-15 mg/kg as a 1% solution in physiologic saline. With severe cases, repeat treatment at a lower dose may be required. In animals that do not succumb, recovery occurs by 24 hours. (Hall 2006) For cyanide toxicity: a) 4-6 g IV per 454 kg (1000 lb. ) of body weight (Oehme 1986b) !THORSES: For methemoglobinemia secondary to chlorate toxicity: a) 4. 4 mg/kg as 1% solution by intravenous drip; may repeat in 15-30 minutes if clinical response is not obtained. (Schmitz 2004) Monitoring !TMethemoglobinemia !TRed cell morphology, red cell indices, hematocrit, hemoglobin Client Information !TBecause of the potential toxicity of this agent and the serious-ness of methemoglobin-related intoxications, this drug should be used with close professional supervision only. !TMethylene blue may be very staining to clothing or skin. Removal may be accomplished using hypochlorite solutions (bleach). Chemistry/Synonyms A thiazine dye, methylene blue occurs as dark green crystals or crys-talline powder that has a bronze-like luster. It may have a slight odor and is soluble in water and sparingly soluble in alcohol. When dis-solved, a dark blue solution results. Commercially available methyl-ene blue injection (human-labeled) has a p H from 3-4. 5.	pppbs.pdf
METHYLPHENIDATE 599 Methylene blue may also be known as: methylthioninium chlo-ride, azul de metileno, blu di metilene, CI basic blue 9, colour index no. 52015, methylene blue, methylenii caeruleum, methylthioninii chloridum, schultz no. 1038, tetramethylthionine chloride trihy-drate, Azul Metile®, Collubleu®, Desmoidpillen®, Vitableu®, Urolene Blue® and Zumetil®. Storage/Stability/Compatibility Unless otherwise instructed by the manufacturer, store methylene blue at room temperature. Methylene blue is reportedly physically incompatible when mixed with caustic alkalies, dichromates, iodides, and oxidizing or reducing agents. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None approved as pharmaceuticals for internal use. A 1% (10 mg/ m L) methylene blue solution (Centaur) is labeled for animal use as a dye, laboratory indicator and reagent. It is available in pint and gallon bottles. Methylene Blue, USP powder may be available from chemical supply houses HUMAN-LABELED PRODUCTS: Methylene Blue Injection: 10 mg/m L in 1 m L and 10 m L amps; ge-neric; (Rx) Methylene Blue Tablets: 65 mg; Urolene Blue® (Star); (Rx) METHYLPHENIDATE (meth-ill-fen-i-date) Ritalin® CNS STIMULANT Prescriber Highlights TT Amphetamine-like drug that may be useful for treating cataplexy/narcolepsy or hyperkinesis/hyperactivity in dogs TT Use with caution in dogs with seizure disorders, cardiac disease/hypertension, or in aggressive animals TT Adverse effects are primarily CNS stimulation-related TT Class-II controlled drug in USA Uses/Indications Methylphenidate may be useful for treating cataplexy/narcolepsy or hyperactivity in dogs. Pharmacology/Actions Methylphenidate has stimulating effects on the central nervous and respiratory systems similar to that of amphetamines. It also has weak sympathomimetic activity, and at normal dosages has little effect on peripheral circulation. Pharmacokinetics Speciﬁc pharmacokinetic studies in dogs were not located. In hu-mans, methylphenidate (regular tablets) is rapidly and well ab-sorbed from the GI tract. Food in the GI tract may increase the rate, but not the extent, of drug absorbed. Peak levels occur about 2 hours post-dose. The drug is extensively metabolized during the ﬁrst-pass; protein binding is low. T erminal elimination half-life is approximately 3 hours; less than 1% is excreted unchanged in the urine. Contraindications/Precautions/Warnings The risks associated with methylphenidate should be carefully con-sidered before using this drug in dogs with seizure disorders, car-diac disease/hypertension, or in aggressive animals. Adverse Effects Most likely adverse effects to be encountered include increased heart and respiratory rates, anorexia, tremors and hyperthermia (particularly exercised-induced). Reproductive/Nursing Safety In humans, the FDA categorizes methylphenidate as a category C drug for use during pregnancy (Animal studies have shown an ad-verse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). Methylphenidate was associated with teratogenic ef-fects in rabbits, but at massive dosages (200 mg/kg/day). It is unknown if methylphenidate enters maternal milk. Overdosage/Acute Toxicity In dogs, dosages of 1 mg/kg (or below) can cause toxic reactions; there is one report of a fatality after a dog ingested 3. 1 mg/kg, but research dogs have survived doses of 20 mg/kg/day for 90 days. A cat given a 5 mg tablet of methylphenidate, showed signs of trem-ors, agitation, mydriasis, tachycardia, tachypnea and hypertension; signs resolved 25 hours post-ingestion with supportive care (dark cage, diazepam, ﬂuids). Expected signs associated with an overdose in dogs are gener-ally CNS over-stimulation and excessive sympathomimetic effects and can include: hyperactivity, salivation, diarrhea, head bobbing, agitation, tachycardia, hypertension, tremors, seizures, and hyper-thermia. Consider the dosage form (extended-release vs. regular tablets) when considering treatment options and expected onset and duration of effects. Employ treatment using standard gut de-toxiﬁcation techniques (emetic, activated charcoal, cathartic, etc. ); however, emesis should be avoided in animals displaying signs as-sociated with toxicity or that are otherwise at risk for emesis-relat-ed adverse effects. Treatment is basically supportive by controlling signs associated with toxicity. Phenothiazines (e. g., acepromazine, chlorpromazine) may be useful in controlling agitation; beta-blockers can help control tachycardia; external cooling may be used for hyperthermia; and cyproheptadine may help prevent serotonin syndrome. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving methylphenidate and may be of signiﬁcance in veterinary patients: T ! ANTICONVULSANTS (phenobarbital, primidone, phenytoin ): Meth-ylphenidate may increase serum levels T ! CLONIDINE : Rare cases (in humans) of cardiovascular effects (in-cluding death); mechanism not understood and causality not established T ! HYPOTENSIVE DRUGS : Methylphenidate may reduce effects T ! MAO INHIBITORS (including amitraz and potentially, selegiline ): Could lead to hypertensive crisis T ! SSRI ANTIDEPRESSANTS (e. g., ﬂuoxetine, sertraline, etc. ): Meth-ylphenidate may inhibit metabolism and increase levels T ! TRICYCLIC ANTIDEPRESSANTS (e. g., amitriptyline, clomipramine, etc. ): Methylphenidate may inhibit metabolism and increase levels T ! WARFARIN : Methylphenidate may inhibit warfarin metabolism and increase INR	pppbs.pdf
600 METHYLPREDNISOLONE Laboratory Considerations No speciﬁc laboratory interactions were noted for this drug. Doses T ! DOGS: a) For treatment of narcolepsy/cataplexy: 5-10 mg (total dose) PO once daily. (Joseph 2000) b) For treatment of narcolepsy/cataplexy (to supplement imi-pramine at 0. 5-1 mg/kg PO q8-12h): Methylphenidate: 0. 25-0. 5 mg/kg PO or 5-10 mg (total dose) PO q12-24h (Shell 2003b) c) For treatment of hyperkinesis: 5-20 mg (total dose) q8-12h; give for 3 days and assess for improvement of target behav-iors (anxiety, overactivity, learning ability) (Siebert 2003c) d) For hyperkinesis-hyperactivity: Small dogs: 5+ mg total dose PO q12h; Large Dogs: 20-40 mg total dose PO q12h (Virga 2002) Monitoring T ! Clinical efﬁcacy T ! Occasional physical exam to monitor vital signs, body weight T ! In humans, it is recommended to do periodic CBC with differen-tial and platelet counts during prolonged therapy. Client Information T ! Clients should understand that this drug has signiﬁcant potential for abuse by humans and to keep it safely secure. T ! Clients should report untoward stimulatory effects to the veterinarian. T ! If using an extended-release product, do not crush tablet or capsule. Chemistry/Synonyms A CNS stimulant related to amphetamines, methylphenidate HCl occurs as ﬁne, white odorless, crystalline powder. It is feely soluble in water and soluble in alcohol. Methylphenidate may also be known as: Attenta®, Daytrana®, Equasym®, Focalin®, Metadate ER®, Methylin®, Rilatine®, Riphenidate®, Ritalina®, Ritalin®, Ritaline®, Ritaphen®, Rubifen®, or Tranquilyn®. Storage/Stability Unless otherwise noted on the label, methylphenidate tablets and extended-release tablets and capsules should be stored in tight, light-resistant containers at room temperature. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 1 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Methylphenidate Tablets: 5 mg, 10 mg & 20 mg; Chewable Tablets: 2. 5 mg, 5 mg & 10 mg; Extended-Release Tablets: 10 mg, 18 mg, 20 mg, 27 mg, 36 mg & 54 mg; Extended-Release Capsules: 20 mg, 30 mg & 40 mg; Methylin® (Mallinckrodt; Alliant); Ritalin®, Ritalin® LA, & Ritalin-SR® (Novartis); Metadate ER® (Mallinckrodt; Celltech); Con-certa® (Mc Neil); (Rx; C-II) Methylphenidate Oral Solution: 5 mg/5 m L & 10 mg/5 m L in 500 m L; Methylin® (Alliant); (Rx; C-II) Methylphenidate Transdermal Patch: 10 mg, 15 mg, 20 mg & 30 mg; Daytrana® (Shire); (Rx; C-II) METHYLPREDNISOLONE METHYLPREDNISOLONE ACETATE METHYLPREDNISOLONE SODIUM SUCCINATE (meth-ill-pred-niss-oh-lone) Medrol®, Depo-Medrol® GLUCOCORTICOID Prescriber Highlights TT Oral & parenteral glucocorticoid that is 4-5X more po-tent than hydrocortisone; no appreciable mineralocorti-coid activity TT Contraindicated (relatively): Systemic fungal infections, manufacturer lists: “in viral infections,... animals with arrested tuberculosis, peptic ulcer, acute psychoses, corneal ulcer, & Cushingoid syndrome. The presence of diabetes, osteoporosis, chronic psychotic reactions, pre-disposition to thrombophlebitis, hypertension, CHF, renal insufﬁciency, & active tuberculosis necessitates carefully controlled use. ” TT Therapy goal is to use as much as is required & as little as possible for as short an amount of time as possible TT Primary adverse effects are “Cushingoid” in nature with sustained use TT Many potential drug & lab interactions Uses/Indications Glucocorticoids have been used in an attempt to treat practically every malady that afﬂicts man or animal, but there are three broad uses and dosage ranges for use of these agents. 1) Replacement of glucocorticoid activity in patients with adrenal insufﬁciency, 2) as an antiinﬂammatory agent, and 3) as an immunosuppressive. Among some of the uses for glucocorticoids include treatment of: endo-crine conditions (e. g., adrenal insufﬁciency), rheumatic diseases (e. g., rheumatoid arthritis), collagen diseases (e. g., systemic lupus), allergic states, respiratory diseases (e. g., asthma), dermatologic dis-eases (e. g., pemphigus, allergic dermatoses), hematologic disorders (e. g., thrombocytopenias, autoimmune hemolytic anemias), neo-plasias, nervous system disorders (increased CSF pressure), GI dis-eases (e. g., ulcerative colitis exacerbations), and renal diseases (e. g., nephrotic syndrome). Some glucocorticoids are used topically in the eye and skin for various conditions or are injected intra-articu-larly or intra-lesionally. The above listing is certainly not complete. For speciﬁc dosages and indications refer to the Doses section. Pharmacology/Actions Methylprednisolone may be administered either orally or parenter-ally. Its relative antiinﬂammatory potency is approximately 5 times that of cortisol. It has negligible mineralocorticoid activity. Glucocorticoids have effects on virtually every cell type and sys-tem in mammals. An overview of the effects of these agents follows: CARDIOVASCULAR SYSTEM: Glucocorticoids can reduce capillary per-meability and enhance vasoconstriction. A relatively clinically in-signiﬁcant positive inotropic effect can occur after glucocorticoid administration. Increased blood pressure can result from both the	pppbs.pdf