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CISPLATIN 201 terminal phase is very long (about 60-80 hours). Approximately 80% of a dose can be recovered as free platinum in the urine within 48 hours of dosing in dogs. Contraindications/Precautions/Warnings The drug is contraindicated in cats because of severe dose-related primary pulmonary toxicoses (dyspnea, hydrothorax, pulmonary edema, mediastinal edema, and death). Cisplatin is also contrain-dicated in patients with preexisting signiﬁcant renal impairment, myelosuppression, or a history of hypersensitivity to platinum-containing compounds. Because of the ﬂuid loading required prior to dosing, it should be used with caution in patients with congestive heart failure. When preparing the product for injection, wear gloves and pro-tective clothing as local reactions may occur with skin or mucous membrane contact. Should accidental exposure occur, wash the area thoroughly with soap and water. Adverse Effects In dogs, the most frequent adverse effect seen after cisplatin treat-ment is vomiting, which usually occurs within 6 hours after dosing and persists for 1-6 hours. This is because of direct effects on the chemoreceptor trigger zone (CTZ). Butorphanol (0. 4 mg/kg IM), dexamethasone (0. 25 mg/kg IV) and metoclopramide (0. 1 mg/kg IV) have all been used successfully as antiemetics when given before cisplatin administration. Nephrotoxicity may occur unless the animal is adequately diure-sed with sodium chloride prior to, and after therapy; diuresis will generally signiﬁcantly reduce the incidence and severity of nephro-toxicity in the majority of dogs. Intravenous methimazole (40 mg/ kg) has been demonstrated to protect cisplatin-induced nephrotox-icity in dogs in experimental models. Other adverse effects that have been reported include hemato-logic abnormalities (thrombocytopenia and/or granulocytopenia), ototoxicity (high-frequency hearing loss and tinnitus), anorexia, diarrhea (including hemorrhagic diarrhea), seizures, peripheral neuropathies, electrolyte abnormalities, hyperuricemia, increased hepatic enzymes, anaphylactoid reactions, and death. Direct IV infusion over 1-5 minutes should be avoided as it may cause increased nephrotoxicity or ototoxicity. Reproductive/Nursing Safety Cisplatin's safe use in pregnancy has not been established. It is teratogenic and embryotoxic in mice. In human males, the drug may cause azoospermia and impaired spermatogenesis. In humans, the FDA categorizes this drug as category D for use during preg-nancy (There is evidence of human fetal risk, but the potential ben-eﬁts from the use of the drug in pregnant women may be acceptable despite its potential risks. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the beneﬁt of therapy clearly outweighs the risks. ) Overdosage/Acute Toxicity The minimum lethal dose of cisplatin in dogs is reportedly 2. 5 mg/ kg (≈80 mg/m 2). Because of the potential for serious toxicity as-sociated with this agent, dosage calculations should be checked thoroughly to avoid overdosing. See Adverse Effects above for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cisplatin and may be of signiﬁcance in veterinary patients: !TAMINOGLYCOSIDES : Potential for increased risk for nephrotoxicity and/or nephrotoxicity; if possible, delay aminoglycoside admin-istration by at least two weeks after cisplatin !TAMPHOTERICIN B : Potential for increased risk for nephrotoxicity; if possible, delay amphotericin B administration by at least two weeks after cisplatin !TFUROSEMIDE (and other loop diuretics ): Potential for increased ototoxicity !TPHENYTOIN : Cisplatin may reduce serum levels of phenytoin Doses For more information on using chlorambucil as part of chemo-therapy protocols, refer to the protocols found in the appendix or other dosages/protocols found in numerous references, including: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). WARNING: Dogs must undergo saline diuresis before and after cis-platin therapy to reduce the potential for nephrotoxicity develop-ment. Some clinicians also recommend using either mannitol or furosemide with saline, but this is somewhat controversial. !TDOGS: For potentially susceptible carcinomas and sarcomas: a) As part of an accepted protocol: 60-70 mg/m2 IV over 20 minutes after a 4-hour IV saline diuresis (normal saline at a rate of 18. 3 m L/kg/hr). After cisplatin infused, continue sa-line diuresis for another 2 hours. Pretreat with antiemetics. (Kitchell and Dhaliwal 2000) b) 30-50 mg/m2 every 3 weeks. Pretreat with ﬂuids at 60 m L/ kg for 12 hours before dosing. Give mannitol 0. 5 mg/kg 30 minutes before cisplatin. Give cisplatin as a slow drip over 1-6 hours and follow with another 12 hours of ﬂuids at 60 m L/kg. (Macy 1986) c) 60-70 mg/m2 IV drip q3-5 weeks. Perform saline diuresis before and after treatment. (Mac Ewen and Rosenthal 1989) Intracavitary administration for palliative control of neoplastic pulmonary effusions: a) Give dog IV normal saline at 10 m L/kg/hr for 4 hours prior to treating. Dose cisplatin at 50 mg/m2 (diluted in normal saline to a total volume of 250 m L/m 2). Warm solution to body temperature; place a 16-gauge over-the-needle cath-eter into the pleural space using sterile technique. Remove as much pleural ﬂuid as possible and then slowly infuse cisplatin solution through same catheter. Once completed, remove catheter. May repeat every 3-4 weeks as needed to control effusion. If resolves completely, discontinue therapy after the 4th treatment. Reinstitute if effusion recurs. (Hawk-ins and Fossum 2000) !THORSES: For intralesional injection of skin tumors: a) Add 10 mg of cisplatin powder (if available) to 1 m L of wa-ter and 2 m L of medical-grade sesame oil. Resultant solution contains 3. 3 mg of cisplatin per m L. Inject 1 mg per cm 3 of tumor/tumor bed intralesionally with a small gauge needle (22-25 gauge) attached to an extension set with Luer-lock connections. Inject in multiple planes no further than 0. 6 to 1 cm apart. Because the volume of tumor is difﬁcult to mea-sure, the rule of thumb is to discontinue injection when ﬂuid	pppbs.pdf
202 CITRATE SALTS Tis extruded from the skin surface. Because recurrence at the periphery of the treated area is the primary cause of treatment failure, injection into 1-2 cm of normal tissue surrounding the tumor has been recommended. Intralesional injection is generally repeated at 2-week intervals for 4 total treatments. (Moll 2002) Monitoring Adapted primarily from the reference by Shapiro (Shapiro 1989). T ! oxicity. Baseline laboratory data: urinalysis, hemogram, platelet count, serum biochemical and electrolyte determination. Repeat tests before each dose if animal is receiving high-dose therapy (≈monthly) or as needed if signs/symptoms of toxicity develop. Animals receiving frequent small doses should be monitored at least weekly. Not recommended to use cisplatin if WBC is <3200/ mcl, platelets <100,000, creatinine clearance is <1. 4 m L/min/kg, or uremia, electrolyte or acid-base imbalance is present. Reduce dose if rapid decreases occur with either WBC or platelets, chang-es in urine speciﬁc gravity or serum electrolytes, elevated serum creatinine or BUN, or if creatinine clearance is >1. 4 but <2. 9 m L/ min/kg. T ! Efﬁcacy. Tumor measurement and radiography at least month-ly. In one study (Knapp et al. 1988), the authors state that dogs should be evaluated at 42 days into therapy. Dogs demonstrat-ing complete or partial remission or stable disease should receive additional therapy. Dogs whose disease has progressed should have cisplatin therapy stopped and receive alternate therapies if warranted. Client Information T ! Clients must be briefed on the possibilities of severe toxicity de-veloping from this drug, including drug-related mortality. Chemistry/Synonyms An inorganic platinum-containing antineoplastic, cisplatin occurs as white powder. One mg is soluble in 1 m L of water or normal sa-line. The drug is available commercially as a solution for injection. Cisplatin injection (premixed solution) has a p H of 3. 7-6. Cisplatin may also be known as: cis-Platinum II, cis-DDP, CDDP, cis-diamminedichloroplatinum, cisplatina, cisplatinum, cis-plati-num, DDP, NSC-119875, Peyrone's salt, or platinum diamminodi-chloride; many trade names are available. Storage/Stability/Compatibility The injection should be stored at room temperature and away from light; do not refrigerate as a precipitate may form. During use, the injection should be protected from direct bright sunlight, but does not need to be protected from normal room incandescent or ﬂuo-rescent lights. Do not use aluminum hub needles or aluminum containing IV sets as aluminum may displace platinum from the cisplatin mol-ecule with the resulting formation of a black precipitate. Should a precipitate form from either cold temperatures or aluminum con-tact, discard the solution. Cisplatin is reportedly compatible with the following intravenous solutions and drugs: dextrose/saline combinations, sodium chloride 0. 225%-0. 9%, magnesium sulfate, and mannitol. It is also compatible in syringes or at Y-sites with: bleomycin sulfate, cyclophosphamide, doxorubicin HCl, droperidol, ﬂuorouracil, furosemide, heparin so-dium, leucovorin calcium, methotrexate, mitomycin, vinblastine sulfate, and vincristine sulfate. Cisplatin compatibility information conﬂicts or is dependent on di-luent or concentration factors with the following drugs or solutions: dextrose/saline combinations, dextrose 5% in water, and metoclo-pramide. Compatibility is dependent upon factors such as p H, con-centration, temperature and diluent used; consult specialized refer-ences or a hospital pharmacist for more speciﬁc information. Cisplatin is reportedly incompatible with the following solutions or drugs: sodium chloride 0. 1% and sodium bicarbonate 5%. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cisplatin Injection: 1 mg/m L in 50 m L, 100 m L and 200 m L multi-dose vials; generic; (Rx) Cisplatin powder or compounded formulations appropriate for intralesional injection may be available from compounding pharmacies. CITRATE SALTS POTASSIUM CITRATE SODIUM CITRATE AND CITRIC ACID (si-trate) Nutrived®, Urocit-K® URINARY ALKALINIZER Prescriber Highlights TT Oral administered precursor to bicarbonate; used for uri-nary alkalization & treatment of chronic metabolic aci-dosis; may be useful to prevent calcium oxalate urolith formation TT Many contraindications to therapy, including heart failure, severe renal impairment, UTI with calcium or struvite stones TT Contraindications for potassium citrate alone include hyperkalemia, ulcer disease; tablets in patients with delayed gastric emptying conditions, esophageal compression, or intestinal obstruction TT Most prevalent adverse effect is GI distress but, poten-tially, hyperkalemia, ﬂuid retention & metabolic alkalosis possible TT Adequate lab monitoring mandatory Uses/Indications Citrate salts serve as source of bicarbonate; they are more pleasant tasting than bicarbonate preparations making them more palatable. They are used as urinary alkalinizers when an alkaline urine is desir-able and in the management of chronic metabolic acidosis accompa-nied with conditions such as renal tubular acidosis or chronic renal insufﬁciency. Potassium citrate alone (Uracit-K®) has been used for the prevention of calcium oxalate uroliths. The citrate can complex with calcium thereby decreasing urinary concentrations of calcium oxalate. The urinary alkalinizing effects of the citrate also increase the solubility of calcium oxalate. Pharmacology/Actions Citrate salts are oxidized in the body to bicarbonate thereby acting as alkalinizing agents. The citric acid component of multi-component products is converted only to carbon dioxide and water and has only a temporary effect on systemic acid-base status.	pppbs.pdf
CITRATE SALTS 203 Pharmacokinetics Absorption and oxidation are nearly complete after oral adminis-tration; less than 5% of a dose is excreted unchanged. Contraindications/Precautions/Warnings Contraindications for products containing sodium citrate and/or potassium citrate: aluminum toxicity, heart failure, severe renal im-pairment (with azotemia or oliguria), UTI associated with calcium, or struvite stones. Additional contraindications for potassium cit-rate alone include hyperkalemia (or conditions that predispose to hyperkalemia such as adrenal insufﬁciency, acute dehydration, renal failure, uncontrolled diabetes mellitus), or peptic ulcer (particularly with the tablets). The potassium citrate tablets are contraindicated in patients with delayed gastric emptying conditions, esophageal compression, or intestinal obstruction or stricture. These products should be used with caution (weigh risks vs. beneﬁt) in severe re-nal tubular acidosis or chronic diarrheal syndromes as they may be ineffective. Sodium citrate products should be used with caution in patients with congestive heart disease. In dosages not resulting in hypernatremia, hyperkalemia or metabolic alkalosis, these products should not cause fetal harm. Adverse Effects The primary adverse effects noted with these agents are gastrointesti-nal in nature, however, most dogs receiving these products tolerate them well. Potassium citrate products have the potential of caus-ing hyperkalemia, especially in susceptible patients. Sodium citrate products may lead to increased ﬂuid retention in patients with car-diac disease. Rarely, metabolic alkalosis could occur. Reproductive/Nursing Safety In humans, the FDA categorizes potassium citrate 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). No speciﬁc data is available on the safety of citrates during nurs-ing, but no documented adverse effects have been reported. Overdosage/Acute Toxicity Overdosage and acute toxicity would generally fall into 4 categories: gastrointestinal distress and ulceration, metabolic alkalosis, hyper-natremia (sodium citrate), or hyperkalemia (potassium citrate). Should an overdose occur and there are reasonable expectations of preventing absorption (especially with the tablets), gut-emptying protocols should be employed if not contraindicated. Otherwise, treat GI effects, if necessary, with intravenous ﬂuids or other sup-portive care. Hyperkalemia, hypernatremia, and metabolic alkalosis should be treated if warranted. It is suggested to refer to an animal poison control center, an internal medicine text or other references for additional information for speciﬁc treatment modalities for these conditions. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving citrates and may be of signiﬁcance in veterinary patients: !TAMPHETAMINES; PSEUDOEPHEDRINE; EPHEDRINE : Alkalinized urine can decrease excretion !TANTACIDS : Citrate alkalinizers used with antacids (particularly those containing bicarbonate or aluminum salts) may cause sys-temic alkalosis, and aluminum toxicity (aluminum antacids only) particularly in patients with renal insufﬁciency. Sodium citrate combined with sodium bicarbonate may cause hypernatremia, and may cause the development of calcium stones in patients with preexisting uric acid stones. !TASPIRIN : Alkalinized urine can increase the excretion of salicylates !TFLUOROQUINOLONES : The solubility of ciproﬂoxacin & enroﬂoxa-cin is decreased in an alkaline environment. Patients with alka-line urine should be monitored for signs of crystalluria. !TLITHIUM : Alkalinized urine can decrease excretion !TMETHENAMINE : Concurrent use with methenamine is not recom-mended as it requires an acidic urine for efﬁcacy. !TQUINIDINE : Alkalinized urine can decrease excretion !TTETRACYCLINES : Alkalinized urine can decrease excretion With potassium citrate products, the following agents may lead to increases in serum potassium levels (including severe hyper-kalemia), particularly in patients with renal insufﬁciency: !!ACE INHIBITORS (e. g., enalapril, lisinopril ) !!CYCLOSPORINE !!DIGOXIN !!HEPARIN !!NONS TEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS ) !!POTASSIUM-CONTAINING DRUGS/FOODS !TSPIRONOLACTONE; TRIAMTERENE Doses !TDOGS: For adjunctive therapy to inhibit calcium oxalate crystal forma-tion in dogs with hypocitraturia: a) Potassium citrate: 40-75 mg/kg PO q12h; avoid overzealous urinary alkalinization as calcium phosphate uroliths may form (Grauer 2003) b) Potassium citrate: Initially 50 mg/kg PO q12h. Monitor urine p H; goal is to obtain values of 7-7. 5 (Bartges 2000) c) T o help decrease the possibility of calcium oxalate stone for-mation using Nutrived® Potassium Citrate Granules: 1 scoop mixed or sprinkled on food per 10 lb. body weight per day. (Label information; Nutrived® Potassium Citrate Granules for Dogs & Cats—Vedco) d) If calcium oxalate crystalluria is persistent or calcium oxalate uroliths occur and dietary and hydrochlorothiazide (2 mg/kg PO q12h) therapy have been implemented, give potassium citrate to effect to achieve a urine p H of 6. 5-7 using a start-ing dose of 50-75 mg/kg PO q12h. If urine p H already above 7-7. 5, do not use potassium citrate. Monitor serum potas-sium levels monthly and reduce dose if hyperkalemia occurs. (Adams and Syme 2005) For adjunctive therapy of chronic renal failure as a potassium supplement and alkalinizing agent: a) Potassium citrate: Initially, 75 mg/kg PO q12h (Bartges 2002a) !TCATS: For adjunctive therapy to inhibit calcium oxalate formation: a) Potassium citrate: initially 50-100 mg kg PO q12h. Goal is to achieve a urine p H of approximately 7. 5 (Bartges 2002a) b) T o help decrease the possibility of calcium oxalate stone for-mation using Nutrived® Potassium Citrate Granules: 1 scoop mixed or sprinkled on food per day. (Label information; Nu-trived ® Potassium Citrate Granules for Dogs & Cats—Vedco) c) Recommended dose is 100-150 mg/kg/day PO, but it is un-clear whether this dose will actually increase urinary citrate in cats. (Westropp, Bufﬁngton et al. 2005) For adjunctive therapy of chronic renal failure as a potassium supplement and alkalinizing agent: a) Potassium citrate: Initially, 75 mg/kg PO q12h (Bartges 2002a)	pppbs.pdf
204 CLARITHROMYCIN b) If cat is signiﬁcantly acidemic: 2. 5 m Eq (total dose) potas-sium or 15-30 mg/kg as potassium citrate PO q12h (Wolf 2006b) c) When cats with CRF are hypokalemic: 2-4 m Eq (total dose) of potassium per day as potassium citrate or potassium glu-conate. (Di Bartola and Chew 2006a) Monitoring Depending on patient's condition, product chosen and reason for use: T ! Serum potassium, sodium, bicarbonate, chloride T ! Acid/base status T ! Urine p H, Urinalysis T ! Serum creatinine, CBC, particularly in chronic renal failure Chemistry/Synonyms Generally used as alkalinizing agents, citric acid and citrate salts are available in several commercially available dosage forms. Citric acid occurs as an odorless or practically odorless, colorless, trans-lucent crystal with a strong acidic taste. It is very soluble in water. Potassium citrate occurs as odorless, transparent crystals or a white, granular powder having a cooling, saline taste. It is freely soluble in water. 108 mg of potassium citrate contains approximately 1 m Eq of potassium. Sodium citrate occurs as colorless crystals or a white, granular powder. The hydrous form is freely soluble in water. Potassium citrate may also be known as citrate of potash, or citric acid tripotassium salt monohydrate. Sodium citrate and citric acid solutions may also be known as Shohl's solution. Storage/Stability Store solutions and potassium citrate tablets in tight containers at room temperature unless otherwise recommended by manufacturer. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Potassium Citrate and Fatty Acids Granules: each 5 grams (one scoop) contains 300 mg potassium citrate (approximately 2. 8 m Eq of potassium) and 423 mg total fatty acids; also contains several amino acids—quantities not labeled; Nutrived® Potassium Citrate Granules for Cats and Dogs (Vedco); (OTC) HUMAN-LABELED PRODUCTS: Potassium Citrate Tablets: 5 m Eq (540 mg), 10 m Eq (1080 mg); Urocit-K®; (Mission); (Rx) Potassium Citrate/Sodium Citrate Combinations: Tablets: 50 mg potassium citrate and 950 mg sodium citrate. Citro-lith® (Beach Pharm); (Rx) Syrup: 550 mg potassium citrate, 500 mg sodium citrate, 334 mg citric acid/5 m L (1m Eq K, 1 m Eq Na per m L equivalent to 2 m Eq bicarbonate); in 120 and 480 m L, Polycitra ® (Willen); (Rx) Solution: 550 mg K citrate, 500 mg sodium citrate, 334 mg citric acid/5 m L (1 m Eq K, 1 m Eq Na per m L; equiv to 2 m Eq bicarbonate) in 120 and 480 m L. Polycitra-LC® (Willen); (Rx). 1100 mg potassium citrate, 334 mg citric acid/5 m L, (2 m Eq K/m L; equiv. to 2 m Eq bicarbonate) in 120 and 480. Polycitra-K® (Willen); (Rx) Crystals for Reconstitution: 3300 mg K citrate, 1002 mg citric acid per UD packet (equiv. T o 30 m Eq bicarbonate) in single dose pack-ets. Polycitra-K® (Willen); (Rx) Citric Acid/Sodium Citrate Combinations: Solutions: Sodium Citrate Dihydrate 490 mg sodium citrate and Citric Acid 640 mg per 5 m L (1 m Eq sodium equiv to 1 m Eq bicar-bonate/m L) in 500 m L and UD 15 and 30 m L, Oracit®; (Carolina Medical); (Rx) Sodium Citrate Dihydrate 500 mg sodium citrate and Citric 334 mg per 5 m L (1 m Eq sodium equiv to 1 m Eq bicarbonate/m L) in 120 and 473 m L and UD 15 and 30 m L; Bicitra®; (Alza Corp); (Rx) Potassium Citrate, Sodium Citrate/Citric Acid Solutions: 550 mg potassium citrate monohydrate, 500 mg sodium citrate dihy-drate, 334 mg citric acid monohydrate per 5 m L (1 m Eq potassium and 1 m Eq sodium per m L and is equivalent to 2 m Eq bicarbonate in 60 oz bottles; Cytra-LC® (Cypress); (Rx) 1100 mg potassium citrate monohydrate and 334 mg citric acid monohydrate per 5 m L (2 m Eq potassium per m L and is equivalent to 2 m Eq bicarbonate) in 473 m L; Cytra-K® (Cypress); (Rx) 20 m Eq potassium, 30 m Eq citrate (20 g dextrose, 5 g fructose, 35 m Eq chloride, 45 m Eq sodium)/L in 1 liter; Naturalyte® Oral Elec-trolyte Solution (Unico); (OTC) CLARITHROMYCIN (klar-ith-ro-my-sin) Biaxin® MACROLIDE ANTIBIOTIC Prescriber Highlights TT Macrolide antibiotic that may useful for treating atypical mycobacterial infections or treatment of Helicobacter spp. infections in dogs, cats, & ferrets; Rhodococcus equi infections in foals TT Appears to be well tolerated by domestic animals, but clinical experience is limited TT Many potential drug interactions TT Expense may be an issue Uses/Indications In small animal medicine, clarithromycin is primarily of inter-est in treating atypical mycobacterial infections or treatment of Helicobacter spp. infections in cats and ferrets. In equine medicine, clarithromycin may be useful in treating Rhodococcus equi infections in foals. Pharmacology/Actions Clarithromycin, like other macrolide antibiotics, penetrate suscep-tible bacterial cell walls and bind to the 50S ribosomal subunit inhib-iting protein synthesis. The drug is usually bacteriostatic, but may be bactericidal at high concentrations in very susceptible organisms. Clarithromycin's spectrum of activity is similar to that of eryth-romycin, but it also has activity against a variety of bacteria that are not easily treated with other antibiotics (e. g., atypical mycobacte-ria). Activity against gram-positive aerobic cocci is similar to that of erythromycin, but lower concentrations are required to be effec-tive against susceptible organisms. The drug is typically not effec-tive against oxacillin-resistant Staph or coagulase-negative Staph. Clarithromycin also has activity against Rhodococcus equi. Activity against gram-negative aerobic bacteria includes Haemophilus inﬂu-enzae, Pasturella multocida, Legionella pneumophilia, Bordetella per-tussis and Campylobacter spp. Clarithromycin has inhibitory activ-ity against a variety of atypical mycobacteria, including M. avium complex and M. leprae. Clarithromycin has good activity against Mycoplasma pneumoniae and Ureaplasma ureatlyticum. Other or-	pppbs.pdf
CLARITHROMYCIN 205 ganisms where clarithromycin may have therapeutic usefulness in-clude: Nocardia spp. Toxoplasma gondii, Helicobacter pylori, Borrelia burgdorferi, and Cryptosporidium parvum. Pharmacokinetics In horses (foals), the drug is apparently well absorbed after intra-gastric administration with peak serum concentrations occurring about 1. 5 hours after dosing. Elimination half-life is about 4. 8 hours. In dogs, clarithromycin bioavailability ranges from 60-83% with the higher values obtained when given to fasted animals. Contraindications/Precautions/Warnings In humans, clarithromycin is contraindicated in patients hyper-sensitive to it or other macrolide antibiotics (e. g., erythromycin, azithromycin). Adverse Effects The adverse effect proﬁle for clarithromycin in domestic animals is not well described. With limited clinical experience, it appears to be well tolerated in dogs, cats, ferrets, and foals. Like all orally admin-istered antibiotics, GI disturbances are possible. Pinnal or general-ized erythema may be associated with this drug when used in cats. Adverse effects in humans include gastrointestinal adverse ef-fects (primarily nausea, vomiting, abdominal pain, abnormal taste, diarrhea) that, when compared with erythromycin, are milder and occur less frequently. Approximately 4% of treated humans develop transient, mildly elevated BUN levels. Rarely, prolonged QT inter-val (torsades de pointes), hepatotoxicity, thrombocytopenia, or hy-persensitivity reactions have been reported. Pseudomembranous colitis secondary to Clostridium difﬁcile has been reported after clarithromycin use. Reproductive/Nursing Safety In humans, the FDA categorizes clarithromycin 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). T eratogenic studies in rats and rabbits failed to docu-ment any teratogenic effects in some studies, but, at high dosages (yielding plasma levels 2-17 times achieved in humans with maxi-mum recommended dosages) in pregnant rats, rabbits and mon-keys, some effects (cleft palate, cardiovascular abnormalities, fetal growth retardation) were noted. Clarithromycin is excreted into milk of lactating animals and levels may be higher in milk than in the dam's plasma, but this is unlikely to be of clinical signiﬁcance. Overdosage/Acute Toxicity Generally, overdoses of clarithromycin are usually not serious with only gastrointestinal effects seen. Patients ingesting large overdoses may be given activated charcoal/cathartic to remove any unab-sorbed drug. Forced diuresis, peritoneal dialysis, or hemodialysis do not appear to be effective in removing the drug from the body. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clarithromycin and may be of signiﬁcance in veterinary patients: !TCISAPRIDE : Clarithromycin can inhibit the metabolism of cisap-ride and the manufacturer states that use of these drugs together (in humans) is contraindicated !TFLUCONAZOLE : Possible increased clarithromycin levels !TDIGOX IN: Clarithromycin may increase the serum levels of digoxin !TOMEPRAZOLE : Clarithromycin and omeprazole can increase the plasma levels of one another !TWARFARIN : Clarithromycin may potentiate the effects of oral an-ticoagulant drugs !TZIDOVUDINE : Clarithromycin may decrease serum concentrations of zidovudine Clarithromycin, like erythromycin, can inhibit the metabolism of other drugs that use the CYP3A subfamily of the cytochrome P450 enzyme system. Depending on the therapeutic index of the drug(s) involved, therapeutic drug monitoring and/or dosage reduction may be required if the drugs must be used together. These drugs include: !TALFENTANIL !TBROMOCRIPTINE !TBUSPIRONE !TCARBAMAZEPINE !TDISOPYRAMIDE (also risk of increased QT interval) !TMETHYLPREDNISOLONE !TMIDAZOLAM, ALPRAZOLAM, TRIAZOLAM !TQUINIDINE (also risk of increased QT interval) !TRIFABUTIN !TTACROLIMUS (systemic ) !TTHEOPHYLLINE Laboratory Considerations !TNo clarithromycin-related laboratory interactions noted. Doses !TDOGS: For treatment of severe or refractory cases of canine leproid granuloma syndrome: a) Using a combination of clarithromycin 15-25 mg/kg total daily dose PO given divided q8-12h; and rifampin 10-15 mg/kg PO once daily. Usually treatment should be continued for 4-8 weeks until lesions are at least substantially reduced in size and ideally have resolved completely. (Malik, Martin et al. 2001) For susceptible infections: a) 2. 5-10 mg/kg PO twice daily (Boothe 1999) b) 5-10 mg/kg PO q12h (Greene and Watson 1998) !TCATS: For treatment of feline leprosy: a) Using a regimen of either two or three of the following drugs: clarithromycin: 62. 5 mg per cat q12h; clofazimine: 25-50 mg once per day or 50 mg every other day; rifampin: 10-15 mg/kg once a day. (Malik, Hughes et al. 2002) For treatment of Nocardia (N. nova) infections: a) Combination therapy with: amoxicillin 20 mg/kg PO twice daily with clarithromycin 62. 5-125 mg (total dose per cat) PO twice daily and/or doxycycline 5 mg/kg or higher PO twice daily. (Malik 2006a) For treatment of H. pylori infections: a) Combination therapy with: clarithromycin 7. 5 mg/kg PO twice daily; metronidazole 10-15 mg/kg PO twice daily; amoxicillin 20 mg/kg PO twice daily for 14 days. (Simpson 2003b) For treatment of M. tuberculosis-bovis variant infections: a) Using all three drugs: Clarithromycin 5-10 mg/kg PO q12h; rifampin 10-20 mg/kg PO once daily, enroﬂoxacin 5-10 mg/kg PO q12-24h. Treatment must continue for at least 2 months. Maintenance for additional 4 months using (at same dosages enroﬂoxacin and clarithromycin or rifampin and enroﬂoxacin). (Greene and Gunn-Moore 1998) For susceptible infections: a) 7. 5 mg/kg PO q12h (Greene and Watson 1998)	pppbs.pdf
206 CLEMASTINE FUMARATE TT ! FERRETS: CLEMASTINE FUMARATE For treatment of Helicobacter mustelae infections: a) Clarithromycin 12. 5 mg/kg PO q8h with ranitidine bismuth (klem-as-teen) Tavist®citrate ( Note : not currently available in the USA) 24 mg/kg PO q8h. Mild to moderate antral gastritis may persist even if H. ANTIHISTAMINE mustelae eradicated. (Marini, Fox et al. 1999) b) 12. 5-50 mg/kg q8-24h with omeprazole at 0. 7 mg/kg PO Prescriber Highlights once daily (q24h) (Fisher 2005) TT Oral antihistamine with greater anticholinergic, but less T ! HORSES: sedative activity For treatment of Rhodococcus equi infection in foals: TT Poor pharmacokinetic proﬁle for oral administration ina) 7. 5 mg/kg PO q12h (Jacks, Giguere et al. 2002), (Chafﬁn dogs or horses2006b) TT Contraindications: Hypersensitivityb) 7. 5 mg/kg PO q12h in combination with rifampin at 5 mg/kg PO q12h or 10 mg/kg PO q24h. (Giguere 2003b) TT Caution: Prostatic hypertrophy, bladder neck obstruction, severe cardiac failure, angle-closure glaucoma, or pyelo-Monitoring duodenal obstruction T ! Antibacterial efﬁcacy TT Most likely adverse effects: DOGS: Sedation, paradoxical T ! Adverse effects hyperactivity & anticholinergic effects (dryness of mu-cous membranes, etc. ); CATS: Diarrhea Client Information T ! If using the oral suspension, do not refrigerate; keep at room tem-perature and discard 14 days after reconstituting Uses/Indications T ! his drug may be given without regard to meals Clemastine may be used for symptomatic relief of histamine 1-relat-T ! Clarithromycin can interact with many other drugs; do not give ed allergic conditions. any drugs to the animal without the veterinarian's knowledge Pharmacology/Actions Chemistry/Synonyms Like other H 1-receptor antihistamines, clemastine acts by compet-Clarithromycin is a semi-synthetic macrolide antibiotic related to ing with histamine for sites on H 1-receptor sites on effector cells. erythromycin. It differs from erythromycin by the methylation of They do not block histamine release, but can antagonize its effects. position 6 in the lactone ring. Clarithromycin occurs as a white Clemastine has greater anticholinergic activity, but less sedation to off-white crystalline powder. It is practically insoluble in water, than average. slightly soluble in ethanol, and soluble in acetone. It is slightly solu-ble in a phosphate buffer at p H's of 2-5. Pharmacokinetics Clarithromycin may also be known as: 6-O-Methylerythromycin, In dogs, oral bioavailability is very low (3%). Clemastine has a high TE-031, A-56268, Adel®, Biaxin®, Biclar®, Bremon®, Clamicin®, volume of distribution (13. 4 L/kg; 98% protein bound) and clear-Clamycin®, Claribid®, Clarimac®, Clarimax®, Claritab®, Cyllind®, ance (2. 1 L/hr/kg). After IV administration, elimination half-life is Gervaken®, Heliclar®, Helicodid®, Karin®, Klacid®, Klaciped®, about 4 hours and completely inhibited wheal formation for 7 hours. Klaricid®, Klaridex®, Kofron®, Lagur®, Mabicrol®, Macladin®, Oral administration at 0. 5 mg/kg only yielded minor inhibition of Maclar®, Mavid®, Monaxin®, Monocid®, Naxy®, Veclam®, and wheal formation. The authors of the study (Hansson, Bergvall et al. Zeclar®. 2004) concluded that most oral dosage regimens in the literature are likely to give too low a systemic exposure of the drug to allow Storage/Stability effective therapy. The conventional 250 mg tablets should be protected from light and In horses, clemastine has poor oral bioavailability (3-4%), a vol-stored in well-closed containers at 15-30°C (59-86°F). The con-ume of distribution at steady-state of 3. 8 L/kg, a clearance (TBC) ofventional or extended-release 500 mg tablets should be stored in 0. 79 L/hr/Kg and a terminal half-life of about 5. 4 hours. The authorswell-closed containers at controlled room temperature (20-25°C; concluded that the drug is not appropriate for oral administration68-77°F). The granules for reconstitution into an oral suspension in the horse and must be dosed at least 3-4 times a day intrave-should be stored in well-closed containers at 15-30°C. After recon-nously to maintain therapeutic plasma concentrations. (T orneke,stitution, it should be stored at room temperature (do not refriger-Ingvast-Larsson et al. 2003)ate) and any unused drug discarded after 14 days. In humans, clemastine has a variable bioavailability (20-70%); Dosage Forms/Regulatory Status its distribution is not well characterized, but does distribute into milk. Metabolic fate has not been clearly determined, but it appears VETERINARY-LABELED PRODUCTS: None to be extensively metabolized and those metabolites are eliminated HUMAN-LABELED PRODUCTS: in the urine. In humans, its duration of action is about 12 hours. Clarithromycin Film-coated Tablets: 250 mg & 500 mg; Extended-release Tablets: 500 mg & 1000 mg; Clarithromycin (T eva; Ranbaxy); Contraindications/Precautions/Warnings Biaxin® & Biaxin® XL (Abbott), generic; (Rx) Clemastine is contraindicated in patients hypersensitive to it. It should be used with caution in patients with prostatic hypertrophy, Clarithromycin Granules for Oral Suspension: 25 mg/m L, 50 mg/ bladder neck obstruction, severe cardiac failure, angle-closure glau-m L in 50 m L and 100 m L; Biaxin® (Abbott), generic; (Rx) coma, or pyeloduodenal obstruction. A pre-packaged combination containing lansoprazole, amoxicillin and clarithromycin for H. pylori is marketed as Prevpak ® (TAP); (Rx) Clavulanate/Amoxicillin — See Amoxicillin/Clavulanate Clavulanate/Ticarcillin — See Ticarcillin /Clavulanate	pppbs.pdf
CLENBUTEROL HCL 207 Adverse Effects The most likely adverse effects seen in dogs receiving clemastine are sedation, paradoxical hyperactivity, and anticholinergic effects (dryness of mucous membranes, etc. ). In cats, diarrhea has been noted most commonly; one cat reportedly developed a ﬁxed drug reaction while on this medication. Reproductive/Nursing Safety Clemastine has been tested in pregnant lab animals in doses up to 312 times labeled without evidence of harm to fetuses. However, be-cause safety has not been established in other species, its use during pregnancy should be weighed carefully. 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. ) Clemastine enters maternal milk and may potentially cause adverse effects in offspring. Use with caution, especially with newborns. Overdosage/Acute Toxicity There are no speciﬁc antidotes available. Signiﬁcant overdoses should be handled using standard gut emptying protocols, when appropriate, and supportive therapy initiated when required. The adverse effects seen with overdoses are an extension of the drug's side effects; principally CNS depression (although CNS stimula-tion may be seen), anticholinergic effects (severe drying of mucous membranes, tachycardia, urinary retention, hyperthermia, etc. ), and possibly hypotension. Physostigmine may be considered to treat serious CNS anticholinergic effects and diazepam employed to treat seizures, if necessary. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clemastine and may be of signiﬁcance in veterinary patients: T ! CNS DEPRESSANT MEDICATIONS : Additive CNS depression may be seen if combining clemastine with other CNS depressant medi-cations such as barbiturates, tranquilizers, etc. T ! MONOAMINE OXIDASE INHIBITORS (including furazolidone, amitraz, and possibly selegiline ) may intensify the anticholinergic effects of clemastine Laboratory Considerations Because antihistamines can decrease the wheal and ﬂair response to skin allergen testing, antihistamines should be discontinued 3-7 days (depending on the antihistamine used and the reference) be-fore intradermal skin tests. Doses T ! DOGS: Note : Recently published information (Hansson, Bergvall et al. 2004) on the pharmacokinetics of clemastine in dogs puts the efﬁ-cacy of previously published doses for this drug in doubt, but some veterinary dermatologists still recommend its use. Usual doses pub-lished are approximately 0. 05-0. 1 mg/kg PO q12h; however oral bioavailability (see Pharmacokinetics above) in dogs is less than 5% versus approximately 20-70% in humans, and an oral dose of 0. 5 mg/kg (10X most published doses) in dogs only inhibited histamine-induced wheal formation to a slight degree, while IV ad-ministration inhibited it for 7 hours. Further dosing studies must be performed before this drug can be recommended for therapeutic use in the dog. T ! CATS: As an antihistamine: a) 0. 68 mg per cat PO twice daily (Miller 2005a) b) 0. 34-0. 68 mg per cat PO q12h (Messinger 2000) c) For atopy: 0. 15 mg/kg PO q 12 hrs. Efﬁcacy may be increased by combining with omega 3 fatty acids. (Campbell 1999) Monitoring T ! Efﬁcacy T ! Adverse Effects, if any Client Information T ! Clients should understand that antihistamines may be useful for symptomatic relief of allergic signs, but are not a cure for the underlying disease. Chemistry/Synonyms Also known as meclastine fumarate or mecloprodin fumarate, cle-mastine fumarate is an ethanolamine antihistamine. It occurs as an odorless, faintly yellow, crystalline powder. It is very slightly soluble in water and sparingly soluble in alcohol. Tavist-D® contains clemastine fumarate in an immediate release outer shell and phenylpropanolamine HCl in a sustained release in-ner matrix. Clemastine fumarate may also be known by the following syn-onyms and internationally registered trade names: clemastini fu-maras, HS-592, meclastine fumarate, mecloprodine fumarate, Agasten®, Aller-Eze®, Antihist-1®, Clamist®, Contac 12 Hour Allergy®, Dayhist-1®, Tavegil®, Tave g y l ®or Tavist®. Storage/Stability Oral tablets and solution 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 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Clemastine Fumarate Tablets: 1. 34 mg (equivalent to 1 mg clemas-tine), 2. 68 mg (equivalent to 2 mg clemastine); Dayhist-1®(Major); Tavist® Allergy (Novartis Consumer Health); generic; (Rx & OTC) Clemastine Syrup: 0. 67 mg/5 m L (equivalent to 0. 5 mg/5m L clem-astine) in 120 m L; generic; (Rx) CLENBUTEROL HCL (klen-byoo-ter-ol) Ventipulmin® Prescriber Highlights TT Beta-2-adrenergic agonist used in horses as a bronchodi-lator in the management of airway obstruction TT Banned in food animals TT In pregnancy, antagonizes the effects of dinoprost (pros-taglandin F2alpha) & oxytocin & can diminish normal uterine contractility TT May cause tachycardia, muscle tremors, sweating, rest-lessness, & urticaria	pppbs.pdf
208 CLENBUTEROL HCL TUses/Indications Clenbuterol is approved for use in horses as a bronchodilator in the management of airway obstruction, such as recurrent airway ob-struction (RAO; formerly COPD). It has been used as a partitioning agent in food producing ani-mals, but its use for this purpose is banned in the USA as relay toxic-ity in humans has been documented. Pharmacology/Actions Like other beta-2 agonists, clenbuterol is believed to act by stimu-lating production of cyclic AMP through the activation of adenyl cyclase. By deﬁnition, beta-2 agonists have more smooth muscle re-laxation activity (bronchial, vascular, and uterine smooth muscle) versus its cardiac effects (beta-1). Clenbuterol appears to have sec-ondary modes of action in horses as it can inhibit the release from macrophages of pro-inﬂammatory cytokines such as interleukin-1(beta) and tumor necrosis factor (alpha), and increase ciliary beat frequency to enhance mucous clearance. Pharmacokinetics After oral administration to horses, peak plasma levels of clenbuterol occur 2 hours after administration and the average half-life is about 10-13 hours. The manufacturer states that the duration of effect varies from 6-8 hours. After multiple oral doses, the drug's volume of distribution is approximately 1. 6 L/kg and clearance was 94 m L/ kg/hr. Urinary concentrations of clenbuterol are approximately 100X those found in plasma and can persist at quantiﬁable levels for 288 hours (12 days) in urine after the last oral dose (Soma, Uboh et al. 2004). Contraindications/Precautions/Warnings The drug is contraindicated in food producing animals (legal rami-ﬁcations). The label states that the drug should not be used in horses suspected of having cardiovascular impairment as tachycardia may occur. Adverse Effects Muscle tremors, sweating, restlessness, urticaria, and tachycardia may be noted, particularly early in the course of therapy. Creatine kinase elevations have been noted in some horses and, rarely, ataxia can oc-cur. Clenbuterol is reported to induce abortion in pregnant animals. Clenbuterol has been touted in some body building circles as an alternative to anabolic steroids for muscle development and body fat reduction; however, its safe use for this purpose is in serious ques-tion. Be alert for scams to divert legitimately obtained clenbuterol for this purpose. Reproductive/Nursing Safety Clenbuterol's safety in breeding stallions and brood mares has not been established. Clenbuterol should not be used in pregnant mares near full-term as it antagonizes the effects of dinoprost (prosta-glandin F2alpha) and oxytocin and can diminish normal uterine contractility. Overdosage/Acute Toxicity Some case reports of clenbuterol overdoses have been reported in various species. In recent years, clenbuterol has been used as an adulterant in illicit heroin. Depending on dosage and species, emp-tying gut may be appropriate, otherwise supportive therapy and ad-ministration of parenteral beta-blockers to control heart rate and rhythm and elevated blood pressure may be considered. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clenbuterol and may be of signiﬁcance in veterinary patients: !TANESTHETICS, INHALANT : Use with inhalation anesthetics (e. g., ha-lothane, isoﬂurane, methoxyﬂurane ), may predispose the patient to ventricular arrhythmias, particularly in patients with preexisting cardiac disease—use cautiously !TBETA-BLOCKERS (e. g., propranolol ): May antagonize clenbuterol's ef-fects !TDIGOXIN : Use with digitalis glycosides may increase the risk of car-diac arrhythmias !TDINOPROST : Clenbuterol may antagonize the effects of dinoprost (prostaglandin F2alpha) !TOXYTOCIN : Clenbuterol may antagonize the effects of oxytocin !TSYMPATHOMIMETIC AMINES, OTHER (e. g., terbutaline, albuterol ): Con-comitant administration with other sympathomimetic amines) may enhance the adverse effects of clenbuterol !TTRICYCLIC ANTIDEPRESSANTS or MONOAMINE OXIDASE INHIBITORS : May potentiate the vascular effects of clenbuterol Doses !THORSES: (Note: ARCI UCGFS Class 3 Drug) As a bronchodilator: a) Initially, 0. 8 micrograms/kg (practically: 0. 5 m L of the com-mercially available syrup/100 lb. BW) twice daily for 3 days; if no improvement increase to 1. 6 micrograms/kg (practically: 1 m L of the commercially available syrup/100 lb. BW) twice daily for 3 days; if no improvement increase to 2. 4 micro-grams/kg (practically: 1. 5 m L of the commercially available syrup/100 lb. BW) twice daily for 3 days; if no improvement increase to 3. 2 micrograms/kg (practically: 2 m L of the com-mercially available syrup/100 lb. BW) twice daily for 3 days; if no improvement discontinue therapy. Recommended du-ration of therapy is 30 days; then withdraw therapy and re-evaluate. If signs return, reinitiate therapy as above. (Package Insert; Ventipulmin®) Monitoring !TClinical efﬁcacy !TAdverse effects (primarily cardiac rate) Client Information !TClients should be instructed on the restricted use requirements of this medication and to keep it secure from children or those who may “abuse” it. !The drug may be prohibited from use by various equine associa-tions (e. g., racing or show). Chemistry/Synonyms A beta-2-adrenergic agonist, clenbuterol HCl's chemical name is 1-(4-Amino-3,5-dichlorophenyl)-2-tert-butyl aminoethanol HCl. Clenbuterol HCl may also be known as: NAB-365, Aeropulmin®, Broncodil®, Broncoterol®, Bronq-C®, Cesbron®, Clembumar®, Clenasma®, Clenbutol®, Contrasmina®, Contraspasmin®, Monores®, Novegam®, Oxibron®, Oxyﬂux®, Prontovent®, Spiropent®, Ventilan®, Ventipulmin® or Ventolase®. Storage/Stability The commercially available syrup is colorless and should be stored at room temperature (avoid freezing). The manufacturer warns to replace the safety cap on the bottle when not in use. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Clenbuterol HCl Oral Syrup: 72. 5 mcg/m L in 100 m L, 330 m L, 460 m L bottles; Ventipulmin® Syrup (Boehringer Ingelheim); Aeropul-min® Syrup (Butler, Phoenix); (Rx). Approved for use in horses not intended for use as food.	pppbs.pdf
CLINDAMYCIN 209 Extra-label clenbuterol use in food animals is prohibited by federal (USA) law. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None CLINDAMYCIN HCL CLINDAMYCIN PA LMITATE HCL CLINDAMYCIN PHOSPHATE (klin-da-mye-sin) Antirobe®, Cleocin® LINCOSAMIDE ANTIBIOTIC Prescriber Highlights TT Lincosamide antibiotic, broad spectrum against many anaerobes, gram-positive aerobic cocci, Toxoplasma, etc. TT Contraindications: Horses, rodents, ruminants, lago-morphs; patients hypersensitive to lincosamides TT Caution: Liver or renal dysfunction; consider reducing dosage if severe TT Adverse Effects: gastroenteritis, esophageal injuries pos-sible if “dry pilled”, pain at injection site if given IM Uses/Indications Clindamycin products are approved for use in dogs and cats. The labeled indications for dogs include wounds, abscesses and osteo-myelitis caused by Staphylococcus aureus. Be cause clindamycin has excellent activity against most pathogenic anaerobic organisms, it is also used extensively for those infections. Clindamycin is used for a variety of protozoal infections, including toxoplasmosis. For fur-ther information, refer to the Dosage or Pharmacology 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 susceptible include: Corynebacterium diphtheriae, Nocardia asteroides, Erysepelothrix, T oxoplasma, and Mycoplasma spp. Anaerobic bacteria that are generally susceptible to the lincosamides include: Clostridium perfringens, C. tetani (not C. difﬁcile), Bacteroides (including many strains of B. fragilis), Fusobacterium, Peptostreptococcus, Actinomyces, and Peptococcus. Pharmacokinetics In dogs, oral bioavailability is about 73%, elimination half-life is reportedly 2-5 hours after oral administration and 10-13 hours after subcutaneous administration. Volume of distribution is about 0. 9 L/kg. In humans, the drug is rapidly absorbed from the gut and about 90% of the total dose is absorbed. Food decreases the rate of ab-sorption, but not the extent. Peak serum levels are attained about 45-60 minutes after oral dosing. IM administration gives peak lev-els about 1-3 hours post injection. Clindamycin is distributed into most tissues. Therapeutic levels are achieved in bone, synovial ﬂuid, bile, pleural ﬂuid, peritoneal ﬂuid, skin, and heart muscle. Clindamycin also penetrates well into abscesses and white blood cells. CNS levels may reach 40% of those in the serum if meninges are inﬂamed. Clindamycin is about 93% bound to plasma proteins. The drug crosses the placenta and can be distributed into milk at concentrations equal to those in plasma. Clindamycin is partially metabolized in the liver to both active and inactive metabolites. Unchanged drug and metabolites are ex-creted in the urine, feces, and bile. Half-lives can be prolonged in patients with severe renal or hepatic dysfunction. Contraindications/Precautions/Warnings Although there have been case reports of parenteral administration of lincosamides to horses, cattle, and sheep, the lincosamides are considered to be contraindicated for use in rabbits, hamsters, chin-chillas, guinea pigs, horses, and ruminants because of serious gas-trointestinal effects that may occur, including death. Clindamycin is contraindicated in patients with known hypersensitivity to it or lincomycin. Patients with very severe renal and/or hepatic disease should re-ceive the drug with caution and the manufacturer suggests moni-toring serum clindamycin levels during high-dose therapy; consider dosage reduction. Clindamycin use is generally avoided in neonatal small animals. Adverse Effects Adverse effects after oral administration reported in dogs and cats include gastroenteritis (emesis, loose stools, and infrequently bloody diarrhea in dogs). There have been case reports of esopha-geal injuries (esophagitis, strictures) occurring in cats when solid dosage forms were given without food or a water bolus. Cats may occasional show hypersalivation or lip smacking after oral adminis-tration. IM injections reportedly cause pain at the injection site. C. difﬁcile-associated pseudomembranous colitis has been re-ported in some species, but does not appear to be a signiﬁcant risk when clindamycin is used in dogs or cats. Reproductive/Nursing Safety Clindamycin crosses the placenta, and cord blood concentrations are approximately 46% 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 trimesters. ) In a separate sys-tem 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 clindamycin is distributed into milk, nursing puppies or kittens of mothers receiving clindamycin may develop diarrhea. However, in humans, the American Academy of Pediatrics consid-ers clindamycin compatible with breastfeeding.	pppbs.pdf
210 CLINDAMYCIN 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 did not result in toxicity. Dogs receiving 600 mg/kg/day, developed anorexia, vomiting, and weight loss. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clindamycin and may be of signiﬁcance in veterinary patients: !TCYCLOSPORINE : Clindamycin may reduce levels !TERYTHROMYCIN : in vitro antagonism when used with clindamycin; concomitant use should probably be avoided !TNEUROMUSCULAR BLOCKING AGENTS (e. g., pancuronium ): Clindamycin 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 associated with these increases. Doses !TDOGS: For susceptible bacterial infections: a) For infected wounds, abscesses and dental infections: 5. 5-33 mg/kg PO q12h; for osteomyelitis: 11-33 mg/kg PO q12h. Treatment may continue for up to 28 days. If no response after 3-4 days, discontinue. (Package insert; Antirobe®—Pﬁzer) b) For staphylococcal pyoderma: 11 mg/kg PO once daily for 7-28 days For wounds, abscesses, dental infections, stomatitis: 5-11 mg/kg PO q12h for 7-28 days. For osteomyelitis: 11 mg/kg PO q12h for 28 days For systemic, bacteremia: 3-10 mg/kg IV, IM SC, PO q8h as long as needed (Greene and Watson 1998) c) 5-11 mg/kg IM, SC or PO q12h avoid or reduce dose in pa-tients with severe liver failure (Vaden and Papich 1995) d) For sepsis: 11 mg/kg IV q12h (Hardie 2000) e) For recurrent superﬁcial pyodermas: 11 mg/kg PO once daily to twice a day; resistance can develop quickly (Logas 2005b) f) For actinomycosis: 5 mg/kg SC q12h (Edwards 2006) g) For susceptible hepatobiliary infections: 10-16 mg/kg SC once daily or 5-10 mg/kg PO q12h. In patients with liver function impairment: 5 mg/kg PO q12h or SC q24h (Center 2006b) h) For anaerobic infections: 5-10 mg/kg PO, IV q12h (Greene and Jang 2006a) i) For intra-abdominal sepsis 5-11 mg/kg IV, SC, PO q8-12h for 5-7 days combined with gentamicin or a parenteral 3rd gen-eration cephalosporin (such as cefotaxime) or enroﬂoxacin. For pancreatitis: 5-11 mg/kg IV, SC, PO q8-12h for 3-5 days. (Greene 2006) j) For susceptible respiratory infections: 10 mg/kg PO, SC q12h (Greene and Reinero 2006) k) For surgical prophylaxis for gram-positive aerobes and anaer-obic coverage: 5-11 mg/kg PO 16-60 minutes preoperatively (Greene and Jang 2006b) For susceptible protozoal infections: a) For T oxoplasmosis: 12. 5 mg/kg PO or IM q12h for 28 days For Neospora: 10 mg/kg q12h for 4 weeks. Used concurrently with trimethoprim/sulfa (15 mg/kg PO q12h for 4 weeks) For Hepatozoon canis: 10 mg/kg PO q8h for 2-4 weeks. Use concurrently with pyrimethamine (0. 25 mg/kg PO once daily for 2-4 weeks) and trimethoprim/sulfa (15 mg/kg PO q12h for 2-4 weeks) For Babesia spp. : 12. 5 mg/kg q12h PO for 2 weeks (Lappin 2000) c) For Babesia infections if speciﬁc antibabesial drugs (e. g., di-minazene, imidocarb, pentamidine) are not available: 25 mg/ kg PO q12h for 7-21 days (Taboada and Lobetti 2006) d) For Hepatozoon americanum infections: 10 mg/kg PO q8h for 14 days. Use concurrently with trimethoprim/sulfa (15 mg/kg PO q12h 14 days) and pyrimethamine (0. 25 mg/kg PO once daily for 14 days) and then follow with decoquinate (for 2 years) once clinical signs have resolved. (Macintire, Vincent-Johnson et al. 2006) !TCATS: For susceptible bacterial infections: a) 5-10 mg/kg PO q12h (Jenkins 1987b); (Trepanier 1999) b) For infected wounds, abscesses and dental infections: 11-33 mg/kg PO once a day (q24h). Do not treat acute infections for more than 3-4 days if no clinical response is seen. Maxi-mum labeled treatment period = 14 days (Package insert; Antirobe®—Pﬁzer) c) For sepsis: 11 mg/kg IV q12h (Hardie 2000) d) For anaerobic infections: 5-10 mg/kg PO, IV q12h (Greene and Jang 2006a) e) For intra-abdominal sepsis 5-11 mg/kg IV,SC,PO q8-12h for 5-7 days combined with gentamicin or a parenteral 3rd gen-eration cephalosporin (such as cefotaxime) or enroﬂoxacin. For pancreatitis: 5-11 mg/kg IV, SC, PO q8-12h for 3-5 days. (Greene 2006) f) For susceptible respiratory infections: 10-15 mg/kg PO, SC q12h (Greene and Reinero 2006) g) For surgical prophylaxis for gram-positive aerobes and anaer-obic coverage: 5-11 mg/kg PO 16-60 minutes preoperatively (Greene and Jang 2006b) For susceptible protozoal infections: a) T oxoplasmosis: T o decrease zoonotic risk to susceptible humans by reducing shedding period in cats suspected of toxoplasmosis after fe-cal exam: 25-50 mg/kg PO daily; alternative medications in-clude sulfonamides at 100 mg/kg PO daily, or pyrimethamine at 2 mg/kg daily PO. For treatment of clinical toxoplasmosis: Clindamycin at 10 mg/kg PO q12h, trimethoprim-sulfonamide combination at 15 mg/kg PO q12h, and azithromycin at 10 mg/kg once daily for at least 28 days. Institute supportive care as needed. Pa-tients with uveitis should receive topical, oral or parenteral glucocorticoids to reduce risk for secondary glaucoma and lens luxations. (Lappin 2004) b) For enteroepithelial toxoplasmosis: 8-16 mg/kg PO or SC q8h for 14-28 days. For systemic toxoplasmosis: 12. 5-25 mg/kg PO or SC q12h for 14-28 days (Greene and Watson 1998)	pppbs.pdf
CLINDAMYCIN 211 !TFERRETS: For susceptible infections: a) 5-10 mg/kg PO twice daily (Williams 2000) !TBIRDS: For susceptible infections: a) 25 mg/kg PO q8h (Tully 2002) b) For mild spore-forming enteric bacterial infections: 50 mg/ kg PO q12h for 5-10 days (Flammer 2006) !TREPTILES: For susceptible infections (anaerobes): a) 5 mg/kg PO once daily (Lewbart 2001) b) For respiratory infections (anaerobes, mycoplasma): 5 mg/kg PO once daily for 14 days (Klaphake 2005b) Monitoring !TClinical efﬁcacy !TAdverse effects; particularly severe diarrhea !TManufacturer recommends doing periodic liver and kidney function tests and blood counts if therapy persists for more than 30 days Client Information !TClients should be instructed to report the incidence of severe, protracted, or bloody diarrhea to the veterinarian !TIf using oral tablets or capsules, especially in cats, give medica-tion followed by at least 6 m L (a little more than a teaspoonful) of liquid Chemistry/Synonyms A semisynthetic derivative of lincomycin, clindamycin is available as the hydrochloride hydrate, phosphate ester, and palmitate hydro-chloride. Potency of all three salts is expressed as milligrams of clin-damycin. The hydrochloride occurs as a white to practically white, crystalline powder. The phosphate occurs as a white to off-white, hygroscopic crystalline powder. The palmitate HCl occurs as a white to off-white amorphous powder. All may have a faint characteristic odor and are freely soluble in water. With the phosphate, about 400 mg are soluble in one m L of water. Clindamycin has a p K a of 7. 45. The commercially available injection has a p H of 5. 5-7. Clindamycin HCl may also be known as: chlorodeoxylincomy-cin hydrochloride, (7S)-chloro-7-deoxy-lincomycin hydrochloride, clindamycini hydrochloridum, U-28508, or U-25179E; many trade names are available. Storage/Stability/Compatibility Clindamycin capsules and the palmitate powder for oral solution should be stored at room temperature (15-30°C). After reconstitu-tion, the palmitate oral solution (human-product) should not be refrigerated or thickening may occur. It is stable for 2 weeks at room temperature. The veterinary oral solution should be stored at room temperature and has an extended shelf life. Clindamycin phosphate injection should be stored at room tem-perature. If refrigerated or frozen, crystals may form which resol-ubolize upon warming. Clindamycin for injection is reportedly compatible for at least 24 hours in the following IV infusion solutions: D 5W, Dextrose com-binations with Ringer's, lactated Ringer's, sodium chloride, D 10W, sodium chloride 0. 9%, Ringer's injection, and lactated Ringer's in-jection. Clindamycin for injection is reportedly compatible with the following drugs: amikacin sulfate, ampicillin sodium, aztreonam, carbenicillin disodium, cefazolin sodium, cefonicid sodium, cefop-erazone sodium, cefotaxime sodium, ceftazidime sodium, ceftizoxi-me sodium, cefuroxime sodium, cimetidine HCl, gentamicin sul-fate, heparin sodium, hydrocortisone sodium succinate, kanamycin sulfate, methylprednisolone sodium succinate, magnesium sulfate, meperidine HCl, metoclopramide HCl, metronidazole, morphine sulfate, penicillin G potassium/sodium, piperacillin sodium, potas-sium chloride, sodium bicarbonate, tobramycin HCl (not in syring-es), verapamil HCl, and vitamin B-complex with C. Drugs that are reportedly incompatible with clindamycin include: aminophylline, ciproﬂoxacin, ranitidine HCl, and ceftriaxone so-dium. Compatibility is dependent upon factors such as p H, con-centration, temperature, and diluent used; consult specialized ref-erences or a hospital pharmacist for more speciﬁc information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Clindamycin (as the HCl) Oral Capsules: 25 mg, 75 mg, 150 mg, 300 mg; Antirobe® Capsules (Pﬁzer) Approved for use in dogs and cats). Also available in 25 mg, 75 mg, 150 mg, and 300 mg capsules as Amtech® Clindamycin HCl Capsules (IVX), Clincaps® (Butler), Clindamycin Hydrochloride Capsules (Phoenix), Clindacure® Cap-sules (no 300 mg caps—Vedco); (Rx). Approved for use in dogs. Clindamycin (as the HCl) Oral Tablets: 25 mg, 75 mg, 150 mg; Clintabs® (Virbac). Approved for use in dogs. Clindamycin (as the HCl) Oral Solution 25 mg/m L in 30 m L bottles. Amtech® Clindamycin Hydrochloride Oral Liquid (Butler, IVX), An-tirobe® Aquadrops (Pﬁzer), Clindacure® (Vedco), Clindrops® (But-ler), Clindamycin Hydrochloride Drops (Phoenix Pharmaceutical), Clinda-Guard®(RXV), Clinsol® (Virbac); (Rx). Approved for use in cats (not Clinda-Guard® or Clindacure®) and dogs. HUMAN-LABELED PRODUCTS: Clindamycin (as the HCl) Capsules: 75 mg, 150 mg, & 300 mg; Cleocin® (Upjohn); generic; (Rx) Clindamycin (as the palmitate HCl) Granules for Oral Solution: 75 mg/5 m L (15 mg/m L) in 100 m L; Cleocin® Pediatric (Upjohn); (Rx) Clindamycin (as the Phosphate) Injection: 150 mg/m L in 2 m L, 4 m L, 6 m L, 60 m L and 100 m L vials; 2 m L, 4 m L and 6 m L ADD-Vantage vials, 50 m L Galaxy containers and 60 m L bulk packages; Cleocin® Phosphate (Upjohn); (Rx); generic; (Rx) Clindamycin Phosphate Suppositories: 100 mg (as base) Cleocin® (Pﬁzer); (Rx) Also available in topical and vaginal preparations.	pppbs.pdf
212 CLOFAZIMINE CLOFAZIMINE (kloe-fa-zi-meen) Lamprene® ANTIMYCOBACTERIAL ANTIBIOTIC Prescriber Highlights TT May be difﬁcult for veterinarians to obtain & accurately dose TT Antimycobacterial antibiotic that may be used as part of multi-drug therapy for leprosy-like or M. avium-related diseases in small animals TT Very limited clinical experience & documentation sup-porting its use in veterinary patients TT Skin, eye, excretion staining noted & dose limiting gastro-intestinal adverse effects TT Treatment usually must continue for weeks to months Uses/Indications In small animals, clofazimine is sometimes used as part of multi-drug therapy against mycobacterial diseases, primarily leprosy-like or M. avium-related disease states. In humans, clofazimine is used primarily as part of a multi-drug regimen in the treatment of all forms of leprosy (with rifampin and dapsone), or the treatment of Mycobacterium avium complex (MAC) (with at least two of the following agents: clarithromycin or azithromycin, rifampin or rifabutin, and ethambutol). It has also been used in some treatment regimens for Crohn's disease, pyoder-ma gangrenosum, etc. Pharmacology/Actions Clofazimine binds to mycobacterial DNA and inhibits growth. It is considered to be slowly bactericidal against susceptible organisms. Clofazimine has activity against a variety of mycobacteria includ-ing: M. leprae, M. tuberculosis, M. avium complex (MAC), M. bovis, and M. chelonei. Resistance is thought to occur only rarely; cross-resistance with dapsone or rifampin apparently does not occur. Clofazimine may have some antileishmanial activity. Clofazimine has antiinﬂammatory and immunosuppressive effects, but the mechanisms of action for these effects are not understood. Pharmacokinetics Clofazimine's pharmacokinetics have apparently not been deter-mined in domestic animals. In humans, the microcrystalline form of the drug is variably absorbed after oral administration; bioavail-ability ranges from 45-70%. Food enhances absorption but increas-ing the dosage decreases the percentage absorbed. Clofazimine is highly lipid soluble and is distributed primarily to lipid tissue and the reticuloendothelial system. Throughout the body macrophages take up clofazimine. The drug crosses the placenta and is distrib-uted into milk, but does not apparently cross into the CNS or CSF. Clofazimine is retained in the body for a long period; its elimination half-life is at least 70 days long. Bile excretion may be responsible for the majority of the drug's excretion, but excretion in sputum, sebum, and sweat may also contribute. Contraindications/Precautions/Warnings It is suggested that clofazimine be used with caution in patients with pre-existing gastrointestinal conditions such as diarrhea or abdomi-nal pain. Adverse Effects There is very limited clinical experience with this medication in do-mestic animals and its adverse effect proﬁle is not well documented. Apparently, the skin, eye, and excretion discoloration (described below) also occurs in animals. One case of a dog receiving clofaz-imine and rifampin to treat canine leproid granuloma resulted in hepatotoxicity. In humans, clofazimine is usually well tolerated, particularly at dosages of 100 mg/day or less. The most troubling adverse effect in many patients is the dose-related skin, eye, and body ﬂuid discolor-ation (pink to brownish-black) that occurs in most patients, as it may cause severe psychosocial effects; other drug regimens, not including clofazimine, are often chosen in patients with light skin color. This discoloration can persist for months to years after clofazimine has been discontinued. In dosages greater than 100 mg/day, gastrointes-tinal effects (pain, nausea, vomiting, diarrhea) become more likely and often limit the dosage that can be administered. Other adverse effects (CNS, increased liver enzymes, etc. ) are reported in less than 1% of patients receiving the drug. Reproductive/Nursing Safety In humans, the FDA categorizes clofazimine as a category C drug for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). Very large doses (12-25X) demonstrated no teratogenic effects in rats or rabbits, but some effects were noted in mice. The World Health Organization (WHO) states that the drug is safe to use during pregnancy when used as part of one of their treatment protocols for leprosy. Clofazimine does enter maternal milk and skin discoloration of nursing offspring can occur. Overdosage/Acute Toxicity Very limited data is available; the LD50 for rabbits is 3. 3 g/kg and is greater than 5 g/kg in mice, rats, and guinea pigs. Treatment, if required, would include gut emptying and supportive care. Contact an animal poison control center for additional guidance. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clofazimine and may be of signiﬁcance in veterinary patients: T ! ISONIAZID : May reduce the clofazimine levels in the skin and in-crease the amounts in plasma and urine; clinical signiﬁcance unclear T ! DAPSONE : There is sketchy evidence that suggests dapsone may re-duce the antiinﬂammatory effects of clofazimine; clinical signiﬁ-cance unclear Laboratory Considerations T ! No clofazimine-related laboratory interactions noted Doses T ! DOGS: For Mycobacterium avium complex (MAC) as part of a multi-drug regimen: a) 4 mg/kg PO once daily. Other drugs that may be used in com-bination include doxycycline, clarithromycin, and/or enro-ﬂoxacin. (Greene and Gunn-Moore 1998) For M. avium intracellularae complex infections, leprosy, or op-portunistic mycobacteriosis: a) 4-8 mg/kg PO once a day for 4 weeks usually as part of a multi-drug protocol. (Greene and Watson 1998)	pppbs.pdf
CLOMIPRAMINE HCL 213 TT ! CATS: For treatment of feline leprosy: a) Using a regimen of either two or three of the following drugs: clarithromycin: 62. 5 mg per cat q12h, clofazimine: 25-50 mg once per day or 50 mg every other day, Rifampin: 10-15 mg/kg once a day. (Malik, Hughes et al. 2002) For treatment of localized atypical mycobacterial infections: a) Perform wide surgical excision of lesion if possible. Give long-term systemic antibacterial therapy, continued at least 4 weeks beyond complete clinical resolution. Base antibi-otic selection on culture and susceptibility results, if avail-able: Clofazimine 8 mg/kg PO once daily. Other doses listed in reference for marboﬂoxacin, doxycycline, minocycline, or clarithromycin. (Hnilica 2003a) For M. avium intracellularae complex infections, leprosy or op-portunistic mycobacteriosis: a) 4-8 mg/kg PO once a day for 4 weeks usually as part of a multi-drug protocol. (Greene and Watson 1998) Monitoring T ! Efﬁcacy against mycobacterial disease T ! Adverse effects (primarily GI, but consider monitoring hepatic function in dogs) Client Information T ! Unless otherwise instructed give this medication with food T ! his medication may cause your animal's skin to turn color (usu-ally pink, but from red to orange to brown). It may also cause dis-coloring of tears, urine, feces, and other body ﬂuids to a brown-ish-black color. This discoloration may persist for many months after therapy is concluded. Chemistry/Synonyms Clofazimine, a phenazine dye antimycobacterial agent, occurs as an odorless or nearly odorless, reddish-brown powder that is highly insoluble in water. In room temperature alcohol, clofazimine's solu-bility is 1 mg/m L. Clofazimine may also be known as:B-663,G-30320,NSC-141046, Chlofazimine, Clofozine®, Hansepran®, Lamcoin®, Lamprene®, or Lampren®. Storage/Stability/Compatibility Clofazimine oral capsules should be stored in tight containers, pro-tected from moisture at temperatures less than 30°C. The commer-cially available capsules are a micronized form of the drug in a wax matrix base; it may be difﬁcult to obtain an accurate dosage for small animals. It is suggested to contact a compounding pharmacist for advice. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: None In November 2004, clofazimine (Lamprene®) became available in the USA only on a limited basis. The FDA now restricts its use to physicians enrolled as investigators under an Investigational New Drug (IND) for treating Hansen's Disease (Leprosy) or multi-drug resistant tuberculosis. Its status for use in veterinary patients is un-certain at the time of writing; contact the FDA Center for Veteri-nary Medicine (see appendix) for more information. CLOMIPRAMINE HCL (kloe-mi-pra-meen) Clomicalm®, Anafranil® TRICYCLIC ANTIDEPRESSANT Prescriber Highlights TT Tricyclic antidepressant used in dogs & cats for obsessive compulsive disorders, but may be useful for other behav-ior disorders TT Contraindications: Hypersensitivity to clomipramine or other tricyclics TT Caution: Seizure disorders, liver disease, cardiac rate/ rhythm disorders, urinary retention or reduced GI motility TT Not a teratogen, but may affect testicular size/function TT Adverse Effects: Emesis, diarrhea, sedation, anticholin-ergic effects (dry mouth, tachycardia, etc. ); cats may be more sensitive than dogs Uses/Indications In veterinary medicine, clomipramine is used primarily in dogs as a treatment for obsessive-compulsive disorders (ritualistic stereo-typical behaviors) and may be useful for dominance aggression and anxiety (separation). Clomipramine may also be useful in cats, particularly for be-haviors such as urine spraying. One prospective, double-blinded controlled study in cats with psychogenic alopecia comparing clo-mipramine (0. 5 mg/kg PO daily) versus placebo showed no statistic differences in study parameters (Mertens, T orres et al. 2006). Pharmacology/Actions While the exact mechanism of action of tricyclic antidepressants is not completely understood, it is believed that their most signiﬁcant effects result from their action in preventing the reuptake of norepi-nephrine and serotonin at the neuronal membrane. Clomipramine is apparently a selective inhibitor of serotonin (5-HT) reuptake. Clomipramine has an active metabolite, desmethylclomipramine which has primarily noradrenergic activity and, at least in humans, may be responsible for the majority of the drug's adverse effects. Pharmacokinetics In dogs, after absorption, clomipramine is rapidly converted in the liver to its active metabolite desmethylclomipramine. Both the parent drug and the active metabolite are highly bound to plasma proteins (96%). Repeated oral dosing increases clomipramine con-centrations but not desmethylclomipramine. The presence of food decreases the area under the curve for the parent compound by about 25% but not the metabolite. Giving without food probably is not necessary for efﬁcacy. After a single dose in dogs, the elimina-tion half-life of clomipramine averages 5 hours. In cats, wide interpatient variability in pharmacokinetic param-eters have been shown after single oral doses; there may be inher-ent differences in pharmacokinetic parameters between male and female cats. In a limited (6 subject) pharmacokinetic study, oral bioavailability averaged 90%. In humans, the drug is well absorbed from the GI tract but a substantial ﬁrst pass effect reduces its systemic bioavailability to ap-proximately 50%. The presence of food in the gut apparently does not signiﬁcantly alter its absorption. Clomipramine is highly lipophilic and widely distributed throughout the body with an apparent volume of distribution of 17 L/kg. The drug crosses the placenta and into maternal milk. Plasma	pppbs.pdf
214 CLOMIPRAMINE HCL levels have been detected in nursing babies of mothers taking the drug. Both clomipramine and its active metabolite (desmethylclo-mipramine) cross the blood-brain barrier and signiﬁcant levels are found in the brain. It should be noted that although therapeutic ef-fects may take several weeks to be seen, adverse effects can occur early on in treatment. Clomipramine is metabolized principally in the liver to several metabolites including desmethylclomipramine, which is active. About two-thirds of these metabolites are eliminated in the urine and the rest in the feces. After a single dose, the elimination half-life of clomipramine averages 32 hours and desmethylclomipramine av-erages 69 hours, but there remains wide interpatient variation. Contraindications/Precautions/Warnings These agents are contraindicated if prior sensitivity has been noted with any other tricyclic. Concomitant use with monoamine oxi-dase inhibitors is generally contraindicated. As aged cheeses can contain high levels of tyramine, avoid giving to animals receiving clomipramine. In humans, these drugs (tricyclic antidepressants) may lower sei-zure threshold. Use with caution in animals with preexisting seizure disorders. Because of their anticholinergic effects, use with caution in patients with decreased GI motility, urinary retention, cardiac rhythm disturbances, or increased in traocular pressure. One study in dogs however, showed little effect on intra-ocular pressure or cardiac rhythm. In humans, tricyclic antidepressants have caused hepatic abnormalities. Baseline and annual monitoring of liver enzymes is suggested for animals receiving clomipramine long-term. Tri cyclics should be used cautiously in patients with hyperthyroidism or those that are receiving thyroid supplementation as there may be an in-creased risk of cardiac rhythm abnormalities developing. Adverse Effects The primary adverse effects reported thus far with the use of clo-mipramine in dogs are anorexia, emesis, diarrhea, elevation of liver enzymes, and sedation/lethargy/depression. At therapeutic dosages dogs rarely develop anticholinergic (dry mouth, etc. ) effects. Cardiac effects such as tachycardia secondary to the drugs anticholinergic activity may also result. Cats have been reported to be more susceptible to the adverse ef-fects (anticholinergic effects, sedation) of clomipramine than dogs. This may be the result of slower elimination of the desmethyl me-tabolite in cats. Reproductive/Nursing Safety No teratogenic effects were noted in mice and rats given clomip-ramine at dosages of up 20X usual maximum human dosage. Data in other domestic species appear to be lacking. The manufacturer warns not to use in breeding male dogs as high dose (12. 5X) toxicity studies demonstrated testicular atrophy. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity Clomipramine has a narrow margin of safety; signiﬁcant clinical signs can be seen at or slightly above therapeutic range (at 2-3 mg/ kg, APCC database). Overdosage with tricyclics can be life-threat-ening (arrhythmias, seizures, cardiorespiratory collapse). In dogs, lethal doses are approximately between 50 and 100 mg/kg/day PO (12. 5-25X recommended dose). There were 99 exposures to clomipramine reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org) during 2005-2006. In these cases 69 were dogs with 12 showing clinical signs and the remaining 30 cases were cats with 6 showing clinical signs. Common ﬁndings in dogs recorded in decreasing frequency included lethargy, tachycardia, agitation, bounding pulse and de-pression. Common ﬁndings in cats recorded in decreasing frequen-cy included mydriasis, bradycardia, disorientation, hypothermia and lethargy. Because the toxicities and therapies for treatment are compli-cated and controversial, contact an animal poison control center for further information in any potential overdose situation. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clomipramine and may be of signiﬁcance in veterinary patients: !TANTICHOLINERGIC AGENTS : Because of additive effects, use with clo-mipramine cautiously !TCIMETIDINE : May inhibit tricyclic antidepressant metabolism and increase the risk of toxicity !TCISAPRIDE : Increased risk for prolonged QT interval !TCLONIDINE : May cause increased blood pressure !TCNS DEPRESSANTS : Because of additive effects, use with clomip-ramine cautiously !TMEPERIDINE, PENTAZOCINE, DEXTROMETHORPHAN : Increased risk for serotonin syndrome !TRIFAMPIN : May decrease tricyclic blood levels !TSSRIs (e. g., ﬂuoxetine, paroxetine, sertraline, etc. ): Increased risk for serotonin syndrome !TSYMPATHOMIMETIC AGENTS : Use in combination with sympathomi-metic agents may increase the risk of cardiac effects (arrhythmias, hypertension, hyperpyrexia) !TMONOAMINE OXIDASE I NHIBITORS (including amitraz and possibly, selegiline ): Concomitant use (within 14 days) with monoam-ine oxidase inhibitors is generally contraindicated (serotonin syndrome) Laboratory Considerations !TECG: Tricyclics can widen QRS complexes, prolong PR intervals and invert or ﬂatten T-waves on ECG !TMETAPYRONE T EST: The response to metapyrone may be decreased by clomipramine !TGLUCOSE, BLOOD : Tricyclics may alter (increase or decrease) blood glucose levels !TTHYROID T ESTS : Clomipramine may decrease T3 and free T4 levels in dogs Doses !TDOGS: a) 2-4 mg/kg once daily or divided twice daily PO. (Label direc-tions; Clomicalm®) b) For adjunctive treatment of compulsive disorders: 2-3 mg/kg PO twice daily (Landsberg 2004) c) 3 mg/kg q12h; start at a low dose (e. g., 1 mg/kg for 2 weeks, then 2 mg/kg for 2 weeks, then 3 mg/kg) (Reisner and Houpt 2000) d) 2-6 mg/kg PO q24h. Begin at lower dose and increase ev-ery 1-2 weeks as necessary. Emesis less likely if given with food and the total daily dose is divided into a twice a day dose (Crowell-Davis 1999) e) For treatment of male dimorphic behaviors (urine marking, mounting, roaming, inter-male aggression); fearful/fear ag-gression behaviors; noise phobias; obsessive/compulsive be-haviors (self-mutilation, excessive grooming, stereotypies): 1 mg/kg PO every 12 hours for 2 weeks; then 2 mg/kg PO q12h	pppbs.pdf
CLONAZEPAM 215 for 2 weeks, then 3 mg/kg PO q12h for 4 weeks and maintain. May take 4-6 weeks to see apparent improvement. (Overall 1997) f) For adjunctive treatment (with alprazolam and behavior modiﬁcation) of storm phobia: Clomipramine 2 mg/kg PO q12h for 3 months, then 1 mg/kg PO q12h, then 0. 5 mg/kg PO q12h for 2 weeks. Alprazolam 0. 02 mg/kg PO as needed 1 hour before anticipated storms and q4h as needed (Crowell-Davis 2003d) T ! CATS: a) For urine marking/spraying; inter-cat aggression related to social hierarchy; redirected aggression; compulsive groom-ing/wool sucking: 0. 5 mg/kg once daily PO (Overall 1997) b) For adjunctive treatment of compulsive disorders: 0. 5-1 mg/ kg PO once daily (Landsberg 2004) c) 0. 5-1 mg/kg once daily (Reisner & Houpt 2000) d) 0. 25-0. 5 mg/kg PO daily (Crowell-Davis 1999) Monitoring T ! Clinical efﬁcacy T ! Adverse Effects: Baseline liver function tests; EKG Client Information T ! Generally used in combination with behavior modiﬁcation treatments T ! May take several weeks before beneﬁcial effects are seen T ! May be given with or without food; if patient vomits from the medication, give with food T ! Do not stop therapy without veterinarian's guidance T ! Keep well out of reach of pets and children; overdoses can be very toxic Chemistry/Synonyms A dibenzazepine-derivative tricyclic antidepressant, clomipramine HCl occurs as a white to off-white crystalline powder and is freely soluble in water. Clomipramine HCl may also be known as: chlorimipramine hydrochloride, clomipramini hydrochloridum, G-34586, mono-chlorimipramine hydrochloride, Clofranil®, Clomicalm®, Clopram®, Clopress®, Equinorm®, Hydiphen®, Maronil®, Novo-Clopamine®, Placil®, Tranquax®, or Zoiral®. Storage/Stability The commercially available veterinary tablets should be stored in a dry place at controlled room temperature (15-30°C) in the origi-nal closed container. The (human label) capsules should be stored at temperatures less than 30°C in tight containers and protected from moisture. An expiration date of 3 years from the date of man-ufacture is assigned to the commercially available capsules. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Clomipramine HCl Oral Tablets: 5 mg, 20 mg, 40 mg, & 80 mg; Ap-proved for dogs. Clomicalm® (Novartis); (Rx) The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Clomipramine Oral Capsules: 25 mg, 50 mg, & 75 mg; Anafranil® (Novartis); generic; (Rx) CLONAZEPAM (kloe-na-ze-pam) Klonopin® BENZODIAZEPINE Prescriber Highlights TT Benzodiazepine anticonvulsant, used primarily as adjunc-tive therapy for short-term treatment of epilepsy in dogs & for longer-term adjunctive treatment of epilepsy in cats; may also be used as an anxiolytic TT Contraindications: Hypersensitivity to benzodiazepines, narrow angle glaucoma, signiﬁcant liver disease TT May exacerbate myasthenia gravis TT Adverse Effects: Sedation & ataxia most prevalent; Cats: Possible hepatic necrosis TT Dogs: Tolerance to efﬁcacy may occur (over a few weeks) TT Controlled substance (C-IV) Uses/Indications Clonazepam is used primarily as an short-term adjunctive anticon-vulsant for the treatment of epilepsy in dogs. It has been consid-ered as long-term adjunctive therapy in dogs not controlled with other, more standard therapies, but like diazepam, tolerance tends to develop in a few weeks of treatment. It can also be used as an anxiolytic agent. Clonazepam has been used as an anxiolytic and in the treatment of epilepsy in cats. Pharmacology/Actions The subcortical levels (primarily limbic, thalamic, and hypotha-lamic) of the CNS are depressed by diazepam and other benzodi-azepines thereby producing the anxiolytic, sedative, skeletal muscle relaxant, and anticonvulsant effects seen. The exact mechanism of action is unknown, but postulated mechanisms include: antago-nism of serotonin, increased release of and/or facilitation of gam-ma-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. In all species studied, receptors are lacking in the white matter. Pharmacokinetics In dogs, clonazepam's oral bioavailability is variable (20-60%) but absorption is rapid. Protein binding is about 82% and the drug rap-idly crosses into the CNS. Clonazepam exhibits saturation kinetics in dogs as elimination rates are dose dependent. In humans, the drug is well absorbed from the GI tract, crosses the blood-brain barrier and placenta and is metabolized in the liver to several metabolites that are excreted in the urine. Peak serum levels occur about 3 hours after oral dosing. Half-lives range from 19-40 hours. Contraindications/Precautions/Warnings Clonazepam is contraindicated in patients who are hypersensitive to it or other benzodiazepines, have signiﬁcant liver dysfunction, or acute narrow angle glaucoma. Benzodiazepines have been reported to exacerbate myasthenia gravis. Adverse Effects There is very limited information on the adverse effect proﬁle of this drug in domestic animals. Sedation (or excitement) and ataxia	pppbs.pdf
216 CLONAZEPAM Tmay occur. Clonazepam has been reported to cause a multitude of various adverse effects in humans. Some of the more signiﬁcant effects include increased salivation, hypersecretion in upper respi-ratory passages, GI effects (vomiting, constipation, diarrhea, etc. ), transient elevations of liver enzymes, and hematologic effects (ane-mia, leukopenia, thrombocytopenia, etc. ). T olerance (usually noted after several weeks) to the anticonvulsant effects has been reported in dogs. In cats, clonazepam may cause sedation, ataxia and acute hepatic necrosis. Patients discontinuing clonazepam, particularly those who have been on the drug chronically at high dosages, should be tapered off or status epilepticus may be precipitated. Vomiting and diarrhea may occur during this process. Reproductive/Nursing Safety Safe use during pregnancy has not been established; adverse terato-genic effects have been seen in rabbits and rats. 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 if clonazepam drug is excreted into milk, but several other benzodiazepines have been documented to enter milk. Theoretically, accumulation of the drug and its metabolites to toxic levels are possible; use with caution in nursing dams. Overdosage/Acute Toxicity When used alone, clonazepam overdoses are generally limited to sig-niﬁcant CNS depression (confusion, coma, decreased reﬂexes, etc. ). Treatment of signiﬁcant oral overdoses consists of standard proto-cols for removing and/or binding the drug in the gut and supportive systemic measures. The use of analeptic agents (CNS stimulants such as caffeine, amphetamines, etc. ) is generally not recommended. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clonazepam and may be of signiﬁcance in veterinary patients: !TANTIFUNGALS, AZOLE (itraconazole, ketoconazole, etc. ): May increase clonazepam levels !TCIMETIDINE : May decrease metabolism of benzodiazepines !TCNS DEPRESSANT DRUGS : If clonazepam administered with other CNS depressant agents (barbiturates, narcotics, anesthetics, etc. ) additive effects may occur !TERYTHROMYCIN : May decrease the metabolism of benzodiazepines !TPHENOBARBITAL : May decrease clonazepam concentrations !TPHENYTOIN : May decrease clonazepam concentrations !TPROPANTHELINE : May decrease clonazepam concentrations !TRIFAMPIN : May induce hepatic microsomal enzymes and decrease the pharmacologic effects of benzodiazepines Laboratory Considerations !TBenzodiazepines may decrease the thyroidal uptake of I123 or I131. Doses !TDOGS: As an adjunctive medication in the treatment of seizures: a) For status: 0. 05-0. 2 mg/kg IV ( Note : IV prep not available in USA) (Boothe 1999) b) 0. 5 mg/kg PO two to three times a day; may need to lower phenobarbital dose by 10-20% (Neer 1994) As an anxiolytic: a) 0. 05-0. 25 mg/kg PO q12-24h (Virga 2005a) b) 0. 1-1 mg/kg PO two to three times a day (Landsberg 2005b) !TCATS: As an anxiolytic: a) 0. 05-0. 25 mg/kg PO q12-24h (Virga 2005a) b) 0. 02-0. 2 mg/kg PO once to two times a day (Landsberg 2005b) As an adjunctive medication in the treatment of seizures: a) 0. 5 mg (total dose) PO q12-24h; may cause ataxia, sedation and acute hepatic necrosis. (Podell 2006a) b) Jth to G of a 0. 5 mg tablet PO two to three times daily; anec-dotally more effective for maintenance and to decrease cluster seizures; acute hepatic necrosis possible (Pearce 2006b) Monitoring !TEfﬁcacy !TAdverse effects !The therapeutic blood level has been reported as 0. 015-0. 07 micrograms/m L. !TCats: Liver function tests Client Information !TA major factor in anticonvulsant therapy failure is lack of compli-ance with the prescribed therapy; it is very important to give doses regularly !TCats: If patient develops lack of appetite, vomits, or yellowish whites of eyes, contact veterinarian immediately Chemistry/Synonyms A benzodiazepine anticonvulsant, clonazepam occurs as an off-white to light yellow, crystalline powder having a faint odor. It is insoluble in water and slightly soluble in alcohol. Clonazepam may also be known as: clonazepamum, Ro-5-4023, Antelepsin®, Clonagin®, Clonapam®, Clonax®, Clonex®, Diocam®, Epitril®, Iktorivil®, Kenoket®, Klonopin®, Kriadex®, Neuryl®, Paxam®, Rivatril®, Rivotril®, or Solﬁdin®. Storage/Stability Tablets should be stored in airtight, light resistant containers at room temperature. After manufacture, a 5-year expiration date is assigned. 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: Clonazepam Oral Tablets: 0. 5 mg, 1 mg, & 2 mg; Klonopin®(Roche); generic; (Rx, C-IV) Clonazepam Orally Disintegrating Tablets: 0. 125 mg, 0. 25 mg, 0. 5 mg, 1 mg & 2 mg (with mannitol); Klonopin® Wafers (Roche); Clon-azepam (Barr); (Rx, C-IV)	pppbs.pdf
CLONIDINE 217 CLONIDINE (kloe-ni-deen) Duraclon®, Catapres® CENTRAL ALPHA-2 AGONIST Prescriber Highlights TT Centrally acting alpha-adrenergic agonist used as a diag-nostic for growth hormone deﬁciency or pheochromocy-toma in dogs, adjunctive treatment for IBD, &, potentially, epidurally as an adjunct for pain &/or anesthesia TT Limited experience in veterinary species for therapeutic purposes TT Potential adverse effects include: Transient hyperglyce-mia, dry mouth, constipation, sedation, aggressive behav-ior, hypotension, collapse, & bradycardia Uses/Indications Clonidine is of interest in veterinary medicine as a diagnostic agent to determine growth hormone deﬁciency or pheochromocytoma in dogs, and as an adjunctive treatment for refractory inﬂammatory bowel disease, particularly in cats. It is being investigated in a vari-ety of species as an epidural adjunct with or without opiates in the treatment of severe pain or for surgical procedures using epidural anesthesia. Pharmacology/Actions Clonidine acts centrally (brain stem), stimulating alpha-adreno-receptors, thereby reducing sympathetic outﬂow from the CNS; decreased renal vascular resistance, peripheral resistance, cardiac rate, and blood pressure result. Renal blood ﬂow and glomerular ﬁltration rates are not affected. Clonidine stimulates growth hor-mone release by stimulating release of GHRH, but this effect does not persist with continued dosing. Clonidine possesses centrally acting analgesic effects probably at presynaptic and postjunctional alpha 2-adrenoreceptors in the spinal cord thereby blocking pain signal transmission to the brain. It may also increase seizure thresh-old but the clinical signiﬁcance for this effect is unclear. Pharmacokinetics Limited information is available on the pharmacokinetics of clo-nidine in domestic animals. In cats, clonidine exhibits a two-com-partment open model and penetrates into tissues rapidly. In humans, the drug is well absorbed after oral administration. Peak plasma concentrations occur approximately 3-5 hours after oral administration. After epidural administration, maximal anal-gesia occurs within 30-60 minutes. Clonidine is apparently widely distributed into body tissues; tissue concentrations are higher than in plasma. Clonidine does enter into the CSF, but brain concentra-tions are low compared with other tissues. In humans with normal renal function, clonidine's half-life is 6-20 hours. Elimination may be prolonged with higher dosages (dose-dependent elimination ki-netics) or in patients with renal dysfunction. Up to 60% of a dose is eliminated unchanged in the urine, but the remainder is metabo-lized in the liver; one active metabolite (p-hydroxyclonidine) has been identiﬁed. Contraindications/Precautions/Warnings Clonidine is contraindicated in patients known to be hypersensitive to it. It should be used with caution in patients with severe cardio-vascular disease, including conduction disturbances or heart fail-ure; it should be used very cautiously in patients with renal failure. Adverse Effects Reported adverse effects most likely to occur include: transient hy-perglycemia, dry mouth, constipation, sedation, aggressive behav-ior, hypotension, collapse, and bradycardia (responsive to atropine). T olerance to its therapeutic effects has been reported in humans. Reproductive/Nursing Safety At reasonable dosages no signiﬁcant teratogenic effects have been described in laboratory animals, but at very high dosages some ef-fects (increased perinatal mortality, growth retardation, cleft pal-ates) have been seen. In humans, the FDA categorizes clonidine as a category C drug for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate stud-ies in humans; or there are no animal reproduction studies and no adequate studies in humans). Clonidine does enter maternal milk at concentrations of about 20% of those found in plasma; clinical signiﬁcance to nursing off-spring is unknown, but clonidine was undetectable in plasma of an infant one hour after nursing from a mother taking clonidine. Overdosage/Acute Toxicity The LD50 values reported for oral clonidine in rats are 465 mg/ kg and mice, 206 mg/kg. Expected signs after clonidine overdose include: transient hypertension followed by hypotension, bradycar-dia, somnolence to agitation to coma, vomiting, respiratory depres-sion, constricted pupils, and cardiac arrhythmias. There were 43 exposures to clonidine reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org ) dur-ing 2005-2006. In these cases 20 were dogs with 8 showing clinical signs and the remaining 23 cases were cats with 6 showing clinical signs. Common ﬁndings in dogs recorded in decreasing frequen-cy included lethargy, bradycardia, agitation, hypotension, weak-ness and ataxia. Common ﬁndings in cats recorded in decreasing frequency included depression, vomiting, ataxia, agitation and bradycardia. Treatment for large overdoses includes gut evacuation using standard protocols. Use of emetics should be carefully considered, as level of consciousness may deteriorate rapidly. Treatment of sys-temic effects is primarily symptomatic and supportive. Hypotensive effects may be treated, if necessary, using ﬂuids or pressors (e. g., do-pamine); bradycardia may be treated with IV atropine, if required. Treatment may be required for many hours, depending on cloni-dine dosage. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clonidine and may be of signiﬁcance in veterinary patients: T ! ANTIHYPERTENSIVE D RUGS, OTHER : Possible additive hypotensive effects T ! BETA-ADRENERGIC BLOCKING AGENTS (i. e., propranolol ) may enhance bradycardia when given with clonidine. In patients receiving clo-nidine and beta-adrenergic blocking agents together: if clonidine is to be discontinued, the beta-blocker should be discontinued prior to clonidine and clonidine gradually discontinued, other-wise rebound hypertension may occur. T ! CNS DEPRESSANT D RUGS (opiates, barbiturates, etc. ): Clonidine may exacerbate the actions of other CNS depressant drugs T ! DIGOXIN : Possible additive bradycardia T ! PRAZOSIN : May decrease the antihypertensive effects of clonidine T ! TRICYCLIC ANTIDEPRESSANTS (e. g., amitriptyline ): May block the an-tihypertensive effects of clonidine	pppbs.pdf
218 CLOPIDOGREL BISULFATE Laboratory Considerations No speciﬁc laboratory interactions were noted for clonidine. Doses T ! DOGS: For diagnosing hyposomatotropism: a) Dosage may be variable depending on the laboratory's proto-col. Contact lab prior to test to determine protocol and sam-ple handling instructions. Usual dose is 10 mcg/kg IV. Obtain plasma for growth hormone (GH) levels, prior to clonidine dosing and at 15, 30, 45, 60, and 120 minutes. Larger dosages may cause a more pronounced and prolonged hyperglycemia and a higher incidence of other adverse reactions that may include sedation, aggressive behavior, hypotension, collapse, and bradycardia (responsive to atropine). Adverse effects may persist for 15-60 minutes post dose. Healthy dogs should demonstrate GH levels of 10 ng/m L after clonidine adminis-tration. (Feldman and Nelson 1996) T ! CATS: For adjunctive antidiarrheal therapy for refractory cases of in-ﬂammatory bowel disease: a) As fourth line therapy after prostaglandin synthetase inhibi-tors ( i. e., sulfasalazine, bismuth subsalicylate), opioid agonists (i. e., loperamide), and 5-HT3 serotonergic antagonists (i. e., ondansetron) are being used: clonidine 5-10 mcg/kg two to three times a day, SC or PO. (Washabau 2000) T ! CATTLE: For epidural analgesia/analgesia: a) 2-3 mcg/kg diluted to 8 m L with sterile normal saline epidu-rally; onset/duration of analgesia = 19 minutes/192 minutes with 2 mcg/kg dose and = 9 minutes/311 minutes with 3 mcg/ kg dose; peak effects from 60-180 minutes (De Rossi, Bucker et al. 2003) Monitoring T ! Dependent upon purpose for use. When used for determining GH levels, adverse effects (noted in dosage section) should be evaluated. T ! Blood pressure and cardiac rate are most likely to be affected, but effects usually only persist for an hour after dose. T ! When used for ongoing diarrhea treatment, evaluation of efﬁcacy and adverse effect proﬁle should be monitored. Client Information T ! When used for chronic therapy, have clients report signs that may indicate adverse effects (weakness, lethargy, behavioral changes, etc. ); caution not to alter or discontinue treatment without vet-erinarian's advice. Chemistry/Synonyms An imidazoline derivative centrally acting alpha-adrenergic agonist, clonidine HCl occurs as an odorless, bitter, white or almost white crystalline powder. It is soluble in water and alcohol. It is also con-sidered highly lipid soluble. The commercially available injection for epidural use has its p H adjusted to between 5 to 7. Clonidine may also be known as: ST-155, clonidini hydro-chloridum, Adesipress-TTS®, Arkamin®, Aruclonin®, Atensina®, Barclyd®, Cantanidin®, Caprysin®, Catanidin®, Catapresan®, Catapresan®, Catapres®, Catapressan®, Clonistada®, Clonnirit®, Dispaclonidin®, Dixarit®, Duraclon®, Epiclodina®, Glausine®, Haemiton®, Menograine®, Mirfat®, Normopresan®, Paracefan®, or Tenso-Timelets®. Storage/Stability Clonidine tablets should be stored in tight, light-resistant containers at room temperature; excursions permitted to 15-30°C (59-86°F). The preservative-free injection for epidural use should be stored at controlled room temperature (25°C). Because it contains no preser-vative, unused portions of the injection should be discarded. 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: Clonidine HCl Injection for epidural use: 100 mcg/m L, 500 mcg/m L preservative-free in 10 m L vials; Duraclon® (aai Pharma); (Rx) Clonidine HCl Tablets: 0. 1 mg, 0. 2 mg & 0. 3 mg; Catapres® (Boeh-ringer Ingelheim); generic; (Rx) Clonidine HCl Transdermal: 0. 1 mg/24hrs (2. 5 mg total cloni-dine content), 0. 2 mg/24hrs (5 mg total clonidine content), & 0. 3 mg/24hrs (7. 5 mg total clonidine content); Catapres-TTS-1®, 2® or 3® (Boehringer Ingelheim); (Rx) CLOPIDOGREL BISULFATE (kloe-pid-oh-grel) Plavix® PLATELET AGGREGATION INHIBITOR Prescriber Highlights TT Oral, once-daily platelet aggregation inhibitor that may be useful in preventing thromboembolic disease in cats TT Limited clinical experience in feline medicine; but appears well tolerated TT Potentially may cause vomiting or bleeding Uses/Indications Clopidogrel, a platelet aggregation inhibitor, may be useful for pre-venting thrombi in susceptible cats. It may also improve pelvic limb circulation in cats after a cardiogenic embolic event via a vasomodu-lating effect secondary to inhibition of serotonin release from plate-lets. Research is ongoing. Pharmacology/Actions Clopidogrel is metabolized to an active, highly unstable compound (not yet identiﬁed) that is responsible for its inhibitory platelet-ag-gregation (both primary and secondary aggregation) activity. This compound binds selectively to platelet surface low-afﬁnity ADP-receptors and inhibits ADP binding to the site. This inhibits activa-tion of the platelet glycoprotein Ib/IIIa complex that is necessary for platelet-ﬁbrinogen binding and inhibits the release from platelets other compounds that enhance platelet aggregation (e. g., serotonin, calcium, ﬁbrinogen, thromobospondin, ADP). Clopidogrel's active metabolite irreversibly alters the ADP receptor; the platelet is af-fected for its lifespan. Clopidogrel's mechanism of action on platelet aggregation is dif-ferent than aspirin's effects. Aspirin acetylates and inactivates COX-1 in platelets, thereby preventing formation of thromboxane A 2.	pppbs.pdf
CLOPROSTENOL SODIUM 219 Pharmacokinetics No speciﬁc information was located for the pharmacokinetics of clopidogrel in cats. In a pharmacodynamic study in cats (Hogan, Andrews et al. 2004), doses as low as 18. 75 mg were as effective as higher dosages in reducing platelet aggregation; maximal effects were seen after 3 days of therapy and platelet function returned to normal 7 days after stopping treatment. While lower dosages may be effective in cats, they have not been evaluated and are not practi-cal to administer with the presently available 75 mg human-labeled dosage form (tablets). In humans, clopidogrel is rapidly absorbed with a bioavailabil-ity of about 50%. Food does not alter its absorption. Clopidogrel is highly bound to plasma proteins in humans and is rapidly hy-drolyzed to a carboxylic acid derivative inactive metabolite that is excreted via the urine and feces. The 2% of drug that is covalently bound to platelets has an approximate elimination half-life of 11 days. Contraindications/Precautions/Warnings No speciﬁc information is available for cats. In humans, clopidogrel is contraindicated in patients with active pathologic bleeding or known hypersensitivity to the drug. Adverse Effects Clopidogrel appears well tolerated by cats, but numbers treated have been relatively few. Some cats may vomit or develop anorexia; giving the drug with food may alleviate these effects. In humans, the primary adverse effects reported have been bleeding related. In a major pre-clinical study, major bleeding oc-curred in approximately 2% of patients treated. Use of aspirin with clopidogrel may increase this incidence. Rashes and gastrointesti-nal effects (diarrhea) have also been reported. Rarely, thrombotic thrombocytopenic purpura (TTP) has been noted; onset can occur after a short period of treatment (<2 weeks). Reproductive/Nursing Safety In pregnant rats and rabbits, dosages of approximately 65X and 78X respectively, of the human dose when compared on mg/m2 basis, caused no teratogenic effects. In humans, the FDA categorizes clopidogrel 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 demonstrat-ed a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In rats, clopidogrel or its metabolites are distributed into milk. Although probably safe to use in nursing veterinary patients, weigh the potential risks to nursing offspring before allowing patients re-ceiving the drug to nurse their young, or use a milk replacer. Overdosage/Acute Toxicity Limited information is available. Reported lethal oral doses for mice and rats were 1500 mg/kg and 2000 mg/kg (460X human adult dose on a mg/m2 basis), respectively. Acute toxic signs may include bleeding or vomiting. Platelet transfusions have been suggested if rapid reversal is required. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clopidogrel and may be of signiﬁcance in veterinary patients: T ! ASPIRIN : Increased risk for bleeding, however many human pa-tients take both medications T ! HEPARIN; LOW MOLECULAR W EIGHT H EPARINS : Clopidogrel appears safe to use with heparin (both unfractionated and LMW) T ! NSAIDS : Increased risk for bleeding; clopidogrel may interfere with metabolism T ! PHENYTOIN : Clopidogrel may interfere with metabolism T ! TORSEMIDE : Clopidogrel may interfere with metabolism T ! WARFARIN : Increased risk for bleeding; clopidogrel may interfere with metabolism Laboratory Considerations None noted Doses T ! CATS: T o prevent thrombus formation: a) 18. 75 mg (practically, G of a 75 mg tablet) PO once daily (Hogan 2006) Monitoring T ! Clinical efﬁcacy T ! Adverse effects (vomiting, bleeding) Client Information T ! May be given without regard to feeding status T ! Potential adverse effects include vomiting, lack of appetite or bleeding T ! If vomiting occurs, give with food T ! Report any bleeding or black, tarry stools to veterinarian Chemistry/Synonyms Clopidogrel bisulfate, a thienopyridine, occurs as a white to off-white powder that is practically insoluble in water at a p H of 7, but freely soluble at a p H of 1. Clopidogrel may also be known as: SR-259990C, PCR-4099, or clopedogreli. Internationally registered trade names for clopidogrel include: Antiplaq, Clodian, Cloﬂow, Clopact, Clopivas, Clopod, Iscover, Iskimil, Nabratin, Noklot, Plavix®, Pleyar, or Troken. Storage/Stability Clopidogrel tablets should be stored at 25°C; excursions are permit-ted to 15-30°C. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Clopidogrel Bisulfate Tablets: 75 mg (as base); Plavix® (Bristol-Myers Squibb); (Rx) CLOPROSTENOL SODIUM (kloe-pros-te-nol) Estrumate® PROSTAGLANDIN (F-CLASS) Prescriber Highlights TT Synthetic F-class prostaglandin used in cattle to induce luteolysis, induce abortion, treat pyometra, endometritis, etc. TT Contraindications: Pregnancy (when abortion or induced parturition are not desired) TT Can cause cholinergic-like adverse effects in dogs TT Do not give IV TT Pregnant women should not handle; caution handling in humans with asthma & women of childbearing age	pppbs.pdf
220 CLOPROSTENOL SODIUM Uses/Indications Cloprostenol is approved for use in beef or dairy cattle to induce luteolysis. It is recommended by the manufacturer for unobserved or undetected estrus in cows cycling normally, pyometra or chronic endometritis, expulsion of mummiﬁed fetus, luteal cysts, induced abortions after mismating, and to schedule estrus and ovulation for controlled breeding. Cloprostenol has been used in dogs for pregnancy termination and treatment of open pyometra. The use of cloprostenol for py-ometra is controversial as some believe dinoprost (PGF2alpha) is more effective and has fewer adverse effects than cloprostenol. Pharmacology/Actions Prostaglandin F alpha and its analogues cloprostenol and ﬂupros-tenol are powerful luteolytic agents. They cause rapid regression of the corpus luteum and arrest its secretory activity. These prostaglan-dins also have direct stimulating effect on uterine smooth muscle causing contraction and a relaxant effect on the cervix. In normally cycling animals, estrus will generally occur 2-5 days after treatment. In pregnant cattle treated between 10-150 days of gestation, abortion will usually occur 2-3 days after injection. Pharmacokinetics No information was located on the pharmacokinetics of cloprostenol. Contraindications/Precautions/Warnings Should not be administered to pregnant animals when abortion is not desired. Women of child-bearing age, persons with asthma or other respi-ratory diseases should use extreme caution when handling clopros-tenol as the drug may induce abortion or acute bronchoconstric-tion. Cloprostenol is readily absorbed through the skin and must be washed off immediately with soap and water. Do not administer IV. Adverse Effects The manufacturer does not list any adverse effects for this product when used as labeled. If used after the 5th month of gestation, in-creased risk of dystocia and decreased efﬁcacy occur. In dogs, cloprostenol can cause increased salivation, tachycardia, increased urination and defecation, gagging, vomiting, ataxia, and mild depression. Pretreatment with an anticholinergic drug (such as atropine) may reduce the severity of these effects. Reproductive/Nursing Safety Cloprostenol is contraindicated in pregnant animals when abortion or induced parturition is not desired. Overdosage/Acute Toxicity The manufacturer states that at doses of 50 and 100 times those rec-ommended, cattle may show signs of uneasiness, slight frothing, and milk let-down. Overdoses of cloprostenol or other synthetic prostaglandin F2alpha analogs in small animals reportedly can result in shock and death. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cloprostenol and may be of signiﬁcance in veterinary patients: !TOXYTOCIC AGENTS, OTHER : Activity may be enhanced by cloprostenol Doses !TDOGS: For adjunctive treatment of open cervix pyometra: a) 1-5 mcg/kg (0. 001-0. 005 mg/kg) (route not speciﬁed) once per day. May require up to 2-3 weeks of treatment. When starting treatment, start with one-half the normal dosage and gradually achieve the full dose within 2-3 days. (Romagnoli 2002a) b) Cloprostenol at 1 mcg/kg SC (not during feeding) every 5 days for 15 days (if not cured earlier) with aglepristone at 10 mg/kg SC every 5 days until cured. Give Clavamox® (12. 5 mg/ kg PO twice daily and supportive hydration throughout pro-tocol, if indicated. (Threlfall 2006) For pregnancy termination: a) 1-2. 5 mcg/kg SC once daily for 4-7 days has been success-ful in terminating pregnancy in dogs after 30 days gestation (Davidson 2004c) b) 1-2. 5 mcg/kg SC every 48 hours for three doses. At higher dose (2. 5 mg/kg); appears very effective starting at 30 days of pregnancy. Anticholinergic drug administration (e. g., at-ropine) 15 minutes prior to dosing appears to lessen adverse effects. (Romagnoli 2006a) !TCATTLE: For treatment of pyometra: a) 500 micrograms IM (up to 97% efﬁcacy) (Mc Cormack 1986) For pyometra or chronic endometritis, mummiﬁed fetus (manual assistance may be required to remove from vagina), luteal cysts: a) 500 micrograms IM (Package Insert; Estrumate®—Miles/ Mobay) For unobserved or undetected estrus in cows with continued ovarian cyclicity and a mature corpus luteum: a) 500 micrograms IM; estrus should commence in 2-5 days at which time the animal may be inseminated. If estrus detec-tion is not possible or practical, animal may be inseminat-ed twice at 72 and 96 hours post injection. (Package Insert; Estrumate®—Miles/Mobay) For abortion, from one week after mating to approximately the 150th day of gestation: a) 500 micrograms IM; abortion generally takes place in 4-5 days after injection (Package Insert; Estrumate®—Miles/ Mobay) For controlled breeding: a) Single injection method: Use only animals with mature corpus luteum. Examine rectally to determine corpus luteum matu-rity, anatomic normality, and lack of pregnancy. Give 500 mi-crograms cloprostenol IM. Estrus should occur in 2-5 days. Inseminate at usual time after detecting estrus, or inseminate once at 72 hours post injection, or twice at 72 and 96 hours post injection. Double injection method: Examine rectally to determine if ani-mal is anatomically normal, not pregnant, and cycling nor-mally. Give 500 micrograms IM. Repeat dose 11 days later. Estrus should occur in 2-5 days after second injection. In-seminate at usual time after detecting estrus, or inseminate once at 72 hours post second injection, or twice at 72 and 96 hours post second injection. Animals that come into estrus after ﬁrst injection may be in-seminated at the usual time after detecting estrus. Any controlled breeding program should be completed by ei-ther observing animals and re-inseminating or hand mating after returning to estrus, or turning in clean-up bull(s) ﬁve to seven days after the last injection of cloprostenol to cover any	pppbs.pdf
CLORAZEPATE DIPOTASSIUM 221 animals returning to estrus. (Package Insert; Estrumate®— Miles/Mobay) T ! HORSES: T o cause abortion prior to the twelfth day of gestation: a) 100 micrograms IM, most effective day 7 or 8 post estrus. Mare will usually return to estrus within 5 days. (Lofstedt 1986) T ! SWINE: T o induce parturition in sows: a) 175 micrograms IM; give 2 days or less before anticipated date of farrowing. Farrowing generally occurs in approxi-mately 36 hours after injection. (Pugh 1982) T ! SHEEP & GOATS: T o induce parturition in does: a) 62. 5-125 micrograms IM at 144 days of gestation in early morning. Deliveries will peak at 30-35 hours after injection. Maintain goat in usual surroundings and minimize outside disturbances. (Williams 1986) CLORAZEPATE DIPOTASSIUM (klor-az-e-pate) Tranxene-SD®, Gen-Xene® BENZODIAZEPINE Prescriber Highlights TT Benzodiazepine anxiolytic, sedative-hypnotic, & anticon-vulsant used in dogs & cats TT Contraindications: Hypersensitivity to benzodiazepines, narrow angle glaucoma, or signiﬁcant liver disease TT Use extreme caution in aggressive animals (especially fear induced) TT May exacerbate myasthenia gravis TT Can interact with phenobarbital TT Adverse Effects: Sedation & ataxia most prevalent Client Information T ! Cloprostenol should be used by individuals familiar with its use and precautions T ! Pregnant women, asthmatics or other persons with bronchial diseases should handle this product with extreme caution T ! Any accidental exposure to skin should be washed off immediately Chemistry/Synonyms A synthetic prostaglandin of the F class, cloprostenol sodium oc-curs as a white or almost white, amorphous, hygroscopic powder. It is freely soluble in water and alcohol. Potency of the commercially available product is expressed in terms of cloprostenol. Cloprostenol sodium may also be known as ICI-80996, Estru-mate®, or estro PLAN®. Storage/Stability Cloprostenol sodium should be stored at room temperature (15-30°C); protect from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Cloprostenol Sodium Injection equivalent to 250 micrograms/m L cloprostenol in 20 m L vials; Estrumate® (Schering-Plough); estro-PLAN® Injection (Pharmacia & Upjohn); (Rx). Approved for use in beef and dairy cattle. No preslaughter withdrawal or milk with-drawal is required; no speciﬁc tolerances for cloprostenol residues have been published. HUMAN-LABELED PRODUCTS: None Uses/Indications Clorazepate has been used in dogs both as an adjunctive anticon-vulsant (usually in conjunction with phenobarbital) and in the treatment of behavior disorders, primarily those that are anxiety or phobia-related. In dogs, clorazepate has been reported to develop tol-erance to its anticonvulsant effects less rapidly than clonazepam. Clorazepate may be useful as an anxiolytic agent in cats. Pharmacology/Actions The subcortical levels (primarily limbic, thalamic, and hypotha-lamic) of the CNS are depressed by clorazepate and other benzo-diazepines thus producing the anxiolytic, sedative, skeletal muscle relaxant and anticonvulsant effects seen. The exact mechanism of action is unknown, but postulated mechanisms include: an-tagonism 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. In all species studied, receptors are lacking in the white matter. Pharmacokinetics In dogs, clorazepate peak serum levels generally occur within 1-2 hours. Volume of distribution is about 1. 8 L/kg after multiple dos-ing. Clorazepate is metabolized to nordiazepam and other metabo-lites. Nordiazepam is active and has a very long half-life (in humans up to 100 hours). In dogs, the sustained release preparation appar-ently offers no pharmacokinetic advantage over the non-sustained preparations (Brown and Forrester 1989). Contraindications/Precautions/Warnings Clorazepate is contraindicated in patients who are hypersensitive to it or other benzodiazepines, have signiﬁcant liver dysfunction or have acute narrow angle glaucoma. Clorazepate should be used very cautiously, if at all, in aggressive patients as it may disinhibit the anxiety that may help prevent these animals from aggressive behavior. Benzodiazepines have been reported to exacerbate myas-thenia gravis. Use with caution in dogs displaying fear-induced aggression; these drugs may actually provoke dogs to attack.	pppbs.pdf
222 CLORAZEPATE DIPOTASSIUM Adverse Effects In dogs, the most likely adverse effects seen include sedation and ataxia. These effects apparently occur infrequently, are mild and usually transient. Physical dependence may occur and abrupt with-drawal of clorazepate may precipitate seizures. In cats, clorazepate may cause sedation, ataxia and, potentially, acute hepatic necrosis. Reproductive/Nursing Safety Safe use during pregnancy has not been established; teratogenic ef-fects of similar benzodiazepines have been noted in rabbits and rats. In humans, the FDA categorizes this drug as category D for use dur-ing pregnancy (There is evidence of human fetal risk, but the potential beneﬁts from the use of the drug in pregnant women may be acceptable despite its potential risks. ) Nordiazepam is distributed into milk and may affect nursing neonates. Overdosage/Acute Toxicity When used alone, clorazepate overdoses are generally limited to sig-niﬁcant CNS depression (confusion, coma, decreased reﬂexes, etc. ). Treatment of signiﬁcant oral overdoses consists of standard proto-cols for removing and/or binding the drug in the gut and support-ive systemic measures. The use of analeptic agents (CNS stimulants such as caffeine, amphetamines, etc. ) is generally not recommend-ed. Flumazenil may be considered for very serious overdoses. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving clorazepate and may be of signiﬁcance in veterinary patients: !TANTIFUNGALS, AZOLE (itraconazole, ketoconazole, etc. ): May increase levels !TCIMETIDINE : May decrease metabolism of benzodiazepines !TCNS DEPRESSANT D RUGS : If clorazepate is administered with other CNS depressant agents ( barbiturates, narcotics, anesthetics, etc. ) additive effects may occur !TERYTHROMYCIN : May decrease the metabolism of benzodiazepines !TPHENOBARBITAL : While used together in the treatment of seizures in dogs, can interact with one another. Clorazepate (especially high serum concentrations), may increase the serum levels of pheno-barbital, particularly if added to patients who received phenobar-bital long-term. In time, clorazepate levels may decrease, leading to decreased phenobarbital levels. !TPHENYTOIN : May decrease clorazepate concentrations !TRIFAMPIN : May induce hepatic microsomal enzymes and decrease the pharmacologic effects of benzodiazepines Laboratory Considerations !TBenzodiazepines may decrease the thyroidal uptake of I123 or I131. !TClorazepate may increase serum alkaline phosphatase and serum cholesterol levels; clinical signiﬁcance is unclear. Doses !TDOGS: As an adjunctive medication in the treatment of seizures: a) In combination with phenobarbital: Clorazepate: 1-2 mg/ kg PO q12h, but may need to divide q12h dose and give q8h to minimize adverse effects and maintain therapeutic levels (Boothe 1999) b) In combination with phenobarbital: Clorazepate: 0. 5-1 mg/ kg PO q8h. No advantage gained with using sustained release products over regular caps or tabs. May affect phenobarb lev-els; monitor 2 and 4 weeks later. (Thomas 2000) c) 1-2 mg/kg PO q12h (Podell 2006a) d) 2-4 mg/kg PO twice daily, some dogs may require three times daily (Dowling 2003c) e) As a third-line agent: 1-2 mg/kg PO q8-12h (Quesnel 2001) f) For management of cluster seizures: Immediately after ﬁrst seizure give clorazepate at 0. 5-2 mg/kg two to three times daily for the next 48-96 hours and then stop clorazepate. It may be used in addition to the existing anticonvulsant main-tenance therapy, but it is used only during the time of seizure activity and not as maintenance therapy. (Hoskins 2005c) As adjunctive therapy for the treatment of fears and phobias: a) 11. 25-22. 5 mg per dog PO once to twice daily (recommends the sustained-delivery product (Tranxene®-SD). (Marder 1991) b) Using the sustained delivery product (Tranxene®-SD), ini-tially give 22. 5 mg for large dogs, 11. 25 mg for medium dogs and 5. 6 mg for small dogs PO; adjust dosage according dog's response (Shull-Selcer and Stagg 1991) c) 0. 55-2. 2 mg/kg PO as needed up to q8h; titrate to clinical sedation—dose may vary for individual dogs (Reisner and Houpt 2000) d) 0. 2-1 mg/kg PO q12-24h (Virga 2002) !TCATS: As an anxiolytic or for compulsive behaviors: a) 0. 2-0. 5 mg/kg PO q12-24h (Virga 2002) Monitoring !TEfﬁcacy !TAdverse effects Client Information !TA major factor in anticonvulsant therapy failure is lack of compli-ance with the prescribed therapy; it is very important to give doses regularly !TDo not stop giving this drug abruptly as convulsions may occur; contact veterinarian for guidance in stopping treatment !TCats: If patient develops lack of appetite, vomits, or yellowish whites of eyes, contact veterinarian immediately Chemistry/Synonyms A benzodiazepine anxiolytic, sedative-hypnotic, and anticonvulsant, clorazepate dipotassium occurs as a light yellow, ﬁne powder that is very soluble in water and slightly soluble in alcohol. Clorazepate dipotassium may also be known as Abbott-35616, AH-3232, 4306-CB, clorazepic acid, dipotassium clorazepate, dikalii clorazepas, or potassium clorazepate; many trade names are avail-able. Storage/Stability Clorazepate dipotassium is unstable in the presence of water. It has been recommended to keep the dessicant packets in with the original container of the capsules and tablets and to consider adding a dessi-cant packet to the prescription vial when dispensing large quantities of tablets or capsules to the client. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. See the appendix for more information.	pppbs.pdf
CLORSULON 223 HUMAN-LABELED PRODUCTS: Clorazepate Dipotassium Tablets (single dose; sustained release): 11. 25 mg & 22. 5 mg; Tranxene-SD® & Half Strength (Abbott); (Rx, C-IV) Clorazepate Dipotassium Tablets: 3. 75 mg, 7. 5 mg, & 15 mg; Tranx-ene® T-tab (Ovation); generic; (Rx, C-IV) CLORSULON (klor-su-lon) Curatrem®, Ivomec Plus® ANTIPARASITIC (FLUKICIDE) Prescriber Highlights TT Adult ﬂukicide (Fasciola hepatica) TT Not for female dairy cattle TT Slaughter withdrawal 8 days at labeled doses for Cura-trem®, 49 days for Ivomec Plus® Uses/Indications Clorsulon is approved for use in the treatment of immature and adult forms of Fasciola hepatica (Liver ﬂuke) in cattle. It is not effec-tive against immature ﬂukes less than 8 weeks old. It also has activ-ity against Fasciola gigantica. Although not approved, the drug has been used in practice in various other species (e. g., sheep, llamas). It has activity against F. magna in sheep, but is not completely ef-fective in eradicating the organism after a single dose, thus severely limiting its clinical usefulness against this parasite. Clorsulon is also not effective against the rumen ﬂuke (Paramphistomum). Pharmacology/Actions In susceptible ﬂukes, clorsulon inhibits the glycolytic enzymes 3-phosphoglycerate kinase and phosphoglyceromutase, thereby blocking the Emden-Myerhof glycolytic pathway; the ﬂuke is de-prived of its main metabolic energy source and dies. Clorsulon at 7 mg/kg is effective against migrating F. hepatica 8 weeks post-infec-tion, but at 2 mg/kg is effective only against adult ﬂukes (14 weeks post infection). Pharmacokinetics After oral administration to cattle, the drug is absorbed rapidly with peak levels occurring in about 4 hours. Approximately 75% of the circulating drug is found in plasma and 25% in erythrocytes. At 8-12 hours after administration, clorsulon levels peak in the ﬂuke. Contraindications/Precautions/Warnings No milk withdrawal time has been determined, and the drug is la-beled not for use in female dairy cattle of breeding age. The combination injectable product (Ivomec Plus®) must be ad-ministered subcutaneously only; do not give IV or IM. The manu-facturer warns to use in cattle only as severe reactions, including fatalities in dogs, may occur. Adverse Effects When used as directed adverse effects are unlikely to occur with the oral suspension (Curatrem®). Local swelling may occur at injection sites with Ivomec Plus®. Reproductive/Nursing Safety Clorsulon is considered safe to use in pregnant or breeding animals. Overdosage/Acute Toxicity Clorsulon is very safe when administered orally to cattle or sheep. Doses of up to 400 mg/kg have not produced toxicity in sheep. A dose that is toxic in cattle has also not been determined. Drug Interactions/Laboratory Considerations None identiﬁed Doses T ! CATTLE: For Fasciola hepatica infections: a) 7 mg/kg PO; deposit suspension over the back of the tongue (Label directions; Curatrem ®—Merial) For Fasciola hepatica infections, round worms, lungworms, cattle grubs, sucking lice, mange mites (see Ivermectin monograph or product label for more information on species covered): a) Inject 1m L per 110 lb. body weight SC behind the shoulder (Label directions; Ivomec Plus®—Merial) T ! SHEEP: For Fasciola hepatica infections: a) 7 mg/kg PO (Roberson 1988a) T ! LLAMAS: For Fasciola hepatica infections: b) 7 mg/kg PO (Fowler 1989) Monitoring T ! Clinical efﬁcacy Client Information T ! Shake well before using (Curatrem®) T ! Follow withdrawal times for slaughter (8 days for Curatrem®, 49 days for Ivomec Plus®) T ! Do not use in female dairy cattle of breeding age Chemistry/Synonyms A benzenesulfonamide, clorsulon has a chemical name of 4-amino-6-trichloroethenyl-1,3-benzenedisulfonamide. Clorsulon may also be known as MK-401, Curatrem®, or Ivomec®. Storage/Stability Unless otherwise instructed by the manufacturer, clorsulon should be stored at room temperature (15-30°C). Dosage Forms/Regulatory Status VETERINARY APPROVED PRODUCTS: Clorsulon 8. 5% (85 mg/m L) Oral Drench in quarts or gallons; Curatrem® (Merial); (OTC). Approved for use in cattle. Slaughter withdrawal = 8 days (when used as labeled); Because a withdrawal time in milk has not been established, do not use in female dairy cattle of breeding age. Clorsulon 10% (100 mg/m L) and Ivermectin 1% (10 mg/m L) In-jection in 50 m L, 200 m L, 500 m L, & 1000 m L. Ivomec® Plus (Me-rial); (OTC). Approved for subcutaneous injection use in cattle. Do not use within 49 days of slaughter; do not use in female dairy cattle of breeding age. HUMAN APPROVED PRODUCTS: None	pppbs.pdf
224 CLOXACILLIN CLOXACILLIN SODIUM CLOXACILLIN BENZATHINE (klox-a-sill-in) Orbenin-DC®, Dry-Clox®, Dariclox® ANTI-STAPHYLOCOCCAL PENICILLIN Prescriber Highlights TT Intramammary isoxazolyal (anti-staphylococcal) penicillin TT Contraindicated: Hypersensitivity to penicillins TT Oral dosage forms (human) no longer marketed in USA Uses/Indications Cloxacillin is used via intramammary infusion in dry and lactating dairy cattle. Pharmacology/Actions Cloxacillin, dicloxacillin and oxacillin have nearly identical spec-trums of activity and can be considered therapeutically equiva-lent when comparing in vitro ac tivity. These penicillinase-resistant penicillins have a narrower spectrum of activity than the natural penicillins. Their antimicrobial efﬁcacy is aimed directly against penicillinase-producing strains of gram-positive cocci, particularly Staphylococcal species. They are sometimes called anti-staphy-lococcal penicillins. There are documented strains of Staphylococci that are resistant to these drugs (so-called methicillin-resistant Staph), but these strains have not yet become a major problem in veterinary species. While this class of penicillins does have activity against some other gram-positive and gram-negative aerobes and anaerobes, other antibiotics (penicillins and otherwise) are usually better choices. The penicillinase-resistant penicillins are inactive against Ri ckettsia, mycobacteria, fungi, Mycoplasma, and viruses. Pharmacokinetics Cloxacillin is only available in intramammary dosage forms in the USA. Contraindications/Precautions/Warnings Penicillins are contraindicated in patients with a history of hyper-sensitivity to them. Because there may be cross-reactivity, use peni-cillins cautiously in patients who are documented hypersensitive to other beta-lactam antibiotics (e. g., cephalosporins, cefamycins, car-bapenems). Adverse Effects Adverse effects with the penicillins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, neutropenia, agranulocytosis, thrombocytopenia, leukopenia, anemias, lymph-adenopathy, or full-blown anaphylaxis. In humans, it is estimated that 1-15% of patients hypersensitive to cephalosporins will also be hypersensitive to penicillins. The incidence of cross-reactivity in veterinary patients is unknown. Reproductive/Nursing Safety Penicillins have been shown to cross the placenta and safe use of them during pregnancy has not been ﬁrmly established, but neither have there been any documented teratogenic problems associated with these drugs. However, use only when the potential beneﬁts outweigh the risks. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although speciﬁc studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) Overdosage/Acute Toxicity Overdosage of intramammary infusions is unlikely to pose much risk to the patient, but may prolong withdrawal times. Drug Interactions No signiﬁcant interactions are likely when intramammary dosage forms are used as labeled. Laboratory Considerations No speciﬁc concerns noted Doses Note : Oral dosage forms are no longer available commercially in the USA—see Dicloxacillin for oral use T ! DOGS: For susceptible infections: a) 20-40 mg/kg PO q8h (Vaden and Papich 1995) b) For Staph. pyoderma, diskospondylitis, osteoarthritis or skin infections: 10-15 mg/kg PO q6h for 14-84 days c) For systemic infections, bacteremia: 10-40 mg/kg PO q6-8h for 7-14 days (Greene and Watson 1998) T ! CATS: For susceptible infections: a) 20-40 mg/kg PO or IM q6-8h (Papich 1988) b) For Staph. pyoderma, diskospondylitis, osteoarthritis or skin infections: 10-15 mg/kg PO q6h for 14-84 days c) For systemic infections, bacteremia: 10-40 mg/kg PO q6-8h for 7-14 days (Greene and Watson 1998) T ! CATTLE: For mastitis (treatment or prophylaxis) caused by susceptible or-ganisms: a) Lactating cow (using lactating cow formula; Dari-Clox®): Af-ter milking out and disinfecting teat, instill contents of sy-ringe; massage. Repeat q12h for 3 total doses. Dry (non-lactating) cows (using dry cow formula; benza-thine): After last milking (or early in the dry period), instill contents of syringe and massage into each quarter. (Package inserts; Dari-Clox®, Orbenin-DC®—Beecham; Dri-Clox®— Fort Dodge) Monitoring T ! Because penicillins usually have minimal toxicity associated with their use, monitoring for efﬁcacy is usually all that is required un-less toxic signs develop. Serum levels and therapeutic drug moni-toring are not routinely done with these agents. Client Information T ! Dry cow products (benzathine; Orbenin-DC®, Dry-Clox®) slaugh-ter withdrawal = 28-30 days (depending on product used) T ! Lactating cow product ( Dariclox®) withdrawal times when used as labeled; milk withdrawal = 48 hours; slaughter withdrawal = 10 days	pppbs.pdf
CODEINE 225 Chemistry/Synonyms An isoxazolyl-penicillin, cloxacillin sodium is a semisynthetic, penicillinase-resistant penicillin. It is available commercially as the monohydrate sodium salt that occurs as an odorless, bitter-tasting, white, crystalline powder. It is freely soluble in water and soluble in alcohol and has a p K a of 2. 7. One mg of cloxacillin sodium contains not less than 825 micrograms of cloxacillin. Cloxacillin benzathine occurs as white or almost white powder that is slightly soluble in water and alcohol. A 1% (10 mg/m L) sus-pension has a p H from 3-6. 5. Cloxacillin sodium may also be known as: BRL-1621, sodium cloxacillin, chlorphenylmethyl isoxazolyl penicillin sodium, meth-ylchlorophenyl isoxazolyl penicillin sodium, cloxacilina sodica, cloxacillinum natricum, or P-25; many trade names are available. Storage/Stability Unless otherwise instructed by the manufacturer, cloxacillin ben-zathine or cloxacillin sodium mastitis syringes should be stored at temperatures less than 25°C in tight containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Cloxacillin Benzathine 500 mg (of cloxacillin) in a peanut-oil gel; 10 m L syringe for intramammary infusion: Orbenin-DC® (Schering-Plough), Dry-Clox® (Fort Dodge); (Rx). Approved for use in dairy cows during the dry period (immediately after last milking or early in the dry period). Do not use within 30 days prior to calving (28 days for Orbenin-DC®). Slaughter withdrawal = 30 days (28 days for Orbenin-DC®). A tolerance of 0. 01 ppm has been established for negligible residues in uncooked edible meat and milk from cattle. CODEINE PHOSPHATE CODEINE SULFATE (koe-deen) OPIATE Prescriber Highlights TT Opiate used for analgesia, cough, & sometimes diarrhea in dogs & cats TT Contraindications: Hypersensitivity to narcotics, receiv-ing MAOI's (amitraz, selegiline?), or diarrhea caused by a toxic ingestion until the toxin is eliminated TT Conditions where narcotics must be used with caution: Hypothyroidism, severe renal insufﬁciency, Addison's, head injuries or increased intracranial pressure, or acute abdominal conditions (e. g., colic) as it may obscure the diagnosis or clinical course of these conditions; in geriat-ric or severely debilitated patients; use extreme caution in patients with respiratory disease or acute respiratory dysfunction TT Adverse Effects most likely noted include: Sedation, con-stipation, high doses may cause respiratory depression. Cats may also show CNS stimulation. TT Controlled Substance (Class-II when used as a sole agent) Cloxacillin Sodium 200 mg (of cloxacillin) in vegetable oils; 10 m L syringe for intramammary infusion: Dariclox® (Schering-Plough); (Rx). Approved for use in lactating dairy cows. When used as la-beled, Milk withdrawal = 48 hours; Slaughter withdrawal = 10 days. HUMAN-LABELED PRODUCTS: None Uses/Indications In small animal medicine, codeine is used principally as an oral analgesic when salicylates are not effective and parenteral opiates are not warranted. It may also be useful as an antitussive or an antidiarrheal. Pharmacology/Actions Codeine possesses activity similar to other opiate agonists. It is an effective antitussive and a mild analgesic. It produces similar re-spiratory depression, as does morphine at equianalgesic dosages. For further information on opiate pharmacology, refer to: Opiate Agonists, Pharmacology. Pharmacokinetics No information was located speciﬁcally for domestic animals; the following information is human data unless otherwise noted. After oral administration, codeine salts are rapidly absorbed. Codeine is about 2/3's as effective after oral administration when compared with parenteral administration. After oral dosing, onset of action is usually within 30 minutes and analgesic effects persist for 4-6 hours. Codeine is metabolized in the liver and then excreted into the urine. Contraindications/Precautions/Warnings All opiates should be used with caution in patients with hypothy-roidism, severe renal insufﬁciency, adrenocortical insufﬁciency (Addison's disease), and in geriatric or severely debilitated patients. Codeine is contraindicated in cases where the patient is hypersen-sitive to narcotic analgesics, or in patients taking monamine oxi-dase inhibitors (MAOIs). It is also contraindicated in patients with diarrhea caused by a toxic ingestion (until the toxin is eliminated from the GI tract) or when used repeatedly in patients with severe inﬂammatory bowel disease.	pppbs.pdf
226 CODEINE Codeine should be used with caution in patients with head in-juries or increased intracranial pressure, and in those with acute abdominal conditions (e. g., colic) as it may obscure the diagnosis or clinical course of these conditions. Use with extreme caution in patients suffering from respiratory disease or from acute respiratory dysfunction (e. g., pulmonary edema secondary to smoke inhala-tion). Opiate analgesics are contraindicated in patients who have been stung by the scorpion species Centruroides sculpturatus Ewing and C. gertschi Stahnke as they may potentiate these venoms. Do not use the combination product containing acetaminophen in cats. Adverse Effects Codeine generally is well tolerated, but adverse effects are possible, particularly at higher dosages or with repeated use. Sedation is the most likely effect seen. Potential gastrointestinal effects include an-orexia, vomiting, constipation, ileus, and biliary and pancreatic duct spasms. Respiratory depression is generally not noted unless the pa-tient receives high doses or is at risk (see contraindications above). In cats, opiates may cause CNS stimulation with hyperexcitabil-ity, tremors, and seizures are possible. Reproductive/Nursing Safety Opiates cross the placenta. V ery high doses in mice have caused de-layed ossiﬁcation. Use during pregnancy only when the beneﬁts out-weigh the risks, particularly with chronic use. In humans, the FDA categorizes this drug as category C for use during pregnancy ( Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have uncovered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term. ) Although codeine enters maternal milk, no documented prob-lems have been associated with its use in nursing mothers. Overdosage/Acute Toxicity Opiate overdosage may produce profound respiratory and/or CNS depression in most species. Other effects can include cardiovascu-lar collapse, hypothermia, and skeletal muscle hypotonia. Oral in-gestions of codeine should be removed when possible using stan-dard gut removal protocols. Because rapid changes in CNS status may occur, inducing vomiting should be attempted with caution. 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 because naloxone's effects may diminish before subtoxic levels of codeine are attained. Mechanical respiratory support should also be considered in cases of severe re-spiratory depression. Serious overdoses involving any of the opiates should be closely monitored; it is suggested to contact an animal poison control center for further information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving codeine and may be of signiﬁcance in veterinary patients: !TANTICHOLINERGIC DRUGS : Use with codeine may increase the chanc-es of constipation developing !TANTIDEPRESSANTS (tricyclic/monoamine oxidase inhibitors ): May po-tentiate CNS depressant effects !TCNS DEPRESSANTS, OTHER (e. g., anesthetic agents, antihistamines, phenothiazines, barbiturates, tranquilizers, alcohol, etc. ) May cause in-creased CNS or respiratory depression when used with codeine !TQUINIDINE : May inhibit the transformation of codeine to morphine in the liver thereby decreasing it efﬁcacy 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: As an antitussive: a) 1-2 mg/kg PO q6-12h (Fenner 1994) b) Starting doses have been as low as 0. 1-0. 3 mg/kg PO q8-12h and as high as 1-2 mg/kg PO q6-12h. Whatever the starting point, the dose may need to be increased to achieve a satisfac-tory effective. (Church 2003) As an analgesic: a) For mild to moderate acute pain: 0. 5-2 mg/kg PO titrated to effect q6-12h. May use for chronic pain at lowest effective dose (Mathews 2000) b) In combination with acetaminophen: Using a 60 mg codeine and 300 mg acetaminophen ﬁxed-dose tablet (e. g., Tylenol® #4), give 1-2 mg/kg (of the codeine) PO q6-8h. Using co-deine alone: 1-4 mg/kg PO q1-6 hours (Hansen 1994); (Hardie 2000) Note : Do not use in cats. As an antidiarrheal: a) 0. 25-0. 5 mg/kg PO q6-8h (Sherding and Johnson 1994) !TCATS: Note : D o NOT use the combination product containing acetaminophen As an analgesic: a) For mild to moderate acute pain: 0. 5-2 mg/kg PO titrated to effect q6-12h. May use for chronic pain at lowest effective dose (Mathews 2000) b) 0. 5-2 mg/kg PO q6-8h (Scherk 2003a) !TRABBITS: Using acetaminophen and codeine elixir: a) 1 m L in 10-20 m L of drinking water (add dextrose to en-hance palatability) (Ivey and Morrisey 2000) Monitoring !TEfﬁcacy !TAdverse effects (see above) Client Information !TKeep out of reach of children !TDo not use any product containing acetaminophen ( e. g., Tylenol #3) in cats !TReport any signiﬁcant changes in behavior or activity level, or GI effects (constipation, lack of appetite, vomiting) to veterinarian Chemistry/Synonyms A phenanthrene-derivative opiate agonist, codeine is available as the base and three separate salts. Codeine base is slightly soluble in wa-ter and freely soluble in alcohol. Codeine phosphate occurs as ﬁne, white, needle-like crystals or white, crystalline powder. It is freely soluble in water. Codeine sulfate's appearance resembles codeine phosphate, but it is soluble in water.	pppbs.pdf
COLCHICINE 227 Codeine phosphate may also be known as: codeine phosphate hemihydrate, codeini phosphas; codeini phosphas hemihydricus, or codeinii phosphas; many trade names are available. Storage/Stability/Compatibility Codeine phosphate and sulfate tablets should be stored in light-resistant, well-closed containers at room temperature. Codeine phosphate injection should be stored at room temperature (avoid freezing) and protected from light. Do not use the injection if it is discolored or contains a precipitate. Codeine phosphate injection is reportedly compatible with glycopyrrolate or hydroxyzine HCl. It is reportedly incompatible with aminophylline, ammonium chloride, amobarbital sodium, chlorothiazide sodium, heparin sodium, methicillin sodium, pen-tobarbital sodium, phenobarbital sodium, phenytoin sodium, seco-barbital sodium, sodium bicarbonate, sodium iodide, and thiopen-tal sodium. 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: There are many products available containing codeine. The follow-ing is a partial listing: Codeine Phosphate Solution: 15 mg/5 m L in 500 m L & UD 5 m L; Codeine Phosphate (Roxane); (Rx, C-II) Codeine Sulfate Tablets: 15 mg, 30 mg & 60 mg; generic; (Rx, C-II) Codeine Phosphate Parenteral Injection: 15 mg/m L & 30 mg/m L in 2 m L Carpuject syringe; generic; (Rx, C-II) Codeine Phosphate Antitussives with expectorants: 10 mg codeine phosphate and 200 mg guaifenesin; 10 mg codeine phosphate and 100 mg guaifenesin; Many different trade names available; (C-V; C-III; certain states may restrict at a higher level; OTC or Rx) Codeine Phosphate 7. 5 mg (#1), 15 mg (#2), 30 mg (#3), 60 mg (#4) with Acetaminophen 300 mg tablets; Tylenol® with Codeine #'s 1, 2, 3, 4 (Mc Neil); generic; (Rx, C-III) WARNING: Do not use in cats. Codeine Phosphate 15 mg (#2), 30 mg (#3), 60 mg (#4) with Aspi-rin 320 mg tablets; Empirin® with Codeine #'s 2, 3, 4 (Glaxo Well-come); generic; (Rx, C-III) Note : Codeine-only products are Class-II controlled substances. Combination products with aspirin or acetaminophen are Class-III. Codeine containing cough syrups are either Class-V or Class-III, depending on the state. COLCHICINE (kol-chi-seen) ANTIINFLAMMATORY Prescriber Highlights TT Unique antiinﬂammatory occasionally used in dogs for hepatic cirrhosis/ﬁbrosis; relatively experimental TT Contraindications: Serious renal, GI, or cardiac dysfunction TT Caution: Geriatric or debilitated patients TT Teratogenic, reduces spermatogenesis TT Most likely adverse effects are GI distress (may be an early sign of toxicity), but several serious effects are possible including bone marrow suppression Uses/Indications In veterinary medicine, colchicine has been proposed as a treat-ment in small animals for amyloidosis. For colchicine to be effec-tive, however, it must be given early in the course of the disease and it will be ineffective once renal failure has occurred. At the time of writing, no conclusive evidence exists for its efﬁcacy for this indica-tion in dogs. Colchicine has also been proposed for treating chronic hepatic ﬁbrosis presumably by decreasing the formation and increasing the breakdown of collagen. Pharmacology/Actions Colchicine inhibits cell division during metaphase by interfering with sol-gel formation and the mitotic spindle. The mechanism for its antiﬁbrotic activity is believed secondary to collagenases activity stimulation. Colchicine apparently blocks the synthesis and secretion of se-rum amyloid A (SAA; an acute-phase reactant protein) by hepato-cytes thereby preventing the formation of amyloid-enhancing fac-tor and preventing amyloid disposition. Colchicine is best known in human medicine for its antigout ac-tivity. The mechanism for this effect is not fully understood, but it probably is related to the drug's ability to reduce the inﬂammatory response to the disposition of monosodium urate crystals. Pharmacokinetics No information was located speciﬁcally for domestic animals; the following information is human/lab animal data unless otherwise noted. After oral administration, colchicine is absorbed from the GI tract. Some of the absorbed drug is metabolized in the liver (ﬁrst-pass effect). These metabolites and unchanged drug are re-secreted into the GI tract via biliary secretions where it is reabsorbed. This “recycling” phenomena may explain the intestinal manifestations noted with colchicine toxicity. Colchicine is distributed into sev-eral tissues, but is concentrated in leukocytes. Plasma half-life is about 20 minutes, but leukocyte half-life is approximately 60 hours. Colchicine is deacetylated in the liver and metabolized in other tis-sues. While most of a dose (as colchicine and metabolites) is excret-ed in the feces, some is excreted in the urine. More may be excreted in the urine in patients with hepatic disease. Patients with severe renal disease may have prolonged half-lives. Contraindications/Precautions/Warnings Colchicine is contraindicated in patients with serious renal, GI, or cardiac dysfunction and should be used with caution in patients in	pppbs.pdf
228 COLCHICINE early stages of these disorders. It should also be used with caution in geriatric or debilitated patients. Colchicine use in veterinary medicine is somewhat controversial as safety and efﬁcacy have not been well documented. Adverse Effects There has been very little experience with colchicine in domestic ani-mals. There are reports that colchicine can cause nausea, vomiting, and diarrhea in dogs, but these are thought to occur infrequently at doses used. Neutropenia is a rare adverse effect. In humans, GI effects have been noted (abdominal pain, anorex-ia, vomiting, diarrhea) and can be an early indication of toxicity; it is recommended to discontinue therapy (in humans) should these occur. Prolonged administration has caused bone marrow depres-sion. Severe local irritation has been noted if extravasation occurs after intravenous administration; thrombophlebitis has also been reported. Reproductive/Nursing Safety Because colchicine has been demonstrated to be teratogenic in labo-ratory animals (mice and hamsters) it should be used during preg-nancy only when its potential beneﬁts outweigh its risks. Colchicine may decrease spermatogenesis. In humans, the FDA categorizes this drug as category C (ORAL) for use during pregnancy (Animal stud-ies 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 (PARENTERAL) for use during pregnancy (There is evidence of human fetal risk, but the potential beneﬁts from the use of the drug in pregnant women may be acceptable despite its potential risks. ) It is unknown if colchicine enters maternal milk; use cautiously in nursing mothers. Overdosage/Acute Toxicity Colchicine can be a very toxic drug after relatively small overdoses. Deaths in humans have been reported with a single oral ingestion of as little as 7 mg, but 65 mg is considered the lethal dose in an adult human. GI manifestations are usually the presenting signs seen. These can range from anorexia and vomiting to bloody diarrhea or paralytic ileus. Renal failure, hepatotoxicity, pancytopenia, paralysis, shock, and vascular collapse may also occur. There is no speciﬁc antidote to colchicine. Gut removal tech-niques should be employed when applicable. Because of the exten-sive GI “recycling” of the drug, repeated doses of activated charcoal and a saline cathartic may reduce systemic absorption. Other treat-ment is symptomatic and supportive. Dialysis (peritoneal) may be of beneﬁt. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving colchicine and may be of signiﬁcance in veterinary patients: !TBONE MARROW D EPRESSANT MEDICATIONS (e. g., antineoplastics, im-munosuppressants, chloramphenicol, amphotericin B ): May cause ad-ditive myelosuppression when used with colchicine Laboratory Considerations !TColchicine may cause false-positive results when testing for erythrocytes or hemoglobin in urine. !TColchicine may interfere with 17-hydroxycorticosteroid determina-tions in urine if using the Reddy, Jenkins, and Thorn procedure. !TColchicine may cause increased serum values of alkaline phosphatase. Doses Colchicine may have some efﬁcacy in the treatment of amyloidosis, but veterinary dosages are apparently unavailable at this time. !TDOGS: For the adjunctive treatment of hepatic cirrhosis/ﬁbrosis: a) 0. 03 mg/kg PO once daily (Leveille-Webster and Center 1995); (Twedt 1999); (Richter 2002); (Willard 2006b) b) 0. 025-0. 03 mg/kg PO once daily (probenecid-free drug). Not recommended for initial use with azathioprine, chloram-bucil or methotrexate due to similar side effects (GI toxicity, bone marrow suppression). Used in many dogs and fewer cats without problems. (Center 2002), (Center 2006a) For amyloidosis: a) For periodic fever syndrome in Shar Pei dogs: 0. 03 mg/kg PO once daily. (Scherk and Center 2005) b) T o reduce the frequency and severity of fever and prevent the development of amyloidosis in dogs with Shar Pei Fe-ver: 0. 025-0. 03 mg/kg PO q24h; no evidence supports use of colchicine once amyloidosis has resulted in renal failure (Vaden 2006a) Monitoring !TEfﬁcacy !TAdverse effects (see above) !TCBC Client Information !TClients should be informed of the “investigational” nature of colchicine use in dogs and should be informed of the potential adverse effects that may be seen !TReport changes in appetite or other GI effects immediately to vet-erinarian !TKeep well out of reach of children or pets !TPregnant women should avoid exposure to the drug or urine of animals being treated Chemistry/Synonyms An antigout drug possessing many other pharmacologic effects, colchicine occurs as a pale yellow, amorphous powder or scales. It is soluble in water and freely soluble in alcohol. Colchicine may also be known as: colchicinum, Artrex ®, Colchily®, Colchicquim®, Colchis®, Colcine®, Colgout ®, Goutichine®, Goutnil®, Reugot®, Ticolcin®, or Tolchicine®. Storage/Stability Colchicine tablets should be stored in tight, light resistant containers. The injection should be diluted only in 0. 9% sodium chloride for injection or sterile water for injection. Do not use D 5W or bacterio-static sodium chloride for injection as precipitation may occur. Do not use solutions that have become turbid. 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.	pppbs.pdf
CORTICOTROPIN (ACTH) 229 HUMAN-LABELED PRODUCTS: Colchicine Tablets: 0. 6 mg (1/100 gr); generic; (Rx); Colchicine Injection: 0. 5 mg/m L in 2 m L vials; Colchicine (Bed-ford); (Rx) A combination oral product (tablets) containing colchicine 0. 5 mg and probenecid 500 mg is also available (not likely to be useful in veterinary patients) Co-Trimoxazole; Co-trimazine — See Sulfa/Trimethoprim CORTICOTROPIN (ACTH) (kor-ti-koe-troe-pin) Acthar® HORMONAL DIAGNOSTIC AGENT Prescriber Highlights TT Stimulates cortisol release; used primarily to test for hyper-or hypoadrenocorticism (ACTH-stimulation test) TT Adverse Effects: Unlikely unless using chronically TT Do not administer gel form IV TT Issues include availability & expense Uses/Indications Availability of corticotropin in FDA-approved products is an issue as no commercially products were commercially available for vet-erinary use at the time writing and either cosyntropin (see mono-graph) or compounded ACTH products are required. In veterinary medicine, an ACTH product (Adrenomone®— Summit Hill) was approved for use in dogs, cats, and beef or dairy cattle for stimulation of the adrenal cortex when there is a deﬁ-ciency of ACTH and as a therapeutic agent in primary bovine keto-sis, but apparently is no longer commercially available. In practice, ACTH tends to be used most often in the diagnosis of hyper-or hypoadrenocorticism (ACTH-stimulation test) and to monitor the response to mitotane therapy in Cushing's syndrome. One reference (Behrend 2003a) recommends using the ACTH stimulation test if the dog has non-adrenal illness, received any form of exogenous glucocorticoids (including topicals), or received phenobarbital. If the dog has no known non-adrenal illness and moderate to severe clinical signs of hyperadrenocorticism, use the low-dose dexamethasone suppression test. If using the ACTH-stim test, the author states that cosyntropin is the agent of choice (see that monograph). ACTH has been used for several purposes in human medicine for its corticosteroid stimulating properties, but as it must be in-jected, it is not commonly employed in veterinary patients. Pharmacology/Actions ACTH stimulates the adrenal cortex (principally the zona fascic-ulata) to stimulate the production and release of glucocorticoids (primarily cortisol in mammals and corticosterone in birds). ACTH release is controlled by corticotropin-releasing factor (CRF) activated in the central nervous system and via a negative feedback pathway, whereby either endogenous or exogenous glucocorticoids suppresses ACTH release. Pharmacokinetics Because it is rapidly degraded by proteolytic enzymes in the gut, ACTH cannot be administered PO. It is not effective if adminis-tered topically to the skin or eye. After IM injection in humans, repository corticotropin injection is absorbed over 8-16 hours. The elimination half-life of circulat-ing ACTH is about 15 minutes but because of the slow absorption after IM injection of the gel, effects may persist up to 24 hours. Contraindications/Precautions/Warnings When used for diagnostic purposes, it is unlikely that increases in serum cortisol levels induced by ACTH will have signiﬁcant delete-rious effects on conditions where increased cortisol levels are con-traindicated (e. g., systemic fungal infections, osteoporosis, peptic ulcer disease, etc. ). ACTH gel should not be used in patients hyper-sensitive to porcine proteins. Adverse Effects Prolonged use may result in ﬂuid and electrolyte disturbances and other adverse effects; if using on a chronic basis, refer to the human literature for an extensive listing of potential adverse reactions. The veterinary manufacturer suggests giving potassium supplementa-tion with chronic therapy. Do not administer the repository form (gel) IV. Reproductive/Nursing Safety ACTH should only be used during pregnancy when the potential beneﬁts outweigh the risks. It may be embryocidal. Neonates born from mothers receiving ACTH should be observed for signs of adrenocortical insufﬁciency. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate stud-ies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity When used for diagnostic purposes, acute inadvertent overdoses are unlikely to cause any signiﬁcant adverse effects. Monitor as re-quired and treat symptomatically if necessary. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving corticotropin for diag-nostic purposes and may be of signiﬁcance in veterinary patients: T ! ANTICHOLINESTERASES (e. g., pyridostigmine ): ACTH may antago-nize effects in patients with myasthenia gravis T ! DIURETICS : ACTH may increase electrolyte loss Laboratory Considerations T ! Patients should not receive hydrocortisone or cortisone on test day T ! ACTH may decrease 131I uptake by the thyroid gland T ! ACTH may suppress skin test reactions T ! ACTH may interfere with urinary estrogen determinations T ! Obtain speciﬁc information from the laboratory on sample han-dling and laboratory normals for cortisol when doing ACTH stimulation tests Doses Note : When using compounded ACTH products, it is recommend-ed to get several post-ACTH samples, at a minimum one and two hours following injection. (Behrend 2005) T ! DOGS: ACTH Stimulation T est: a) Draw baseline blood sample for cortisol determination and administer 2. 2 Units/kg of ACTH gel IM. Draw sample 120 minutes after injection. (Feldman and Peterson 1984), (Kemppainen and Zerbe 1989b)	pppbs.pdf
230 COSYNTROPIN b) Draw baseline blood sample for cortisol determination and administer 0. 5 Units/kg of ACTH gel IM. Draw sample 120 minutes after injection. Normals: Pre-ACTH 1. 1-8 micrograms/dl; Post-ACTH 6. 2-16. 8 micrograms/dl. Hyperadrenocorticism: Pre-ACTH 4-10. 8 micrograms/dl; Post-ACTH 11. 7-50 micrograms/dl. Hypoadrenocorticism: Pre-ACTH and Post-ACTH: ≤ 1 mi-crograms/dl (Morgan 1988) T ! CATS: ACTH Stimulation T est: a) Draw baseline blood sample for cortisol determination and administer 2. 2 Units/kg of ACTH gel IM. Draw samples at 60 minutes and 120 minutes after injection. (Peterson and Ran-dolph 1989), (Kemppainen and Zerbe 1989b) b) Draw baseline blood sample for cortisol determination and administer 0. 5 Units/kg of ACTH gel IM. Draw sample 120 minutes after injection. Normals: Pre-ACTH 0. 33-2. 6 micrograms/dl; Post-ACTH 4. 8-7. 6 micrograms/dl. Hyperadrenocorticism: Pre-ACTH 4-10. 8 micrograms/dl; Post-ACTH 11. 7-50 micrograms/dl. Hypoadrenocorticism: Pre-ACTH and Post-ACTH: ≤ 1 mi-crograms/dl (Morgan 1988) T ! CATTLE: For ACTH deﬁciency or for primary bovine ketosis: a) 200-600 Units initially followed by daily or semi-daily dose of 200-300 Units (Package Insert; Adrenomone®—Summit Hill) b) 200 Units IM daily (Howard 1986) T ! HORSES: ACTH Stimulation T est: a) Draw baseline blood sample for cortisol determination and administer 1 Unit/kg IM of ACTH gel. Draw second sample 8 hours later. Normal stimulation will result in serum cortisol levels will increase 2-3 times. Horses with pituitary tumors will increase cortisol fourfold after ACTH. (Beech 1987b) b) Obtain pre-dose level. Administer 1 Unit/kg IM of ACTH gel between 8 and 10 AM; take post ACTH cortisol levels at 2 and 4 hours post dose. Horses with a functional adrenal gland should have a 2-to 3-fold increase in plasma cortisol when compared with baseline. (T oribio 2004a) T ! BIRDS: ACTH Stimulation T est: a) Draw baseline blood sample for corticosterone (not cortisol) determination and administer 16-25 Units IM. Draw second sample 1-2 hours later. Normal baseline corticosterone levels vary with regard to species, but generally range from 1. 5-7 ng/m L. After ACTH, corticosterone levels generally increase by 5-10 times those of baseline. Speciﬁc values are listed in the reference. (Lothrop and Harrison 1986) Chemistry/Synonyms A 39 amino acid polypeptide, corticotropin is secreted from the anterior pituitary. The ﬁrst 24 amino acids (from the N-terminal end of the chain) deﬁne its biologic activity. While human, sheep, cattle and swine corticotropin have different structures, the ﬁrst 24 amino acids are the same and, therefore, biologic activity is thought to be identical. Commercial sources of ACTH have generally been obtained from porcine pituitaries. One USP unit of corticotropin is equivalent to 1 mg of the international standard. Corticotropin may also be known as: ACTH, adrenocorti-cotrophic hormone, adrenocorticotrophin, corticotrophin, corti-cotropinum, Acethropan®, Acortan simplex®, Actharn®, Acthelea®, Acton prolongatum®, H. P. Acthar® or Cortrophin-Zinc®. Storage/Stability/Compatibility Corticotropin in the past has been available commercially as cor-ticotropin for injection, repository corticotropin for injection, and corticotropin zinc hydroxide suspension. Corticotropin is common-ly called ACTH (abbreviated from adrenocorticotropic hormone). Repository corticotropin is often called ACTH gel and is the most commonly used ACTH product in veterinary medicine. Corticotropin for injection (aqueous) can be stored at room temperature (15-30°C) before reconstitution. After reconstitution, it should be refrigerated and used within 24 hours. Repository cor-ticotropin injection should be stored in the refrigerator (2-8°C). T o allow ease in withdrawing the gel into a syringe, the vial may be warmed with warm water prior to use. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None Compounded ACTH products may be available from compounding pharmacies. HUMAN-LABELED PRODUCTS: Corticotropin, Repository for Injection: 80 Units/m L in m L 5 m L multi-dose vials; H. P. Acthar® Gel (Questcor); (Rx) Note : This prod-uct is only available through a specialty pharmacy distribution sys-tem and is not available via regular retail pharmacies or drug whole-salers. COSYNTROPIN (koh-sin-troh-pin) Cortrosyn®, Synacthen® HORMONAL DIAGNOSTIC AGENT Prescriber Highlights TT Alternative to ACTH for adrenal function tests TT Drug-lab interactions TT Availability & expense have been issues Uses/Indications Cosyntropin is used primarily as an alternative to ACTH to test for adrenocortical insufﬁciency (Addison's), or hyperadrenocorticism, particularly in animals who have reacted immunologically to corti-cotropin in the past or if ACTH gel is unavailable. Pharmacology/Actions Like endogenous corticotropin, cosyntropin stimulates the adrenal cortex (in normal patients) to secrete cortisol, corticosterone, etc. Because of its structure, corticotropin is not as immunogenic as en-dogenous corticotropin. Apparently, the bulk of immunogenicity resides in the C-terminal portion of corticotropin (22-39 amino acids) and cosyntropin ends after amino acid #24. Pharmacokinetics Cosyntropin must be given parenterally because it is inactivated by gut enzymes. It is rapidly absorbed after being given IM. After giv-ing IM or rapid IV, plasma cortisol levels reach their peak within an hour. It is unknown how cosyntropin is inactivated or eliminated.	pppbs.pdf
COSYNTROPIN 231 Contraindications/Precautions/Warnings Contraindicated in patients with known hypersensitivity to co-syntropin. Use caution in patients who have shown hypersensitive reactions to ACTH in the past; there is a distinct possibility that cross-reactivity could occur. Adverse Effects When used short-term, the only real concern is hypersensitivity reactions. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity Unlikely to be of clinical consequence if used one-time only. Laboratory Considerations !TPatients should not receive hydrocortisone or cortisone on test day; dexamethasone sodium phosphate does not interfere with corti-sol assays !TIf using a ﬂuorometric analysis: Falsely high values may be ob-served if the patient is taking spironolactone !TFalsely high values may be observed in patients with high bilirubin or if free plasma hemoglobin present Doses !TDOGS: For testing (screening) adrenal function: a) For tentative diagnosis of Addison's disease: 1) Draw blood for hemogram, serum biochemistry and basal cortisol; 2) Begin IV ﬂuids and give 2-5 mg/kg dexamethasone sodium phosphate; 3) Immediately give 0. 25 mg of cosyntropin IV or IM; 4) Draw a second blood sample for plasma cortisol 45-60 minutes later. Blood levels of <1 mcg/d L are typical for hypoadrenocorticism, while those stimulating to only 2-3 mcg/d L are also suggestive. (Schaer 2006) b) 5 mcg/kg IV; measure serum cortisol at 0 and 1 hour. (Wat-son, Church et al. 1998) c) 5 mcg/kg with a maximum of 250 mcg IV. Once reconsti-tuted, the solution may be frozen for up to six months and used. (Behrend 2003a) d) For ACTH Stimulation test: Two different protocols: 1 mcg/ kg or 250 mcg/dog IV or IM with serum cortisol measured before and 1 hour post injection. 80-85% of dogs with pi-tuitary-dependent hyperadrenocorticism (PD) and 60% of dogs with adrenal tumor/hyperplasia (AT) will have an exag-gerated response. Unfortunately, just about any other extra-adrenal illness can cause an exaggerated post-ACTH level. (Reine 2006) !TCATS: For testing (screening) adrenal function: a) For tentative diagnosis of Addison's disease: 1) Draw blood for hemogram, serum biochemistry and basal cortisol; 2) Begin IV ﬂuids and give 2-5 mg/kg dexamethasone sodium phosphate; 3) Immediately give 0. 125 mg of cosyntropin IV or IM; 4) Draw a second blood sample for plasma cortisol 45-60 minutes later. Blood levels of <1 mcg/d L are typical for hypoadrenocorticism, while those stimulating to only 2-3 mcg/d L are also suggestive. (Schaer 2006) b) 0. 125 mg (total dose—125 mcg) IM or IV. Begin test between 8-9 AM; obtain preinjection cortisol level and 30 minutes and 1 hour post. (Feldman 2000) c) For diagnosis of hyperadrenocorticism in cats: 125 mcg/cat IM or IV with cortisol measurements before and at 30 and 60 minutes post. (Reine 2006) !THORSES: For testing (screening) adrenal function: a) For relative adrenal insufﬁciency (RIA) evaluation in criti-cally ill horses: Draw blood for baseline cortisol and give co-syntropin at 0. 1 mcg/kg; cortisol will peak after 30 minutes. (Stewart 2006) b) Obtain pre-dose level. Administer 1 mg IV of cosyntropin between 8 and 10 AM; take post ACTH cortisol levels at 2 hours post dose. Horses with a functional adrenal gland should have at least a two-fold increase in plasma cortisol when compared with baseline. (T oribio 2004a) Monitoring !TSee speciﬁc protocols for test procedures Chemistry/Synonyms A synthetic polypeptide that mimics the effects of corticotropin (ACTH), cosyntropin is commercially available as a lyophilized white to off-white powder containing mannitol. Cosyntropin's structure is identical to the ﬁrst 24 (of 39) amino acids in natural corticotropin. 0. 25 mg of cosyntropin is equivalent to 25 units of corticotropin. Cosyntropin may also be known as: tetracosactide, al-pha(1-24)-corticotrophin, beta(1-24)-corticotrophin, tetracosac-tido, tetracosactidum, tetracosactrin, tetracosapeptide, Cortrosina®, Cortrosyn®, Nuvacthen Depot®, Synacthen®, Synacthen Depot®, Synacthen Retard®, or Synacthene®. Storage/Stability/Compatibility After reconstituting with sterile normal saline, the solution is stable for 24 hours at room temperature; 21 days if refrigerated. Do not add the drug to blood or plasma infusions. One study (Frank and Oliver 1998) showed that cosyntropin can be reconstituted and stored frozen (-20°C) in plastic syringes for up to 6 months and still show biologic activity in the dog. It is recommended to freeze in small aliquots as it is unknown what effect thawing and refreezing has on potency. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cosyntropin Powder for Injection: 0. 25 mg lyophilized (250 mcg) in vials with 10 mg mannitol with diluent; Cortrosyn® (Ampha-star); (Rx)	pppbs.pdf
232 CROMOLY N SODIUM T TCROMOLYN S ODIUM ( SYSTEMIC) (kroh-mah-lin) Disodium Cromoglycate, Sodium Cromoglicate, Intal® MAST CELL STABILIZER For ophthalmic use, see the monograph in the Ophthalmic Drug Appendix Prescriber Highlights TT Inhaled mast cell stabilizer that may be useful adjunctive treatment in preventing airway hyper-reactivity in horses with type 2 (high mast cell count in BAL) IAD or with RAO (heaves) TT Not for treatment of acute bronchoconstriction; used as a preventative agent TT May take several days or weeks for efﬁcacy Uses/Indications Cromolyn sodium is a mast cell stabilizer that may be useful in re-ducing airway hyper-reactivity in horses with type 2 (high mast cell count in bronchoalveolar lavage ﬂuid; mast cells of >2% of the to-tal cell count) inﬂammatory airway disease (IAD) or with recurrent airway obstruction (RAO; heaves). Use of this agent is somewhat controversial; studies have yielded conﬂicting efﬁcacy results. Pharmacology/Actions Cromolyn inhibits the release of histamine and leukotrienes from sensitized mast cells found in lung mucosa, nasal mucosa and eyes. Its exact mechanism of activity is not understood, but it is thought to be a result from blocking indirect entry of calcium ions into cells. Other effects of cromolyn include inhibiting neuronal reﬂexes in the lung, inhibiting bronchospasm secondary to tachykins, inhibit-ing the movement of other inﬂammatory cells (neutrophils, mono-cytes, eosinophils), and preventing the down-regulation of beta-2 adrenergic receptors on lymphocytes. Cromolyn does not possess antihistaminic, anticholinergic, antiserotonin, corticosteroid-like, or antiinﬂammatory actions. Pharmacokinetics Limited information is available for horses. The amount of cromo-lyn reaching the distal airways is probably variable and dependent on the type of nebulizer used and the amount of concurrent bron-choconstriction present. Absorbed cromolyn is eliminated in the urine and via the bile into the feces. In humans, less than 2% is absorbed from the GI tract after oral dosing. Approximately 8% is absorbed when inhaled into the lung. Absorbed drug is eliminated via the feces and urine as unchanged drug. Contraindications/Precautions/Warnings Do not use in patients with documented hypersensitivity to cromolyn. Unlikely to be of beneﬁt in treating horses with types 1and 3 IAD. Cromolyn has no efﬁcacy in treating acute bronchospasm. Adverse Effects Adverse effects associated with inhaled cromolyn use in horses are not well documented. Cough and treatment avoidance (secondary to bad taste?) have been reported. It has been proposed that pre-treatment with albuterol may reduce the incidence of cough. Humans can occasionally develop cough, throat irritation or complain of unpleasant taste. Rarely, bronchoconstriction and ana-phylaxis (<0. 0001%) have been reported. Reproductive/Nursing Safety Laboratory animal studies have shown no effect on fertility. T eratogenicity studies in mice, rats and rabbits have not demon-strated any teratogenic effects and it is likely safe to use during preg-nancy. Extremely low (or undetectable) levels have been detected in milk; cromolyn is most likely safe to use during nursing. Overdosage/Acute Toxicity Because of the drug's low systemic bioavailability after inhalation or oral administration, acute overdoses are unlikely to cause signiﬁcant morbidity. Drug Interactions No notable drug interactions have been reported. Laboratory Considerations No notable laboratory interactions or alterations have been reported. Doses T ! HORSES: a) For type 2 inﬂammatory airway disease: Using a jet nebulizer: 200 mg (total dose) q12 hours; using an ultrasonic nebulizer 80 mg once daily (q24h). (Couetil 2002) b) For RAO/IAD (either as long-term therapy or before exposure to allergens): Using the aerosol (800 mcg/puff) and a suitable delivery system: 8-12 mg (10-15 puffs) once to twice daily. (Mazan 2003) Monitoring T ! Clinical efﬁcacy T ! For horses with type 2 IAD, reductions in mast cell counts in bronchoalveolar lavage ﬂuid could help conﬁrm efﬁcacy Client Information T ! his medication does not treat airway constriction but used to prevent airway constriction by reducing the release of substances from cells that can cause it; it should not be used to treat acute bronchoconstriction (difﬁculty breathing). T ! his medicine must be must be dosed once to twice daily and it may take several days or weeks before it can be determined if it is working. T ! Proper use of the drug delivery device is very important; if any questions arise regarding proper use, contact the veterinarian. Chemistry/Synonyms Cromolyn sodium occurs as a white, odorless, hygroscopic, crystal-line powder that is soluble in water and insoluble in alcohol. Cromolyn sodium may also be known as cromoglicic acid, cro-moglycic acid, sodium cromoglicate, disodium cromoglycate, sodi-um cromoglycate, DSCG, SCG, FPL-670, or DNSG; there are many international trade names. Storage/Stability/Compatibility Cromolyn sodium solution for inhalation should be stored below 40°C (104°F); preferably between 15-30°C. Protect from freezing, light and humidity. Store in foil pouch until ready for use. Do not use solution if it is cloudy or contains a precipitate. Solution remain-ing in nebulizers after use should be discarded.	pppbs.pdf
CYANOCOBALAMIN (VITAMIN B12) 233 Cromolyn solution is reportedly compatible with acetylcysteine, albuterol, epinephrine, isoetherine, isoproterenol, metaproterenol, or terbutaline solutions for up to 60 minutes. It is not compatible with bitolterol. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cromolyn Sodium Solution for Inhalation: 20 mg/2 m L vials or amps; Intal® (Aventis), generic; (Rx) Cromolyn Sodium Aerosol for Inhalation: 800 mcg/actuation in 8. 1 g (112 sprays) and 14. 2 g (200 sprays) canisters; Intal® (Aventis); (Rx) There is also an OTC nasal solution ( Nasalcrom ®), and an oral con-centrate ( Gastrocrom ®) indicated for mastocystosis available, but these dosage forms are unlikely to be of use in veterinary medicine. CYANOCOBALAMIN (VITAMIN B 12) (sye-an-oh-koe-bal-ah-min) VITAMIN/NUTRITIONAL Prescriber Highlights Used for parenteral treatment of vitamin B12 deﬁciency TT Very safe TT Uses/Indications Cyanocobalamin is used for treating deﬁciencies of vitamin B12. Malabsorption of the nutrient secondary to gastrointestinal tract disease, or dietary chromium deﬁciencies (in ruminants) can be as-sociated with dietary deﬁciencies of vitamin B12. As there appears to be a high percentage of cats with exocrine pancreatic insufﬁcien-cy or gastrointestinal disease that are deﬁcient in cobalamin, there is considerable interest in evaluating serum cobalamin (vitamin B12) in these patients. Giant schnauzers may have a genetic defect af-fecting the location of the cobalamin-intrinsic factor, causing coba-lamin deﬁciency. Dogs with inﬂammatory bowel disease may also develop cobalamin deﬁciency. Pharmacology/Actions Vitamin B12 (cobalamin), a cobalt-containing water-soluble vita-min, serves as an important cofactor for many enzymatic reactions in mammals that are required for normal cell growth, function and reproduction, nucleoprotein and myelin synthesis, amino acid me-tabolism, and erythropoiesis. Cobalamin is required for folate utili-zation; B12 deﬁciency can cause functional folate deﬁciency. Unlike humans, macrocytic anemias do not appear to be a signiﬁcant com-ponent to cobalamin deﬁciency in dogs or cats. Clinical signs associated with cobalamin deﬁciency in cats may include weight loss, poor haircoat, vomiting, or diarrhea. Increases in serum methionine and methylmalonic acid, and decreased se-rum cystathionine and cysteine values may be noted. Homocysteine levels do not appear to be affected. In dogs, cobalamin deﬁciency may cause or contrib-ute to inappetance, diarrhea, weight loss, leukopenia, or methylmalonylaciduria. In ruminants, vitamin B12 appears to be synthesized by rumen microﬂora and requires dietary cobalt to be present for its forma-tion. Clinical signs seen with cobalamin deﬁciency states associated with cobalt deﬁciency in cattle and sheep include inappetance, las-situde, poor haircoat/ﬂeece, poor milk production, weight loss, or failure to grow. Pharmacokinetics After food is consumed in monogastric mammals,cobalamin in food is bound to a protein (haptocorrin) in the stomach. Haptocorrin/ cobalamin is degraded by pancreatic proteases in the duodenum, but cobalamin is then bound by Intrinsic factor (IF), a protein pro-duced in the stomach and pancreas in dogs, in the pancreas (only) in cats, and in the stomach (only) in humans. The cobalamin-IF complex is absorbed in the small intestine where it binds to cubu-lin, which facilitates its entry into the portal circulation. A protein called transcobalamin 2 (TCII) then binds to cobalamin allowing its entry into target cells. Some cobalamin is rapidly excreted into the bile where entero-hepatic recirculation occurs. Dogs and cats, unlike humans, do not possess cobalamin-binding protein TC1. This means that dogs and cats with B12 dietary deﬁciency or ma-labsorption can rapidly deplete their stores of B12 in one to two months, whereas in humans it may require 1-2 years. In normal cats, circulating half-life of cobalamin is approxi-mately 13 days, but in two cats with inﬂammatory bowel disease, it was only 5 days (Simpson, Fyfe et al. 2001). Contraindications/Precautions/Warnings For injectable use, no contraindications are documented for do-mestic animals. In humans, cyanocobalamin is contraindicated in patients hypersensitive to it or hydroxocobalamin. Adverse Effects Cyanocobalamin appears very well tolerated when used parenter-ally in animals. In humans, anaphylaxis has been reported rarely after parenteral use. Some human patients complain of pain at the injection site, but this is uncommon. Reproductive/Nursing Safety Studies documenting safety during pregnancy have apparently not been done in humans or animals, but it is likely safe to use. Vitamin B12 deﬁciency states are thought to cause teratogenic effects. While vitamin B12 can be excreted into milk, it is safe to use while nursing. Overdosage/Acute Toxicity No overdose information was located, but an inadvertent overdose of cyanocobalamin given via SC or IM injection is unlikely to cause signiﬁcant morbidity. Drug Interactions No signiﬁcant drug interactions have been identiﬁed when cyano-cobalamin is administered parenterally. Laboratory Considerations T ! Serum samples to be analyzed for cobalamin and/or folate should be protected from bright light and excessive heat T ! If a microbiologic method assay is used to determine cobalamin values, concurrent use of antibiotics can cause falsely low serum or red blood cell values Doses T ! DOGS: a) Cobalamin deﬁciency in dogs with severe GI disease: Inject-able cyanocobalamin at 25 mcg/kg once per week for 4-6 weeks, then once monthly thereafter to maintain normal se-rum levels. (Zoran 2006d)	pppbs.pdf
234 CYCLOPHOSPHAMIDE b) Cobalamin deﬁciency associated with GI disease: Based on body size, 250-800 mcg SC once weekly for 6 weeks, one more dose a month later and a re-check one month after that. Re-evaluation is important to determine if continued cobala-min supplementation is indicated. (Stiener 2005) c) Cobalamin deﬁciency associated with exocrine pancreatic insufﬁciency: 250-500 mcg parenterally; repeat treatment based upon serum levels. (Westermarck, Wiberg et al. 2005) T ! CATS: a) Cobalamin deﬁciency in cats with IBD: 250-500 mcg (total dose per cat) SC once per week for 6 weeks, then every 1-2 months. (Marks 2003) b) Cobalamin deﬁciency associated with GI disease: Based on body size, 150-250 mcg SC once weekly for 6 weeks, one more dose a month later and a re-check one month after that. Re-evaluation is important to determine if continued cobala-min supplementation is indicated. (Stiener 2005) c) Cobalamin deﬁciency associated with exocrine pancreatic insufﬁciency: 100-250 mcg SC once weekly; periodically as-sess cobalamin and folate levels. (Westermarck, Wiberg et al. 2005) T ! HORSES: a) For vitamin B12 deﬁciency: 1-2 m L of a 1000 mcg/m L in-jection (1000-2000 mcg) injected IM or SC; dosage may be repeated once or twice weekly, as indicated by condition or response. (Label information; Amtech Vitamin B12 1000 mcg—IVX) T ! CATTLE, SHEEP: a) For treatment of vitamin B12 deﬁciency associated with co-balt deﬁciency: Lambs: 100 mcg injected once weekly. Adult sheep: 300 mcg injected once weekly. (Baxter 1986) b) For treatment of vitamin B12 deﬁciency associated with co-balt deﬁciency: Cattle and sheep: 0. 2-0. 4 m L of a 5000 mcg/ m L injection (1000-2000 mcg) injected IM or SC; dosage may be repeated in weekly intervals if necessary. (Label infor-mation; Vitamin B12 5000 mcg—Butler) T ! SWINE: a) For vitamin B12 deﬁciency: 0. 1-0. 4 m L of a 5000 mcg/m L injection (500-2000 mcg) injected IM or SC; dosage may be repeated in weekly intervals if necessary. (Label information; Amtech Vitamin B12 5000 mcg—IVX) Monitoring T ! Cobalamin levels T ! In small animals: folate status; both before and after treatment with cyanocobalamin T ! Clinical signs associated with deﬁciency T ! CBC, baseline and ongoing if abnormal Client Information T ! Several weeks after starting B12 therapy may be required before improvement is seen T ! Vitamin B12 deﬁciency in animals may require life-long treatment T ! As cyanocobalamin may be administered SC, clients can be in-structed to administer at home, but the importance of ongoing follow-up with the veterinarian must be stressed Chemistry/Synonyms Cyanocobalamin occurs as dark red crystals or crystalline powder. It is sparingly soluble in water (1 in 80) and soluble in alcohol. When in the anhydrous form, it is very hygroscopic and can absorb sub-stantial amounts of water from the air. Vitamin B12 may also be known as cobalamins. Cyanocobalamin may also be known as: cyanocobalamine, cyanocobalaminum, co-bamin, cianokobalaminas, cianocobalamina, or cycobemin; many internationally registered trade names. Storage/Stability/Compatibility Cyanocobalamin injection should be stored below 40°C; protect from light and freezing. Cyanocobalamin injection is reportedly compatible with all commonly used intravenous ﬂuids. Dosage Forms VETERINARY-LABELED PRODUCTS: Cyanocobalamin (Vitamin B 12) Injection 1000, 3000 and 5000 mcg/ m L in 100 m L, 250 m L and 500 m L multi-dose vials depending on source; generic; (Rx). Products may be labeled as cyanocobalamin or vitamin B12, and be labeled for use in cattle, horses, dogs, cats, sheep, or swine. There are many combination products, both oral and injectable, con-taining cyanocobalamin as one of the ingredients. These are not rec-ommended for use when cobalamin deﬁciency states exist. HUMAN-LABELED PRODUCTS: Cyanocobalamin (crystalline, Vitamin B 12) Injection 100 mcg (0. 1 mg) per m L and 1000 (1 mg) per m L, vial sizes range from 1 m L single-use to 10 and 30 m L multi-dose; generic; (Rx). Besides ge-nerically labeled products, there are several products available with a variety of trade names, including Cyanoject®, Rubesol®, Crysti®, or Crystamine®. Oral tablet dosage forms are also available, but are not appropriate for therapy of cobalamin deﬁcient states in small animal medicine. A nasally administered product is marketed, but there is no infor-mation on its use in dogs or cats. CYCLOPHOSPHAMIDE (sye-kloe-foss-fa-mide) Cytoxan®, Neosar® IMMUNOSUPPRESSIVE/ANTINEOPLASTIC Prescriber Highlights TT Antineoplastic/immunosuppressive used in dogs & cats for a variety of conditions TT Contraindications: Prior anaphylaxis; caution in patients with leukopenia, thrombocytopenia, previous radio-therapy, impaired hepatic or renal function, or in those for whom immunosuppression may be dangerous (e. g., infection) TT Potentially teratogenic, fetotoxic TT Primary adverse effects are myelosuppression, GI effects, alopecia (especially Poodles, Old English Sheepdogs, etc. ), & hemorrhagic cystitis TT Adequate monitoring essential Uses/Indications In veterinary medicine, cyclophosphamide is used primarily in small animals (dogs and cats) in combination with other agents both as an antineoplastic agent (lymphomas, leukemias, carcinomas, and sarcomas) and as an immunosuppressant (SLE, ITP, IMHA, pem-phigus, rheumatoid arthritis, proliferative urethritis, etc. ). Its use in treating acute immune-mediated hemolytic anemia is controversial;	pppbs.pdf
CYCLOPHOSPHAMIDE 235 there is some evidence that it does not add beneﬁcial effects when used with prednisone. Cyclophosphamide has been used as a chemical shearing agent in sheep. Pharmacology/Actions While commonly categorized as an alkylating agent, the parent compound (cyclophosphamide) is a prodrug and cyclophosph-amide's metabolites, such as phosphoramide mustard, act as alky-lating agents interfering with DNA replication, RNA transcription and replication, and ultimately disrupting nucleic acid function. The cytotoxic properties of cyclophosphamide are also enhanced by the phosphorylating activity the drug possesses. Cyclophosphamide has marked immunosuppressive activity and both white cells and antibody production are decreased, but the ex-act mechanisms for this activity have not been fully elucidated. Pharmacokinetics While the pharmacokinetics of cyclophosphamide apparently have not been detailed in dogs or cats, it is presumed that the drug is handled in a manner similar to humans. The drug is well absorbed after oral administration with peak levels occurring about 1 hour after dosing. Cyclophosphamide and its metabolites are distributed throughout the body, including the CSF (albeit in subtherapeutic levels). The drug is only minimally protein bound and is distrib-uted into milk and presumed to cross the placenta. Cyclophosphamide is metabolized in the liver to several metabo-lites. Which metabolites account for which portion of the cytotoxic properties of the drug is a source of controversy. After IV injection, the serum half-life of cyclophosphamide is approximately 4-12 hours, but drug/metabolites can be detected up to 72 hours after administration. The majority of the drug is excreted as metabolites and unchanged drug in the urine. Contraindications/Precautions/Warnings Cyclophosphamide should not be used in patients with prior ana-phylactic reactions to the drug otherwise, there are no absolute con-traindications to the use of cyclophosphamide. It must be used with caution, however in patients with leukopenia, thrombocytopenia, previous radiotherapy, impaired hepatic or renal function, or in those for whom immunosuppression may be dangerous (e. g., in-fected patients). Patients who develop myelosuppression should have subsequent doses delayed until adequate recovery occurs. Because of the potential for development of serious adverse ef-fects, cyclophosphamide should only be used in patients who can be adequately and regularly monitored. Adverse Effects Primary adverse effects in animals associated with cyclophosph-amide are myelosuppression, gastroenterocolitis (anorexia, nausea, vomiting, diarrhea), alopecia (especially in breeds where haircoat continually grows, e. g., Poodles, Old English Sheepdogs), and hem-orrhagic cystitis. Cyclophosphamide's myelosuppressant effects primarily impact the white cells lines, but may also affect red cell and platelet produc-tion. The nadir for leukocytes generally occurs between 7-14 days after dosing and may require up to 4 weeks for recovery. When used with other drugs causing myelosuppression, toxic effects may be exacerbated. Sterile hemorrhagic cystitis induced by cyclophosphamide is thought to be caused by the metabolite acrolein. Up to 30% of dogs receiving long-term (>2 months) cyclophosphamide can develop this problem. Furosemide administered with cyclophosphamide may reduce the occurrence of this adverse effect. In cats, cyclophosphamide-induced-cystitis (CIC) is rare. Initial signs may present as hematuria and dysuria. Because bacterial cys-titis is not uncommon in immunosuppressed patients, it must be ruled out by taking urine cultures. Diagnosis of CIC is made by a negative urine culture and inﬂammatory urine sediment found during urinalysis. Because bladder ﬁbrosis and/or transitional cell carcinoma of the bladder is also associated with cyclophosphamide use, these may need to be ruled out by contrast radiography. It is believed that the incidence of CIC may be minimized by increasing urine production and frequent voiding. The drug should be given in the morning and animals should be encouraged to drink/urinate whenever possible. Recommendation for treatment of CIC includes discontinuing cyclophosphamide, furosemide, and corticosteroids. Refractory cases have been treated by surgical debridement, 1% for-malin or 25% DMSO instillation in the bladder. Other adverse effects that may be noted with CTX therapy in-clude pulmonary inﬁltrates and ﬁbrosis, depression, immune-sup-pression with hyponatremia, and leukemia. In recovering dogs with immune-mediated hemolytic anemia, taper the withdrawal of the drug slowly over several months and monitor for early signs of relapse. Rapid withdrawal can lead to a rebound hyperimmune response. Reproductive/Nursing Safety Cyclophosphamide's safe use in pregnancy has not been established and it is potentially teratogenic and embryotoxic. Cyclophosphamide may induce sterility (may be temporary) in male animals. In hu-mans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential beneﬁts from the use of the drug in pregnant women may be accept-able despite its potential risks. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the beneﬁt of therapy clearly outweighs the risks. ) Cyclophosphamide is distributed in milk and nursing is gener-ally not recommended when dams are receiving the drug. Overdosage/Acute Toxicity There is only limited information on acute overdoses of this drug. The lethal dose in the dogs has been reported as 40 mg/kg IV. If an oral overdose occurs, gut emptying should proceed if indicated and the animal should be hospitalized for supportive care. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cyclophosphamide and may be of signiﬁcance in veterinary patients: !TALLOPURINOL : May increase the myelosuppression caused by cyclophosphamide !TCARDIOTOXIC D RUGS (e. g., doxorubicin ): Use caution when using cy-clophosphamide with other cardiotoxic agents as potentiation of cardiotoxicity may occur !TCHLORAMPHENICOL : May inhibit cyclophosphamide metabolism !TIMIPRAMINE : May inhibit cyclophosphamide metabolism !TPHENOBARBITAL (or other barbiturates ) given chronically may increase the rate of metabolism of cyclophosphamide to active metabolites via microsomal enzyme induction and increase the likelihood of toxicity development !TPHENOTHIAZINES : May inhibit cyclophosphamide metabolism !TPOTASSIUM IODIDE : May inhibit cyclophosphamide metabolism !TSUCCINYLCHOLINE : Metabolism may be slowed with resulting pro-longation of effects, as cyclophosphamide may decrease the levels of circulating pseudocholinesterases	pppbs.pdf
236 CYCLOPHOSPHAMIDE T T!TTHIAZIDE DIURETICS : May increase the myelosuppression caused by cyclophosphamide !TVITAMIN A : May inhibit cyclophosphamide metabolism Laboratory Considerations !TUric acid levels (blood and urine) may be increased after cy-clophosphamide use. !The immunosuppressant properties of cyclophosphamide may cause false negative antigenic skin test results to a variety of anti-gens, including tuberculin, Candida, and Trichophyton. Doses For more information on using cyclophosphamide 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). Note : In oral tablets, the active ingredient is contained within an inner tablet surrounded by an inert ﬂecked outer tablet. Accurate dosing may be difﬁcult if splitting or crushing tablets. When dosing in very small dogs or cats, compounding pharmacies may be able to compound oral dosage forms containing less than 25 mg. !TDOGS: For susceptible neoplastic diseases: a) 50 mg/m2 PO 4 days/week or a single dose of 250 mg/m2 PO once every 3 weeks; IV doses range from 100-300 mg/m2 weekly, depending on the protocol used (Kitchell 2005) As an immunosuppressant: a) For adjunctive therapy for immune-mediated hemolytic ane-mia (probably should be reserved for dogs with fulminant in-travascular hemolysis, autoagglutination or those that require repeated transfusion or have persistent reticulocytopenia): Initially at 2 mg/kg/day IV or PO for 4 days; no treatment for 3 days and then repeat cycle. (Bucheler and Cotter 1995) b) For immune-mediated thrombocytopenia: If corticosteroid therapy is ineffective, may use either vincristine, azathioprine, or cyclophosphamide. CTX dose: 50 mg/m2 PO once daily for 3-4 days/week. May give initial doses IV. Decrease dose if re-nal or hepatic impairment exists. After 1-4 weeks, taper dose and discontinue after platelet count is >100,000/µl. Serious bleeding secondary to thrombocytopenia and hemorrhagic cystitis can occur; use cautiously. (Y oung 1988) c) For rheumatoid arthritis: In conjunction with a glucocorti-coid (predniso(lo)ne); give CTX PO once daily in the AM for 4 consecutive days each week at 2. 5 mg/kg if weighs <10 kg, 2 mg/kg if 10-35 kg, and 1. 5 mg/kg if >35 kg. Discontinue: 1 month after remission of synovial inﬂammation (determined from joint tap), after 4 months of treatment, or if hemorrhag-ic cystitis develops. If cystitis develops, switch to azathioprine. (Tangner and Hulse 1988) d) For polymyositis: In conjunction with steroids, if steroids alone are ineffective: 1 mg/kg PO once daily for 4 days, then off 3 days. Decrease concurrent prednisone dose to 1 mg/kg/ day. (Knaack 1988) e) For polyarthritis: In most cases initial treatment is to attempt immunosuppression with high doses of corticosteroids (pred-nisolone at 2-4 mg/kg in a daily divided dose for 2 weeks and then gradually reduced over the next 4-8 weeks); maintain therapy to help prevent relapses. If relapses occur or the re-sponse to prednisolone is poor, add cyclophosphamide given PO daily at a dose of 1. 5 mg/kg for dogs over 30 kg, 2 mg/kg for dogs 15-30 kg, and 2. 5 mg/kg for dogs for dogs under 15 kg. Give cyclophosphamide doses on 4 consecutive days each week as close to the above dosing regimen as possible, allowing that tablets cannot be split. Oral prednisolone also given each day at 0. 25-0. 5 mg/kg. Continue treatment for 2-4 months, but do not treat with cyclophosphamide longer than 4 months because of bladder toxicity. T est urine weekly for blood, stop if overt blood detected. Monitor CBC q7-14 days; if white count falls below 6,000/mm3 or platelet count is <125,000/mm3 reduce dosage by Gth; if white count falls be-low 4,000/mm3 or platelet count is <100,000/mm3 stop drug for 2 weeks and the resume at H prior dose. If relapses occur or response still poor, may add levamisole (5-7 mg/kg PO every other day; max dose of 150 mg). Goal is to stop therapy in 3-6 months. (Bennett 2005) f) As an alternative immunosuppressive agent for glomerulone-phritis: 2. 2 mg/kg PO q24h for 4 days, discontinue for 3 days and then repeat. (Labato 2006) !TCATS: For susceptible neoplastic diseases: a) For advanced mammary carcinoma: Doxorubicin: 30 mg/m2 IV every 3 weeks up to 4-8 treatments. Cyclophosphamide: 100 mg/m2 PO once daily on days 3, 4, 5, and 6 after doxoru-bicin (Loar 1988) As an immunosuppressant: a) Give 2. 5 mg/kg once daily PO for 4 consecutive days out of 7 for up to 3 weeks. Alternatively, 7 mg/kg IV may be given once a week. (Hurvitz and Johnessee 1985) b) For immune-mediated hemolytic anemia: 50 mg/m2 for 4 consecutive days per week. May be over-treatment; efﬁcacy not proven. (Weiser 1989a) c) For rheumatoid arthritis: In conjunction with a glucocor-ticoid (predniso(lo)ne); give CTX PO once daily in the AM for 4 consecutive days each week at 2. 5 mg/kg. Discontinue 1 month after remission of synovial inﬂammation (determined from joint tap), after 4 months of treatment, or if hemorrhag-ic cystitis develops. If cystitis develops, switch to azathioprine. (Tangner and Hulse 1988) d) T o slow progression of FIP: 2-4 mg/kg PO four times a week. (Foley 2005) !TSHEEP: As a chemical deﬂeecing agent: a) 25 mg/kg, PO once (Mc Connell and Hughey 1989) Monitoring !TEfﬁcacy; See the Protocol section or refer to the references from the Dosage section above for more information !Toxicity, see Adverse Effects above. Regular hemograms and uri-nalyses are mandatory. Client Information !TClients must be briefed on the possibilities of severe toxicity de-veloping from this drug, including drug-related mortality. !TClients should contact veterinarian should the animal exhibit any signs of abnormal bleeding and/or bruising. !TAlthough no special precautions are necessary when handling in-tact tablets, direct exposure should be avoided with crushed tab-lets, oral elixir, or the animal's urine or feces. Should exposure occur, wash the area thoroughly with soap and water.	pppbs.pdf
CYCLOSPORINE 237 Chemistry/Synonyms A nitrogen-mustard derivative, cyclophosphamide occurs as a white, crystalline powder that is soluble in water and alcohol. The commercially available injection has p H of 3 to 7. 5. Cyclophosphamide may also be known as: CPM, CTX, CYT, B-518, ciclofosfamida, cyclophosphamidum, cyclophosphanum, NSC-26271, WR-138719, Alkyloxan®, Carloxan®, Ciclosmida®, Cicloxal®, Cyclan®, Cyclo-cell®, Cycloblastin®, Cycloblastine®, Cyclostin®, Cycloxan®, Cytophosphan®, Cytoxan®, Endoxan®, Endoxana®, Enduxan®, Fosfaseron®, Genoxal®, Genuxal®, Ledoxina®, Neosar®, Procytox®, or Sendoxan®. Storage/Stability/Compatibility Cyclophosphamide tablets and powder for injection should be stored at temperatures less than 25°C. They may be exposed to tem-peratures up to 30°C for brief periods, but should not be exposed to temperatures above 30°C. Tablets should be stored in tight con-tainers. The commercially available tablets (Cytoxan®) are manu-factured in a bi-level manner with a white tablet containing the cyclophosphamide found within a surrounding ﬂecked outer tab-let. Therefore, the person administering the drug need not protect their hands from cyclophosphamide exposure unless the tablets are crushed. Because of their construction, accurately splitting tablets is problematic and cannot be recommended. Cyclophosphamide injection may be dissolved in aromatic elixir to be used as an oral solution. When refrigerated, it is stable for 14 days. After reconstituting the powder for injection with either sterile water for injection or bacteriostatic water for injection, the product should be used within 24 hours if stored at room temperature; 6 days if refrigerated. Cyclophosphamide is reportedly compatible with the following intravenous solutions and drugs: Amino acids 4. 25%/dextrose 25%, D5 in normal saline, D 5W, sodium chloride 0. 9%. It is also compat-ible in syringes or at Y-sites for brief periods with the following: bleomycin sulfate, cisplatin, doxorubicin HCl, droperidol, ﬂuorou-racil, furosemide, heparin sodium, leucovorin calcium, methotrex-ate sodium, metoclopramide HCl, mitomycin, vinblastine sulfate, and vincristine sulfate. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more speciﬁc in-formation. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cyclophosphamide Tablets: 25 mg & 50 mg; Cytoxan® (Mead John-son Oncology); Cyclophosphamide (Gensia Sicor); (Rx) Cyclophosphamide Powder for Injection: 75 mg mannitol/100 mg cyclophosphamide and 82 mg sodium bicarbonate/100 mg cyclo-phosphamide in 100 mg, 200 mg, 500 mg, 1 g and 2 g vials; Cytox-an® Lyophilized (Mead Johnson Oncology); (Rx), Neosar® (Gensia Sicor); (Rx) CYCLOSPORINE (SYSTEMIC) (sye-kloe-spor-een) Atopica®, Neoral®, Sandimmune® IMMUNOSUPPRESSIVE Note : Cyclosporine topical ophthalmic information is found in the oph-thalmology section in the appendix. Prescriber Highlights TT Immunosuppressant (primarily cellular immunity) TT Adverse Effects: Primarily GI related, but uncommon at usual dosages TT If using human-labeled products, don't confuse Sand-immune® with Atopica®/Neoral®/Gengraf® dosages; they are not bioequivalent. When using generically la-beled products, determine with which product they are bioequivalent & dose appropriately. TT Serum levels should be measured to assure efﬁcacy & minimize adverse effect potential TT Cost may be an issue TT Drug-drug interactions Uses/Indications Cyclosporine may be useful as an immunosuppressant for immune-mediated diseases (see dosage section) and as part of a protocol to reduce the rejection of allografts in transplant medicine in dogs and cats. Pharmacology/Actions Cyclosporine is an immunosuppressant that focuses on cell-me-diated immune responses (but it has some humoral immunosup-pressive action). While cyclosporine's exact mechanism of action is not known, it is believed that it acts by a speciﬁc, reversible inhi-bition of immunocompetent lymphocytes in the G 0-or G 1-phase of the cell cycle. T-helper lymphocytes are the primary target, but T-suppressor cells are also affected. Lymphokine production and release (including interleukin-2, T-Cell Growth factor) are also in-hibited by cyclosporine. Pharmacokinetics Cyclosporine is poorly absorbed after oral administration and bio-availability can vary widely between patients. The emulsion form oral product ( Neoral®) reportedly achieves much higher blood lev-els in dogs and cats for a given dose and dosage recommendations change accordingly. Note : Neoral®/Atopica® and Sandimmune® are NOT bioequivalent. In dogs, the veterinary-labeled oral product (Atopica®) is rap-idly absorbed, but bioavailability is variable and can range from 23-45%. Food in the GI increases variability of bioavailability and reduces it by about 20%. Cyclosporine is distributed in high levels into the liver, fat and blood cells (RBC's lymphocytes). It does not appreciably enter the CNS. The drug is primarily metabolized in the liver via the cyto-chrome P450 system and excreted into the bile. Less than 1% of a dose is excreted unchanged into the urine. Elimination half-life in the dog is approximately 9-12 hours.	pppbs.pdf
238 CYCLOSPORINE Contraindications/Precautions/Warnings Cyclosporine is contraindicated in patients hypersensitive to it or any component (e. g., polyoxyethylated castor oil) in the injectable micro-emulsion products. It is labeled as being contraindicated in dogs with a history of malignant neoplasia. Cyclosporine should be used with caution in patients with hepatic or renal disease. Adverse Effects In dogs, vomiting, anorexia, and diarrhea are most commonly seen; gingival hyperplasia, hypertrichosis, excessive shedding, and papil-lomatosis have been reported. In order to reduce the incidence of vomiting in dogs when start-ing therapy, some clinicians will start at a low dose, give with food and gradually increase oral doses over the ﬁrst week or so. One pro-tocol (Bloom 2006a) is: 1-2 mg/kg PO once daily for 2 days, 2-3 mg/kg PO once daily for 2 days, 3-4 mg/kg PO once daily for 3 days, and then 5 mg/kg PO once daily for 30 days. For the ﬁrst 10 days metoclopramide is given 30 minutes prior to cyclosporine. For the ﬁrst 14 days cyclosporine is given with a meal and after that, 2 hours prior to a meal. Cats with high blood levels (1,000 ng/m L) may develop anorex-ia. Increased hair growth has been noted in feline patients on cy-closporine. A case of a cat developing fatal systemic toxoplasmosis while on cyclosporin therapy has been reported. While nephrotoxicity and hepatotoxicity are potentially an issue in dogs and cats, it appears that extremely high blood levels (>3,000 ng/m L) are necessary before this is a signiﬁcant problem. Animals who have levels greater than 1,000 ng/m L that persist for weeks or months may be more susceptible to bacterial or fungal infections. Long-term use, particularly in combination with other immunosuppressants (steroids), may predispose the patient to de-velop neoplastic diseases. Because the drug has an unpleasant taste, it has been suggested that compounded dosages be placed in gelatin capsules. Reproductive/Nursing Safety Cyclosporine has been shown to be fetotoxic and embryotoxic in rats in rabbits at dosages 2-5 times normal. Use during pregnancy only when the risks outweigh the beneﬁts. 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. ) Cyclosporine is distributed into milk and safety cannot be as-sured for nursing offspring. In humans, it is not recommended that women nurse while taking cyclosporine. Overdosage/Acute Toxicity Acute overdoses may cause transient renal-or hepato-toxicity. Over doses may be treated with gut evacuation (emesis is apparently effective in humans if used within 2 hours of ingestion); otherwise, treat supportively and symptomatically. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cyclosporine and may be of signiﬁcance in veterinary patients: The following drugs may increase cyclosporine blood levels and increase the risk for cyclosporine toxicity: !!ALLOPURINOL !!AMIODARONE !!AZOLE ANTIFUNGALS (e. g., ketoconazole, ﬂuconazole ), !!BROMOCRIPTINE !!CALCIUM CHANNEL BLOCKERS (e. g., verapamil, diltiazem ) !!CIMETIDINE !!CISAPRIDE !!CORTICOSTEROIDS !!DANAZOL !!DIGOXIN !!GRAPEFRUIT JUICE/GRAPEFRUIT JUICE POWDER !!LOSARTAN, VALSARTAN !!MACROLIDE ANTIBIOTICS (e. g., erythromycin, clarithromycin ) !!METOCLOPRAMIDE !!OMEPRAZOLE !!SERTRALINE The following drugs may decrease the blood levels of cyclosporine: !TNAFCILLIN !TRIFAMPIN !!PHENOBARBITAL !!PHENYTOIN !!St. JOHN'S WORT !TDIGOXIN : Cyclosporine can cause increased digoxin levels with pos-sible toxicity !TKETOCONAZOLE and other azole antifungals : Have been shown that they can substantially reduce the metabolism of cyclosporine in dogs or cats and many clinicians are using this interaction to re-duce the dose and resultant cost of cyclosporine treatment. At-tempt this with caution only, and with the realization that moni-toring of cyclosporine levels may be required. !TMETHOTREXATE : Cyclosporine may increase MTX levels !TNEPHROTOXIC D RUGS, OTHER (e. g., acyclovir, amphotericin B, aminogly-cosides, colchicine, vancomycin, NSAIDs ): Possible additive nephro-toxicity !TSPIRONOLACTONE and other potassium sparing diuretics : Increased risk for hyperkalemia !TVACCINATIONS : May be less effective while patients are receiving cy-closporine; avoid the use of live attenuated vaccines Doses Note : Dosages are for Sandimmune® unless otherwise noted. Atopica ® or Neoral ® are not interchangeable with Sandimmune® dosages. !TDOGS: For control of atopic dermatitis using Atopica® in dogs weighing at least 1. 8 kg: a) 5 mg/kg (3. 3-6. 7 mg/kg) PO once daily for 30 days. Follow-ing this initial treatment period, dosage may be tapered to every other day, and then 2 times per week, until a minimum frequency is reached that will maintain the desired therapeu-tic effect. Give at least one hour before, or two hours after meals. (Label information; Atopica®—Novartis) b) 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 ketoconazole (5 mg/kg/day) may give good results and reduce expenses. (White 2007) For inﬂammatory bowel disease using Neoral® or modiﬁed cy-closporine (Atopica®): a) 2-5 mg/kg PO q12h; dose can be very individual, so it is rec-ommended to monitor trough levels (aim for 500 ng/m L) (Moore 2004) For severe immune-mediated hemolytic anemia that has not re-sponded to other treatments: a) Initiate dose at 10 mg/kg PO one to two times a day; usu-ally in combination with cyclophosphamide and prednisone. May consider discontinuing cyclosporine when remission has been maintained for 2 weeks. (Miller 2000)	pppbs.pdf
CYCLOSPORINE 239 TAs an immunosuppressant (usually as part of an immunosup-pressive protocol): a) 10-25 mg/kg/day PO divided q12h. Neoral®: 5-10 mg/kg/ day PO divided q12h. Trough level of approximately 500 ng/ m L is goal (values are dependent on methodology used); may check level 24-48 hours after starting therapy. T o reduce the cost of treatment in large dogs, may give ketoconazole at 10 mg/kg/day divided q12h with cyclosporine. (Gregory 2000) b) For inﬂammatory bowel disease refractory to azathioprine and prednisone: 5 mg/kg PO once daily (Marks 2007b) c) For pemphigus: Using Atopica® or Neoral®: 5-10 mg/kg PO q24h with ketoconazole (5 mg/kg PO q24h). May be used as a sole agent or in combination with glucocorticoids. (Rosen-krantz 2004) d) As an alternative immunosuppressive agent for glomerulo-nephritis: 15 mg/kg PO q24h (Labato 2006) e) As an alternative immunosuppressive agent for refractory IMHA, especially those that are non-regenerative: 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 be-lieved this is a typo). Large breed dogs can be dosed concur-rently with ketoconazole (10 mg/kg/day) to allow reduction of cyclosporine dose. (Macintire 2006d) For perianal ﬁstulas: a) 5-7. 5 mg/kg PO q12h until lesions heal and then taper (Campbell 1999) For anal furunculosis: a) Week 1: Tuesday: Hospitalization. Clip perineum to monitor healing and improve hygiene. Wednesday: Start treatment with: Cyclosporine (Cy A) 10 mg/kg/day (Neoral®, 100 mg capsules) and Ketoconazole (KC) 5 mg/kg/day (Nizoral®, 200 mg tablets); Thursday: Maintain Cy A dose; Friday: Check Cy A plasma concentration, Maintain Cy A dose; Saturday: Adjust Cy A dose to obtain a trough plasma concentration of 240-400 ng/m L; Maintain KC dose during the entire period of treatment; Sunday: Maintain Cy A dose Week 2: Monday: Check Cy A plasma concentration, Main-tain Cy A dose; Tuesday: Adjust Cy A dose if needed; Wednes-day: Maintain Cy A dose; Thursday: Check Cy A plasma concentration; Maintain Cy A dose; Friday: Adjust Cy A dose if needed; Discharge from hospital Week 3-Week 8: Check Cy A plasma concentration every Tuesday. Check for possible side effects: Hair loss and hyper-trichosis (Cy A), pruritus (KC), gingival hyperplasia (Cy A), vomiting (Cy A, KC), diarrhea (Cy A), kidney (Cy A) and liver (Cy A, KC) damage, cholestasis (KC), cutaneus papillomato-sis (Cy A), and viral and fungal infections (Cy A). Cy A dose is adjusted if needed, KC dose is maintained. Discontinue treatment after 8 weeks. Serious cases that are not healed but show substantial improvement may be treated for another 4 weeks. (van Sluijs 1999) !TCATS: Note : Dosages are for Sandimmune® unless otherwise noted. As an immunosuppressant (usually as part of an immunosup-pressive protocol): a) 4-15 mg/kg/day PO divided q12h. Neoral®: 1-5 mg/kg/day PO divided q12h. Trough level of approximately 250-500 ng/m L is goal; may check level 24-48 hours after starting therapy. (Gregory 2000) For feline asthma (in chronic severe cases where patients either require large doses of steroids or are steroid resistant): a) Initial dose of 10 mg/kg PO q12h. Check blood levels at least weekly until a stable dose achieves trough blood levels of 500-1,000 ng/m L. (Padrid 2000) For inﬂammatory bowel disease using Neoral® or modiﬁed cy-closporine (Atopica®): a) 1-4 mg/kg PO q12-24h; dose can be very individual, so it is recommended to monitor trough levels (aim for 500 ng/m L). (Moore 2004) Monitoring !Therapeutic efﬁcacy !TAdverse effects !TConsider therapeutic drug monitoring, particularly when re-sponse is poor or adverse effects occur; ideally after 24-48 hours after starting therapy and then every 2-4 weeks; target trough levels (12 hours after last dose) have been suggested as 100-500 ng/m L in dogs and 250-1,000 ng/m L for cats (see dosage refer-ences) for immunosuppression. Because different methodologies may yield different results; contact the laboratory for recommen-dations on the evaluation of levels !TCBC and biochem proﬁle: baseline and then monthly to every 3 months has been suggested; others believe this is not warranted Client Information !TClients should be briefed on the expense of this medication be-fore prescribing !TGive to an animal with an empty stomach (one hour before or two hours after meals). Importance of regular dosing must be stressed. If a dose is missed, the next dose should be administered (without doubling) as soon as possible, but dosing should be no more frequent than once daily. Chemistry/Synonyms Also known as Cyclosporin A, cyclosporine is a naturally produced immunosuppressant agent. It is a non-polar, cyclic, polypeptide antibiotic consisting of 11 amino acids and occurs as a white, ﬁne crystalline powder. It is relatively insoluble in water, but generally soluble in organic solvents and oils. Commercially cyclosporine is available in several dosage forms, including an oral liquid, capsules, and a concentrate for injection. T o increase oral absorption, a micro emulsion forming preparation (Neoral®) is also available in capsules and oral liquid. The veteri-nary product, Atopica®, is a micro-emulsion product equivalent to Neoral®. Cyclosporine may also be known as: ciclosporin, 27-400, ciclosporinum, cyclosporine, cyclosporine A, OL-27-400, Atopica®, Cermox®, Ciclohexal®, Cicloral®, Colosina®, Consupren®, Cysporin®, Deximune®, Gengraf®, Immulem®, Imusporin®, Neoral-Sandimmun®, Panimun Bioral®, Restasis®, Sandimmun®, Sandimmun Neoral®, Sandimmune®, Sangcya®, or Sigmasporin®. Storage/Stability/Compatibility The veterinary product (Atopica®), should be stored and dispensed in the original unit-dose container at controlled room temperature (15-35°C; 59-77°C). The oral liquid and oral capsules (Sandimmune®) should be stored in their original containers at temperatures less than 30°C; protect from freezing and do not refrigerate. After opening the oral liquid, use within 2 months.	pppbs.pdf
240 CYPROHEPTADINE HCL The oral liquid and capsules for emulsion (Neoral®) should be stored in their original containers at 25°C. T emperatures below 20°C may cause the solution to gel or ﬂocculate. Rewarming to 25° can reverse this process without harm. The injection should be stored at temperatures less than 30°C and be protected from light. After diluting to a concentration of ap-proximately 2 mg/m L, the resultant solution is stable for 24 hours in D5W or normal saline; if diluting with normal saline it would be wise to use the solution within 12 hours. It does not need to be protected from light after diluting. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Cyclosporine (Modiﬁed) Capsules: 10 mg, 25 mg, 50 mg, & 100 mg; Atopica® (Novartis); (Rx). Approved for use in dogs. See the appendix for more information on the topical ophthalmic preparation. HUMAN-LABELED PRODUCTS: Note : Determining bioequivalence between cyclosporine products is complicated; for the latest information see the FDA 's Orange Book Website http://www. fda. gov/cder/ob / and search on cyclosporine. Cyclosporine Capsules (Soft-gelatin): 25 mg, 50 mg & 100 mg; San-dimmune® (Novartis); generic; (Rx) Cyclosporine (Microemulsion) Oral Capsules (Soft-gelatin): 25 mg, & 100 mg; Neoral® (Novartis); Gengraf® (Abbott); generic; (Eon Labs), (Pliva); (Rx) Cyclosporine Oral Solution: 100 mg/m L in 50 m L btls with syringe; Sandimmune® (Novartis); (Rx) Cyclosporine Oral Solution Microemulsion: 100 mg/m L in 50 m L btls; Neoral® (Novartis); generic, (Abbott; Pliva); (Rx) Cyclosporine Injection: 50 mg/m L in 5 m L amps; Sandimmune® (Novartis); Cyclosporine Injection (Bedford Labs); (Rx) CYPROHEPTADINE HCL (sip-roe-hep-ta-deen) Periactin® ANTIHISTAMINE Prescriber Highlights TT Serotonin antagonist antihistamine used as an appetite stimulant in cats & as an antipruritic/antihistamine in dogs & cats; used in horses for photic head shaking or treatment of equine Cushing's; may be useful for treating serotonin-syndrome in small animals TT Contraindications: Hypersensitivity to cyproheptadine TT Caution: Urinary or GI obstruction, severe CHF, narrow angle glaucoma TT Adverse Effects: Sedation (cats may demonstrate para-doxical hyperexcitability) & anticholinergic effects; some reports of hemolytic anemia in cats Uses/Indications Cyproheptadine may be useful in cats as an appetite stimulant. It po-tentially may be of beneﬁt in the treatment of feline asthma or pruri-tus in cats, but clinical experience is marginal for this indication. Cyproheptadine is an antihistamine but its efﬁcacy is question-able for this indication in dogs. The drug may be useful as adjunctive therapy for Cushing's syndrome probably as result of its antis erotonin activity, however one study demonstrated efﬁcacy in less than 10% of dogs treated for pituitary dependent hyperadrenocorticism. Cyproheptadine may be useful as adjunctive treatment in dogs or cats with serotonin syndrome. In horses, cyproheptadine has been used for treating photic head shaking and pars intermedia dysfunction (Equine Cushing's Disease). Pharmacology/Actions Like other H 1-receptor antihistamines, cyproheptadine acts by com-peting with histamine for sites on H 1-receptor sites on effector cells. Antihistamines do not block histamine release, but can antagonize its effects. Cyproheptadine also possesses potent antiserotonin activ-ity and, reportedly, has calcium channel blocking action as well. Pharmacokinetics Limited data is available. Cyproheptadine is well absorbed after oral administration. Its distribution characteristics are not well described. Cyproheptadine is apparently nearly completely metabolized in the liver and these metabolites are then excreted in the urine; elimina-tion is reduced in renal failure. Contraindications/Precautions/Warnings Cyproheptadine 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 most likely adverse effects seen with cyproheptadine are related to its CNS depressant (sedation) and anticholinergic effects (dryness of mucous membranes, etc. ). Cats can develop a paradoxical agitat-ed state that resolves upon dose reduction or discontinuation. There have been reports of cyproheptadine induced hemolytic anemia in cats. Horses may show mild depression, anorexia, or lethargy. At higher dosages, cyproheptadine has caused signiﬁcant polyphagia in dogs. Reproductive/Nursing Safety Cyproheptadine has been tested in pregnant lab animals in dos-es up to 32X labeled dose without evidence of harm to fetuses. Nevertheless, because safety has not been established in other spe-cies, its use during pregnancy should be weighed carefully. 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. ) It is not known if cyproheptadine is distributed into milk. Overdosage/Acute Toxicity There are no speciﬁc antidotes available. Signiﬁcant overdoses should be handled using standard gut emptying protocols when appropri-ate and supportive therapy when required. The adverse effects seen with overdoses are an extension of the drug's side effects, principally CNS depression (although CNS stimulation may be seen), anticho-linergic effects (severe drying of mucous membranes, tachycardia, urinary retention, hyperthermia, etc. ) and possibly hy potension. Physostigmine may be considered to treat serious CNS anticholin-ergic effects, and di azepam employed to treat seizures, if necessary.	pppbs.pdf
CYTARABINE 241 Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cyproheptadine and may be of signiﬁcance in veterinary patients: T ! CNS DEPRESSANT MEDICATIONS : Additive CNS depression may be seen if combining cyproheptadine with other CNS depressant medications, such as barbiturates, tranquilizers, etc. T ! SSRIs (including sertraline, ﬂuoxetine, paroxetine, etc. ): Cyprohep-tadine may decrease the efﬁcacy of the SSRI Laboratory Considerations T ! Because antihistamines can decrease the wheal and ﬂair response to skin allergen testing, antihistamines should be discontinued from 3-7 days (depending on the antihistamine used and the reference) before intradermal skin tests. T ! Cyproheptadine may increase amylase and prolactin serum levels when administered with thyrotropin-releasing hormone. Doses T ! DOGS: As an antihistamine: a) 0. 3-2 mg/kg PO twice daily (Bevier 1990), (Mac Donald 2002a) As an appetite stimulant: a) 0. 2 mg/kg PO q12h. May be dosed less frequently if inap-petance is mild. (Moore 2005) For adjunctive treatment of serotonin syndrome: a) 1. 1 mg/kg PO; doses may be repeated q4-6h as needed until signs have resolved. In cases where PO dosing not possible (severe vomiting), may crush tablets and mix with saline and give rectally. (Wismer 2006b) T ! CATS: As an appetite stimulant: a) 2-4 mg per cat PO once or twice daily (Davenport 1994), (Ogilvie 2003b) b) 1-4 mg/cat PO, or 0. 35-1 mg/kg PO once or twice a day (Frimberger 2000) c) 2 mg per cat PO q12h (Smith 2003a) d) 0. 35-1 mg/kg PO q12h. May be dosed less frequently if inap-petance is mild. (Moore 2005) As an antihistamine/antipruritic: a) 2 mg per cat PO q12h (Messinger 2000) b) 2 mg per cat or 1. 1 mg/kg PO q12h (Hnilica 2003b) c) For feline asthma (particularly when cats are maxed out on dosages of corticosteroids and terbutaline): 2 mg PO q12h. Therapeutic response may not be seen for 4-7 days, but CNS depression can occur in 24 hours. (Padrid 2000) For adjunctive treatment of serotonin syndrome: a) 2-4 mg (total dose) PO; doses may be repeated q4-6h as needed until signs have resolved. In cases where PO dosing not possible (severe vomiting), may crush tablets and mix with saline and give rectally. (Wismer 2006b) T ! HORSES: (Note : ARCI UCGFS Class 4 Drug) For photic head shaking: a) 0. 3-0. 6 mg/kg PO q12h (Dowling 1999) b) 0. 3 mg/kg PO twice daily (Mealey 2004) For treatment of equine Cushing's: a) 0. 25 mg/kg PO once a day for 4-8 weeks; if no response (clinical signs and plasma ACTH), increase dosage frequency to twice daily. Approximately N of horses may beneﬁt, non-responders should be switched to pergolide. (T oribio 2004b) Monitoring T ! Efﬁcacy (weight if used for anorexia) T ! Adverse effects, if any T ! With long-term use, should occasionally monitor serum BUN in cats Client Information T ! Possible side effects include sedation/lethargy and mucous mem-brane dryness T ! Cats may respond with agitation; contact veterinarian if this oc-curs; if cat becomes very lethargic, weak or develops pale mucous membranes contact veterinarian immediately T ! Horses may show mild depression, anorexia, or lethargy Chemistry/Synonyms An antihistamine that also possesses serotonin antagonist proper-ties, cyproheptadine HCl occurs as a white to slightly yellow crystal-line powder. Approximately 3. 64 mg are soluble in one m L of water and 28. 6 mg in one m L of alcohol. Cyproheptadine HCl may also be known as: cyproheptadini hydrochloridum, Ciplactin®, Cyheptine®, Cyprogin®, Cyprono®, Cyprosian®, Klarivitina®, Nuran®, Periactine®, Periactinol®, Periatin®, Peritol ®, Polytab®, Practin®, Preptin ®, Supersan®, or Trimetabol®. Storage/Stability Cyproheptadine HCl tablets and oral solution should be stored at room temperature and freezing should be avoided. 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 informa-tion. HUMAN-LABELED PRODUCTS: Cyproheptadine HCl Tablets: 4 mg; generic; (Rx) Cyproheptadine HCl Syrup: 2 mg/5 m L in 473 m L; generic; (Rx) CYTARABINE (sye-tare-a-bean) Cytosine arabinoside, Cytosar-U® ANTINEOPLASTIC Prescriber Highlights TT Parenteral antineoplastic (lymphoreticular neoplasms, leukemias) for dogs & cats TT Contraindications: Hypersensitivity; potentially, embryo-toxic & teratogenic TT Adverse Effects: Primarily myelosuppression, but GI & other toxicities can occur TT Adequate monitoring essential Uses/Indications In veterinary medicine, cytarabine is used primarily in small ani-mals as an antineoplastic agent for lymphoreticular neoplasms, myeloproliferative disease (leukemias), and CNS lymphoma. Refer to the Dosages below or the Protocols (in the appendix), for more information.	pppbs.pdf
242 CYTARABINE TPharmacology/Actions Cytarabine is converted intracellularly into cytarabine triphosphate that apparently competes with deoxycytidine triphosphate, thereby inhibiting DNA polymerase with resulting inhibition of DNA syn-thesis. Cytarabine is cell phase speciﬁc, and acts principally during the S-phase (DNA synthesis). It may also, under certain conditions, block cells from the G 1 phase to the S phase. Pharmacokinetics Cytarabine has very poor systemic availability after oral administra-tion and is only used parenterally. Following IM or SC injections, the drug peaks in plasma within 20-60 minutes, but levels attained are much lower than with an equivalent IV dose. Cytarabine is distributed widely throughout the body, but crosses into the CNS in only a limited manner. If given via continuous IV infusion, CSF levels are higher than with IV bolus injection and can reach 20-60% of those levels found in plasma. Elimination half-life in the CSF is signiﬁcantly longer than that of serum. In humans, cytarabine is only about 13% bound to plasma proteins. The drug apparently crosses the placenta, but it is not known if it enters milk. Circulating cytarabine is rapidly metabolized by the enzyme cy-tidine deaminase, principally in the liver but also in the kidneys, in-testinal mucosa, and granulocytes, to the inactive metabolite ara-U (uracil arabinoside). About 80% of a dose is excreted in the urine within 24 hours as both ara-U (≈90%) and unchanged cytarabine (≈10%). Contraindications/Precautions/Warnings Cytarabine is contraindicated in patients hypersensitive to it. Because of the potential for development of serious adverse reac-tions, cytarabine should only be used in patients who can be ad-equately and regularly monitored. The person preparing or administering cytarabine for injection, need not observe any special handling precautions other than wear-ing gloves, however, should any contamination occur, thoroughly wash off the drug from skin or mucous membranes. Adverse Effects The principal adverse effect of cytarabine is myelosuppression (with leukopenia being most prevalent), but anemia and thrombocytope-nia can also be seen. Myelosuppressive effects are more pronounced with IV administration and reach a nadir at 5-7 days, and generally recover at 7-14 days. GI disturbances (anorexia, nausea, vomiting, diarrhea), conjunc-tivitis, oral ulceration, neurotoxicity, hepatotoxicity and fever may also be noted with cytarabine therapy, but occur rarely in veterinary patients. Anaphylaxis has been reported, but is believed to occur very rarely. Cytarabine is a mutagenic and, potentially, carcinogenic agent. Reproductive/Nursing Safety Cytarabine's safe use in pregnancy has not been established and it is potentially teratogenic and embryotoxic. 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. ) It is unknown if cytarabine enters milk; safe use during nursing cannot be assured. Overdosage/Acute Toxicity Cytarabine efﬁcacy and toxicity (see Adverse Effects) are dependent not only on the dose, but also the rate the drug is given. In dogs, the IV LD 50 is 384 mg/kg when given over 12 hours and 48 mg/kg when infused IV over 120 hours. Should an inadvertent overdose occur, supportive therapy should be instituted. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving cytarabine and may be of signiﬁcance in veterinary patients: !TDIGOXIN : Presumably due to causing alterations in the intestinal mucosa, cytarabine may decrease the amount of digoxin (tablets only) absorbed after oral dosing; this effect may persist for several days after cytarabine has been discontinued !TFLUCYTOSINE (5-FC): Limited studies have indicated that cytara-bine may antagonize the anti-infective activity of ﬂuorocytosine; monitor for decreased efﬁcacy !TGENTAMICIN : Limited studies have indicated that cytarabine may antagonize the anti-infective activity of gentamicin; monitor for decreased efﬁcacy Laboratory Considerations None reported Doses For more information on using cytarabine 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: For susceptible neoplastic diseases: a) 100 mg/m2 IV (continuous infusion) for 48-96 hours, or 100 mg/m2 divided three times daily to four times daily SC for 48-96 hours (Kitchell and Dhaliwal 2000) b) 100 mg/m2 IV (continuous infusion) for 2-4 days (up to 4 days depending on myelosuppression), or 100 mg/m2 divided three times daily to four times daily SC over 4 days; continu-ous infusion results in both increased efﬁcacy and myelosup-pression (Kitchell 2005) c) 100 mg/m2 IV or SC once daily for 2-4 days; repeat as needed 20 mg/m2 intrathecally for 1-5 days (Thompson 1989a) d) 100 mg/m2 IV (slowly), IM, or SC once daily for 4 days, if no toxicity develops may increase dose by 50% (Coppoc 1988) For granulomatous meningoencephalitis: a) 50 mg/m2 IV (continuous infusion) SC or IV twice daily for 2 days, then 100 mg/m2 SC once a week; rarely effective. (Taylor 2003b) !TCATS: For susceptible neoplastic diseases: a) 100 mg/m2 IV (continuous infusion) for 2 days or 100 mg/ m2 divided three times daily to four times daily SC over 4 days; continuous infusion results in both increased efﬁcacy and myelosuppression (Kitchell 2005) b) 100 mg/m2 IV or SC once daily for 2-4 days; repeat as needed 20 mg/m2 intrathecally for 1-5 days (Thompson 1989a) c) 100 mg/m2 once daily for 2 days; 10 mg/m2 once daily for 2 weeks (Couto 1989b) Monitoring !TEfﬁcacy; see the Protocol section or refer to the references from the Dosage section above for more information !Toxicity; see Adverse Effects above. Regular hemograms are man-datory. Periodic liver and kidney function tests are suggested.	pppbs.pdf
DACARBAZINE (DTIC) 243 Client Information T ! Clients must be briefed on the possibilities of severe toxicity de-veloping from this drug, including drug-related mortality T ! Clients should contact the veterinarian should the patient ex-hibit any signs of profound depression, abnormal bleeding and/ or bruising Chemistry/Synonyms A synthetic pyrimidine nucleoside antimetabolite, cytarabine oc-curs as an odorless, white to off-white, crystalline powder with a p K a of 4. 35. It is freely soluble in water and slightly soluble in alcohol. Cytarabine may also be known as: 1-beta-d-arabinofuranosyl-cytosine, arabinosylcytosine, ara-C, cytarabine liposome, cytara-binum, cytosine arabinoside, liposomal cytarabine, NSC-63878, U-19920, U-19920A, WR-28453, ARA-cell®, Alexan®, Arabine®, Aracytin®, Aracytine®, Citab®, Citagenin®, Citaloxan®, Cylocide Cytarbel®, Cytarine®, Depo Cyt ®, Depo Cyte ®, Erpalfa®, Ifarab®, Laracit®, Medsara®, Novutrax®, Serotabir®, Starasid®, Tabine®, Tarabine® or Udicil®. Storage/Stability/Compatibility Cytarabine sterile powder for injection should be stored at room temperature (15-30°C). After reconstituting with bacteriostatic water for injection, solutions are stable for at least 48 hours when stored at room temperature. One study, however, demonstrated that the reconstituted solution retains 90% of its potency for up to 17 days when stored at room temperature. If the solution develops a slight haze, the drug should be discarded. Cytarabine is reportedly compatible with the following intra-venous solutions and drugs: amino acids 4. 25%/dextrose 25%, dextrose containing solutions, dextrose-saline combinations, dex-trose-lactated Ringer's injection combinations, Ringer's injection, lactated Ringer's injection, sodium chloride 0. 9%, sodium lac-tate 1/6 M, corticotropin, lincomycin HCl, methotrexate sodium, metoclopramide HCl, potassium chloride, prednisolone sodium phosphate, sodium bicarbonate, and vincristine sulfate. Cytarabine compatibility information conﬂicts or is dependent on diluent or concentration factors with the following drugs or so-lutions: cephalothin sodium, gentamicin sulfate, hydrocortisone sodium succinate, and methylprednisolone sodium succinate. 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. Cytarabine is reportedly incompatible with the following solu-tions or drugs: carbenicillin disodium, ﬂuorouracil, regular insulin, nafcillin sodium, oxacillin sodium, and penicillin G sodium. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Cytarabine Powder for Injection: 100 mg, 500 mg, 1 g and 2 g in vials; generic; (Rx) Cytarabine Injection: 10 mg/m L (liposomal) preservative free in 5 m L vials; Depo Cyt ® (Enzon); (Rx); Cytarabine Injection: 20 mg/m L in 5 m L single-& multi-dose vials & preservative free 50 m L bulk package vials; Tarabine® PFS (Adria); Cytarabine (Mayne); (Rx) d-Panthenol — see Dexpanthenol DACARBAZINE (DTIC) (da-kar-ba-zeen) ANTINEOPLASTIC Prescriber Highlights TT Parenteral antineoplastic used in dogs for relapsed lymphomas, soft tissue sarcomas, & melanoma TT Not recommended for use in cats TT Contraindications: Hypersensitivity; potentially teratogenic. TT Primary adverse effects are GI (can be severe & dose limiting) & bone marrow suppression; adequate monitor-ing essential TT Must give diluted IV; extravasation injuries can be serious Uses/Indications Dacarbazine has been used to treat relapsed canine lymphoma, soft tissue sarcomas and melanoma in dogs. In combination with doxo-rubicin, dacarbazine has been evaluated to treat dogs with relapsed lymphosarcoma. Ongoing studies evaluating various protocols are ongoing for this indication. Pharmacology/Actions The mechanism for dacarbazine's antineoplastic activity has not been precisely determined, but it is believed the drug acts as an al-kylating agent through the formation of reactive carbonium ions. Dacarbazine also possesses antimetabolic activity by inhibiting DNA 's of purine nucleoside. It possesses minimal immunosuppres-sant activity and is probably not a cell cycle-phase speciﬁc drug. Pharmacokinetics Dacarbazine (DTIC) is poorly absorbed from the GI tract and is administered intravenously. It is converted into an active form of the drug in the liver. The drug's distribution characteristics are not well known, but it is only slightly bound to plasma proteins and probably concentrates in the liver. Only limited amounts cross the blood-brain barrier; it probably crosses the placenta, but it is un-known if it is distributed into milk. Dacarbazine is extensively me-tabolized in the liver and is excreted in the urine via tubular secre-tion. Elimination half-life is about 5 hours. Contraindications/Precautions/Warnings Dacarbazine is not recommended for use in cats as it is unknown whether the feline liver can adequately metabolize it. Dacarbazine (DTIC) is contraindicated in patients who are hypersensitive to it. DTIC can cause life-threatening toxicity. It should only be used where adequate monitoring and support can be administered. It should be used with caution in patients with preexisting bone marrow depression, hepatic or renal dysfunction, or infection. Adverse Effects Gastrointestinal toxicity (including vomiting, anorexia, diarrhea) can commonly be seen after administration and is dose limiting. Pretreatment with an antiemetic (e. g., dolasetron, ondansetron) is used by some oncologists. Bone marrow toxicity is usually asymptomatic with leukocyte and platelet nadirs seen several weeks after therapy. Occasionally	pppbs.pdf
244 DACARBAZINE (DTIC) Tsevere hematopoietic toxicity can occur with fatal consequences. Other delayed toxic effects can include, alopecia, severe hepatotoxic-ity, renal impairment, and photosensitivity reactions. These delayed reactions appear rarely. Because DTIC can cause extensive pain and tissue damage, avoid extravasation injuries. Venous spasm and phlebitis may occur dur-ing IV administration. Severe pain at the injection site can occur if giving the concentrated drug; dilution and administration by IV infusion is recommended. Pretreatment with dexamethasone and/ or butorphanol has been suggested to reduce vasospasm, phlebitis and pain. There is increasing evidence that chronic exposure by health care givers to antineoplastic drugs increases the mutagenic, teratogenic, and carcinogenic risks associated with these agents. Proper pre-cautions in the handing, preparation, administration, and disposal of these drugs and supplies associated with their use are strongly recommended. Reproductive/Nursing Safety DTIC is teratogenic in rats at higher than clinically used dosages. It should be used during pregnancy only when the potential beneﬁts outweigh its risks. In humans, the FDA categorizes this drug as cat-egory C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) While it is unknown if DTIC enters milk, the potential carcino-genicity of the drug warrants using extreme caution in allowing the mother to continue nursing while receiving DTIC. Overdosage/Acute Toxicity Because of the toxic potential of this agent, iatrogenic overdoses must be avoided. Recheck dosage calculations. See Adverse Effects above for additional information on toxicity. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dacarbazine and may be of signiﬁcance in veterinary patients: !TMYELOSUPPRESSIVE DRUGS, OTHER (e. g., other antineoplastics, immu-nosuppressives, chloramphenicol, ﬂucytosine, colchicine, etc. ): May cause additive myelosuppression when used with DTIC !!RIFAMPIN : May increase the metabolism of DTIC !!PHENOBARBITAL : May increase the metabolism of DTIC !!PHENYTOIN : May increase the metabolism of DTIC Doses For more information on using dacarbazine 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: a) With doxorubicin as a lymphoma rescue protocol: Doxoru-bicin at 30 mg/m2 (for dogs >1 m2) or at 1 mg/kg (for dogs <1 m2) IV slowly over 30 minutes. DTIC is given at 800 mg/ m2 IV slowly over 5 hours. Dilute DTIC in 0. 9% Na Cl: Dogs >1 m2 in 1 liter; Dogs > 0. 4 m 2, but less than 1 m2 in 250 m L; and dogs < 0. 4 m2 in 100 m L. For acute and delayed vomit-ing, we administer dolasetron at 0. 6 mg/kg IV immediately before DTIC and send home oral metoclopramide for 7 days. Check CBC on day 7 and protocol can be repeated on day 21 if the dog achieves complete or partial response. Consult with cardiologist if lifetime doxorubicin dose exceeds 180 mg/ m2 (Rassnick 2006) b) 800-1,000 mg/m2 IV over an 8-hour period (no difference in efﬁcacy or toxicity with this regimen when compared with giving the drug divided (200 mg/m2 per day) over 5 days. ) May repeat every 21 days provided that the bone marrow has recovered. It is recommended that dogs be pretreated with dexamethasone through the IV catheter to prevent vasospasm and phlebitis associated with DTIC. Treatment with butor-phanol for injection discomfort may be helpful if using the high dose 8-hour infusion protocol. (Kitchell and Dhaliwal 2000), (Kitchell 2005) Monitoring !TEfﬁcacy !Toxicity, including CBC with differential and platelets; renal and hepatic function tests Client Information !TInform clients of the potential toxicities and risks associated with this therapy and report immediately any signs associated with se-rious toxicity (e. g., bloody vomiting or diarrhea, abnormal bleed-ing, bruising, urination, depression, infection, shortness of breath, etc. ). Chemistry/Synonyms An antineoplastic agent, dacarbazine occurs as a colorless to ivory colored crystalline solid. It is slightly soluble in water or alcohol. After reconstituting with sterile water, the injection has a p H of 3-4. Storage/Stability/Compatibility Dacarbazine may also be known as: dacarbazinum, DIC, DTIC, imidazole carboxamide, diemthyl triazeno imadazol carbox-amide, NSC-45388, WR-139007, Asercit®, DTI®, DTIC-Dome®, Dacarb®, Dacarbaziba®, Dacatic®, Deticene®, Detilem®, Detimedac®, Fauldetic®, Ifadac®, or Oncocarbil®. The powder for injection should be protected from light and kept refrigerated. If exposed to heat, the powder may change color from ivory to pink indicating some decomposition. After reconstituting with sterile water for injection the resultant solution is stable for up to 72 hours if kept refrigerated; up to 8 hours at room temperature. If further diluted (up to 500 m L) with either D 5W or normal saline, the solution is stable for at least 24 hours when refrigerated; 8 hours at room temperature under nor-mal room lighting. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Dacarbazine Powder for Injection: 100 mg & 200 mg (may contain mannitol) vials; DTIC-Dome® (Bayer); generic; (Rx)	pppbs.pdf
DACTINOMYCIN 245 DACTINOMYCIN ACTINOMYCIN D (dak-ti-noe-mye-sin) Cosmegen® ANTINEOPLASTIC Prescriber Highlights TT Parenteral antibiotic antineoplastic used in dogs & cats TT Contraindications: Hypersensitivity. Caution: Preexist-ing bone marrow depression, hepatic dysfunction, or infection TT Teratogenic TT Primary adverse effects are GI & bone marrow depres-sion (may be life threatening); adequate monitoring essential TT Speciﬁc administration techniques required, avoid extravasation injuries Uses/Indications Dactinomycin has been used as adjunctive treatment of lymphore-ticular neoplasms, bone and soft tissue sarcomas, and carcinomas in small animals. It appears to have low efﬁcacy against most carci-nomas and sarcomas. It is being investigated as a part of protocols for rescue therapy for canine lymphomas. Pharmacology/Actions Dactinomycin is an antibiotic antineoplastic. While it has activity against gram-positive bacteria, the drug's toxicity precludes its use for this purpose. Dactinomycin's exact mechanism of action for its antineoplastic activity has not been determined, but it apparently inhibits DNA-dependent RNA synthesis. Dactinomycin forms a complex with DNA and interferes with DNA 's template activity. Dactinomycin also possesses immunosuppressing and some hy-pocalcemic activity. Pharmacokinetics Because dactinomycin is poorly absorbed it must be given IV. It is rapidly distributed and high concentrations may be found in bone marrow and nucleated cells. Dactinomycin crosses the placenta, but it is unknown whether it enters maternal milk. The majority of the drug is excreted unchanged in the bile and urine. Contraindications/Precautions/Warnings Dactinomycin can cause life-threatening toxicity. It should only be used where adequate monitoring and support can be administered. Dactinomycin is contraindicated in patients who are hypersensitive to it. It should be used with caution in patients with preexisting bone marrow depression, hepatic dysfunction, or infection. Dactinomycin is actively transported by the p-glycoprotein pump and certain breeds susceptible to MDR1-allele mutation (Collies, Australian Shepherds, Shelties, Long-haired Whippet) are at higher risk for toxicity. It is suggested to test susceptible breeds prior to treating (test available at Washington State Univ. Vet. School). Adverse Effects Adverse effects that may be seen more frequently include: anemia, leukopenia, thrombocytopenia (or other signs of bone marrow de-pression), diarrhea, and ulcerative stomatitis or other GI ulceration. Because dactinomycin may cause increased serum uric acid levels, allopurinol may be required to prevent urate stone formation in susceptible patients. Hepatotoxicity is potentially possible with this agent. Because dactinomycin can cause extensive pain and tissue dam-age, avoid extravasation injuries. Dilution and administration by IV infusion is recommended or to administer slowly into a running IV line; use the “two-needle” technique. There is increasing evidence that chronic exposure by health care givers to antineoplastic drugs increases the mutagenic, teratogenic and carcinogenic risks associated with these agents. Proper pre-cautions in the handing, preparation, administration, and disposal of these drugs and supplies associated with their use are strongly recommended. Reproductive/Nursing Safety Dactinomycin has been demonstrated to be embryotoxic and teratogenic in rats, rabbits, and hamsters at higher than clinically used dosages. It should be used during pregnancy only when the potential beneﬁts outweigh its risks. In humans, the FDA categoriz-es 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. ) While it is unknown if dactinomycin enters maternal milk, the potential mutagenicity and carcinogenicity of the drug warrants using extreme caution in allowing the mother to continue nursing while receiving dactinomycin. Overdosage/Acute Toxicity Because of the toxic potential of this agent, iatrogenic overdoses must be avoided; recheck dosage calculations. See Adverse Effects above for additional information on toxicity. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dactinomycin and may be of signiﬁcance in veterinary patients: T ! DOXORUBICIN : Additive cardiotoxicity may occur if used concur-rently or sequentially with doxorubicin T ! MYELOSUPPRESSIVE D RUGS, OTHER (e. g., other antineoplastics, chloramphenicol, ﬂucytosine, colchicine, etc. ): May cause additive myelosuppression when used with dactinomycin T ! VITAMIN K : Patients requiring vitamin K may require higher dos-ages when receiving dactinomycin Laboratory Considerations T ! Dactinomycin may interfere with determination of antibacterial drug levels if using bioassay techniques. Doses For more information on using dactinomycin as part of chemo-therapy protocols, refer to the protocols found in the appendix or other dosages/protocols found in numerous references, including: Withrow and Mac Ewen's Small Animal Clinical Oncology, 4th Ed. (Withrow and Vail 2007); Canine and Feline Geriatric Oncology (Villalobos 2007); Small Animal Internal Medicine, 3rd Edition (Nelson and Couto 2003); Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat 6th Edition (Ettinger and Feldman 2005); and The 5-Minute Veterinary Consult Canine & Feline, 3rd Ed. (Tilley and Smith 2004). T ! DOGS: a) 0. 5-0. 9 mg/m2 IV over 20 minutes every 2-3 weeks (Kitch-ell and Dhaliwal 2000) b) 0. 7-1 mg/m2 IV every 3 weeks (Moore 2005)	pppbs.pdf
246 DALTEPARIN SODIUM Tc) For lymphoma rescue using the DOPP protocol (particularly when mechlorethamine is not available): Dactinomycin: 0. 5 DALTEPARIN SODIUM mg/m2 IV days 0 and 7; (dahl-tep-ah-rin) Fragmin®Vincristine: 0. 7 mg/m2 IV days 0 and 7; Procarbazine: 50 mg/m2 (for dogs > 0. 8 mg/m2 give dose to ANTICOAGULANT the nearest 50 mg; >0. 4 mg, but <0. 8 mg/m2 give to the near-est 50 mg, but give every other day; dogs < 0. 4 mg/m2 (refor-Prescriber Highlights mulate into 10 mg capsules and give to the nearest 20 mg) PO TT Low molecular weight (fractionated) heparin that may bedaily days 0-13; useful for treatment or prophylaxis of thromboembolic Prednisone: 30-40 mg/m2 PO daily days 0-13. disease No treatment given days 15-28 and then protocol is repeat-TT Preferentially inhibits factor Xa & usually only minimallyed at 4 weeks. Protocol may be severely myelosuppressive. If impacts thrombin & clotting time (TT or a PTT)neutrophil count is <2,000 cells/mc L, delay treatment for 3 days and recheck; monitor for cumulative thrombocytopenia. TT Hemorrhage unlikely, but possible (Rassnick 2006) TT Must be given subcutaneously TT Cats & dogs may require very frequent dosing making Monitoring outpatient administration impractical T ! Efﬁcacy T ! oxicity: including CBC with differential and platelets; hepatic TT Expense may be an issue, particularly in large dogs/ horses function tests; check inside patient's mouth for ulceration Client Information T ! Inform clients of the potential toxicities and risks associated with Uses/Indications this therapy and to report immediately any signs associated with Dalteparin may be useful for prophylaxis or treatment of deep vein serious toxicity (e. g., bloody vomiting or diarrhea, abnormal thrombosis or pulmonary embolus. Recent pharmacokinetic work bleeding, bruising, urination, depression, infection, shortness of in dogs and cats, raises questions whether the drug can be effec-breath, etc. ). tively and practically administered long-term. In humans, it is also indicated for prevention of ischemic complications associated with Chemistry/Synonyms unstable angina/non Q-wave MI. An antibiotic antineoplastic agent, dactinomycin (also known as ac-tinomycin D) occurs as a bright red, crystalline powder. It is some-Pharmacology/Actions what hygroscopic and soluble in water at 10°C and slightly soluble at By binding to and accelerating antithrombin III, low molecular 37°C. The commercially available preparation is a yellow lyophilized weight heparins (LMWHs) enhance the inhibition of factor Xa and mixture of dactinomycin and mannitol. thrombin. The potential advantage to using these products over Dactinomycin may also be known as: DTIC, ACT, actinomy-standard (unfractionated) heparin is that they preferentially inhibit cin C(1), actinomycin D, meractinomycin, NSC-3053, Ac-De®, factor Xa and only minimally impact thrombin and clotting time Bioact-D®, or Dacmozen®. (TT or a PTT). Storage/Stability/Compatibility Pharmacokinetics The commercially available powder should be stored at room tem-In dogs, dalteparin is completely absorbed after SC injection. It has perature and protected from light. When reconstituting, sterile wa-a volume of distribution of 50-70 m L/kg and a half-life of about 2 ter for injection without preservatives must be used as preservatives hours. Dogs have a shorter half-life than do humans. may cause precipitation. After reconstituting, the manufacturer Cats appear to have a much shorter duration of activity (anti-Xa) recommends using the solution immediately and discarding any associated with LMWHs than do humans and to maintain a thera-unused portion (no preservatives). When stored in the refrigera-peutic target of anti-XA activity of 0. 5-1 IU/m L requires 150 Units/ tor, reconstituted solution loses 2-3% potency over 6 hours. The kg SC q4h dosing of dalteparin. (Alwood, Downend et al. 2007) reconstituted solution may be added to D 5W or normal saline IV In horses, dalteparin's pharmacokinetics are similar to humans. infusions. IV ﬂuid sterilizing ﬁlters (cellulose ester membrane) may In humans, after subcutaneous injection, dalteparin is absorbed partially remove dactinomycin. rapidly with a bioavailability of about 87%; peak plasma levels (ac-tivity) occur in about 4 hours. Anti-factor Xa activity persists for Dosage Forms/Regulatory Status up to 24 hours and doses are usually given once to twice a day. VETERINARY-LABELED PRODUCTS: None Dalteparin is excreted via the kidneys in the urine; elimination half-HUMAN-LABELED PRODUCTS: life is about 3-5 hours. Half-life may be prolonged in patients with Dactinomycin Powder for Injection, lyophilized: 500 mcg with man-renal dysfunction. nitol 20 mg in vials; Cosmegen® (Merck); (Rx) Contraindications/Precautions/Warnings Dalteparin is contraindicated in patients who are hypersensitive to it, heparin, or pork products. It is also contraindicated in patients with major bleeding, or thrombocytopenia associated with posi-tive in vitro tests for anti-platelet in the presence of dalteparin. Use dalteparin cautiously in patients with signiﬁcant renal dysfunction as drug accumulation could result. It should be used with extreme caution in patients with heparin-induced thrombocytopenia or in-creased risk of hemorrhage.	pppbs.pdf
DALTEPARIN SODIUM 247 Adverse Effects In humans adverse effects do not routinely occur, but hemorrhage is a possibility. Injection site hematomas or pain, allergic reactions, and neurologic sequelae secondary to epidural or spinal hemato-mas have been reported. Do not administer via IM or IV routes; dalteparin must be given via subcutaneous injection only. Dalteparin cannot be used inter-changeably with other LMWHs or heparin sodium, as dosages dif-fer for each. Reproductive/Nursing Safety In humans, dalteparin 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. ) Dalteparin is likely safe to use during nursing. Overdosage/Acute Toxicity Overdosage may lead to hemorrhagic complications. If treatment is necessary, protamine sulfate via slow IV may be administered. 1 mg of protamine sulfate can inhibit the effects of 100 units of adminis-tered anti-Xa dalteparin. Avoid overdoses of protamine. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dalteparin and may be of signiﬁcance in veterinary patients: !TANTICOAGULANTS, ORAL (warfarin ): Increased risk for hemorrhage !TPLATELET-AGGREGATION I NHIBITORS (aspirin, clopidogrel ): Increased risk for hemorrhage !TTHROMBOLY TIC AGENTS : Increased risk for hemorrhage Laboratory Considerations !TLow molecular weight heparins may cause asymptomatic, ful-ly-reversible increases in AST or ALT; bilirubin is only rarely in-creased in these patients, therefore, interpret these tests with caution, as increases do not necessarily indicate hepatic damage or dysfunction. Doses !TDOGS: a) Dogs: 150 Units/kg SC three times daily; twice daily dosing may be effective. Studies are ongoing to clarify efﬁcacy and dosages. (Dunn 2006) !TCATS: a) Cats appear to have a much shorter duration of activity (anti-Xa) associated with LMWHs than do humans and to maintain a therapeutic target of anti-XA activity of 0. 5-1 IU/m L requires 150 Units/kg SC q4h dosing of dalteparin. (Alwood, Downend et al. 2007) b) For cardiogenic embolism: Current recommended protocols are 100 Units/kg SC q12-24h. (Hogan 2006) !THORSES: a) For prophylaxis of coagulation disorders in colic patients: 50 IU/kg SC once daily (q24h) (Feige, Schwarzwald et al. 2003) Monitoring !TBaseline and ongoing during therapy CBC (with platelet count) !TUrinalysis !TStool occult blood test !TRoutine coagulation tests (a PTT, PT) are usually insensitive mea-sures of activity and normally not warranted !TFactor Xa activity (available at Cornell Coagulation Laboratory) may be useful, particularly if bleeding occurs or patient has re-nal dysfunction. Note : T o measure peak anti-Xa activity in cats, sample at 2 hours post-dose Client Information !TIf this drug is to be used on an outpatient basis, clients must be instructed in proper injection technique for subcutaneous injec-tion and to immediately report any signs associated with bleed-ing or pulmonary thrombosis. If not using the pre-ﬁlled syringes, use a very small gauge insulin or tuberculin syringe and needle (e. g., 27 gauge). !TClients must understand that if they do not use the drug regu-larly (as prescribed), clots may form. Chemistry/Synonyms A low molecular weight heparin (LMWH), dalteparin sodium is obtained by nitrous acid depolymerization of heparin derived from pork intestinal mucosa. The average molecular weight is about 5000 and 90% ranges from 2000-9000 daltons (heparin sodium has a molecular weight around 12000). 1 mg of dalteparin is equivalent to not less than 110 units and not more than 210 units of anti-factor Xa. Dalteparin sodium may also be known by as: Daltaparinum natricum, Kabi-2165, Boxol ®, Fragmine®, Ligofragmin®, or Low Liquemine®. Storage/Stability/Compatibility The manufacturer of the commercially available injection states the product should be stored at controlled room temperature (20-25°C, 68-77°F). Do not use if particulate matter or discolor-ation occur. Once the multi-dose vial is punctured, store at room temperature; discard any unused solution after 2 weeks. A study showed that commercially available dalteparin solution was stable when drawn into syringes for up to 30 days when stored at room temperature or refrigerated. (Laposata and Johnson 2003) Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Dalteparin Sodium Injection (Anti-factor Xa international units): 2500 units (16 mg/0. 2 m L), preservative free, in 0. 2 m L single-dose syringes; 5000 IU (32 mg/0. 2 m L), preservative free, in 0. 2 m L sin-gle-dose syringes; 7500 units (48 mg/0. 3 m L), preservative free, in 0. 3 m L single-dose syringes; 10,000 units (64 mg/m L), preservative free, in 1 m L single-dose graduated syringes & 9. 5 m L multi-dose vials; 25,000 units (160 mg/m L), contains 14 mg/m L benzyl alcohol in 3. 8 m L multidose vials; Fragmin® (Pﬁzer); (Rx)	pppbs.pdf
248 DANAZOL DANAZOL (da-na-zole) Danocrine® ANDROGEN Prescriber Highlights TT Synthetic androgen; suppresses the pituitary-ovarian axis. Used primarily for adjunctive treatment of auto-immune hemolytic anemia/thrombocytopenia in dogs & cats TT Caution: Severe cardiac, renal or hepatic function impair-ment, or undiagnosed abnormal vaginal bleeding TT Teratogenic TT Rare hepatotoxicity in dogs TT Expense may be an issue Uses/Indications Because of expense and unpredictable efﬁcacy, danazol is not com-monly used in veterinary medicine, but has been used as adjunctive therapy (with corticosteroids) in the treatment of canine immune-mediated thrombocytopenia and hemolytic anemia, particularly if the patient becomes refractory to glucocorticoids and other im-munosuppressive therapy. There is apparently synergism when da-nazol is combined with corticosteroids for these indications. Once remission is attained, some dogs may have their dosage reduced or other medications may be eliminated and be controlled with dana-zol alone. In humans, danazol has been used for the treatment of en-dometriosis, ﬁbrocystic breast disease, idiopathic thrombocytopenic purpura and a variety of other conditions. Pharmacology/Actions Danazol is a synthetic androgen with weak androgenic effects. It suppresses the pituitary-ovarian axis. Danazol probably directly in-hibits the synthesis of sex steroids and binds to sex steroid receptors in tissues where it may express anabolic, weak androgenic, and an-tiestrogenic effects. Danazol appears to reduce afﬁnity of antibody with the mononuclear phagocytic system Fc receptor. It also may compete with glucocorticoids on steroid-binding globulin, thereby allowing greater free glucocorticoid to act. Pharmacokinetics There is very limited data available. Danazol is absorbed from the GI tract, but appears to be a rate limited process as increasing the dosage does not yield a corresponding increase in serum level. Distribution information is practically nonexistent; the drug apparently crosses the placenta. Danazol is believed to be principally metabolized in the liver. In humans, half-lives average about 4-5 hours. Contraindications/Precautions/Warnings Danazol should be used in patients with severe cardiac, renal, or hepatic function impairment, or undiagnosed abnormal vaginal bleeding only when its beneﬁts outweigh its risks. Adverse Effects Hepatotoxicity (incidence is rare) is the most signiﬁcant of the ad-verse effects that have been reported thus far in dogs. Otherwise vi-rilization in females is the most likely other effect that may be seen. Rarely, danazol may cause weight gain or lethargy. Human patients have developed vaginitis. Other potential adverse effects include edema, testicular atrophy, hirsutism, or alopecia. Reproductive/Nursing Safety Because of documented teratogenic effects, danazol is contraindi-cated during pregnancy. In humans, the FDA categorizes this drug as category X for use during pregnancy (Studies in animals or humans demonstrate fetal abnormalities or adverse reaction; reports indicate evidence of fetal risk. The risk of use in pregnant women clearly out-weighs any possible beneﬁt. ) While it is unknown if danazol enters milk, the potential adverse effects associated with androgens in young animals warrants cau-tion. In humans, breastfeeding is contraindicated in patients taking danazol. Overdosage/Acute Toxicity No information was located. Signiﬁcant overdoses should initially be handled by contacting an animal poison control center and initi-ate gut emptying protocols when applicable. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving danazol and may be of signiﬁcance in veterinary patients: T ! CYCLOSPORINE : May signiﬁcantly increase cyclosporine levels T ! INSULIN : By affecting carbohydrate metabolism, danazol may af-fect insulin requirements (doses may need to be increased) in dia-betic patients T ! WARFARIN : Concomitant use of danazol with anticoagulants may enhance the anticoagulant effect as danazol may decrease the syn-thesis of procoagulant factors in the liver Laboratory Considerations T ! Danazol may decrease total serum thyroxine (T4) and increase T3 uptake; because thyroid-binding globulin is decreased, free T4 and TSH remain normal. T ! ALT (SGPT) and AST (SGOT) may increase early in therapy but decrease towards baseline later in therapy. After discontinuation of danazol, levels usually return to baseline. Doses T ! DOGS: For adjunctive treatment of immune-mediated hemolytic ane-mia or thrombocytopenia: a) As adjunctive therapy with glucocorticoids in non-regener-ative forms of IMHA: 5 mg/kg PO three times daily. Used to reduce the dose of glucocorticoids needed for long-term therapy. (Chabanne 2006) b) 5 mg/kg PO q12h; usually used for the ﬁrst two weeks of ther-apy in combination with corticosteroids (Thompson 1994) c) 5 mg/kg PO twice daily; can taper dose once patient is on low dose alternate day prednisone (Trepanier 1999) d) Initially, (in addition to prednis(ol)one) danazol may be given at 10 mg/kg/day PO. Once anemia improves, corticosteroids may be slowly tapered and eventually DC'd. When remis-sion maintained by danazol alone, may lower to 5 mg/kg/day. Slowly taper after 2-3 months of normal hemograms with frequent monitoring of hemograms. (Bucheler and Cotter 1995) T ! CATS: For adjunctive treatment of immune-mediated hemolytic anemia: a) 5 mg/kg PO twice daily (Loar 1994)	pppbs.pdf
DANOFLOXACIN MESYLATE 249 Monitoring For autoimmune hematologic disorders: T ! Efﬁcacy (CBC, platelets, etc. ) T ! Hepatic function, baseline and at regular intervals while on therapy Client Information T ! Clients should be informed that it may take several (2-3) months to see a positive response with this drug T ! Clients should monitor for hepatotoxicity (jaundice) or changes in hematologic status (bleeding, tarry stools, etc. ) Chemistry/Synonyms A synthetic derivative of ethisterone (ethinyl testosterone), danazol occurs as a white to pale yellow, crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. Danazol may also be known as: Win-17757, Anargil®, Azol ®, Cyclomen®, D-Zol®, Danalem®, Danatrol®, Danazant®, Danogen®, Danocrine®, Danokrin®, Danol®, Ectopal®, Gonablok®, Kendazol®, Ladazol®, Ladogal®, Lisigon®, Mastodanatrol®, Norciden®, Vabon®, Winobanin®, Zendol®, or Zoldan-A®. Storage/Stability Danazol capsules should be stored in well-closed containers at room temperature. 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: Danazol Capsules: 50 mg, 100 mg, & 200 mg; generic; (Rx) DANOFLOXACIN MESYLATE (dan-oh-ﬂoks-a-sin) A180®, Advocin® INJECTABLE FLU OROQUINOLONE Prescriber Highlights TT Parenteral ﬂuoroquinolone antibiotic labeled for use in cattle (not dairy or veal) to treat BRD associated with Mannheimia (Pasturella) hemolytica & P. multocida; may also be of beneﬁt in treating ﬂuoroquinolone-susceptible infections in non-food producing species (horses, cam-elids, exotics) TT Labeled in cattle for two SC injections 48 hours apart TT FDA prohibits extra-label use in food animals Monograph by Elaine Lust, Pharm D Uses/Indications Danoﬂoxacin mesylate injection is indicated for the treatment of Bovine Respiratory Disease (BRD) associated with Mannheimia (Pasturella) hemolytica and P. multocida in cattle (not dairy or veal). Because of the drug's spectrum of activity, it may also be of beneﬁt in the treatment of infections caused by Histophilus somni (Haemophilus somnus) or M. bovis, but the drug is not labeled (at the time of writing) for treating these pathogens. In other coun-tries, danoﬂoxacin may be labeled for use in swine and chickens (non-laying), but in the USA it is illegal to use the drug in an extra-label manner in food-producing species. Danoﬂoxacin may be of beneﬁt in treating susceptible infections in adult horses, camelids and other non-food producing species. Pharmacology/Actions Danoﬂoxacin is a ﬂuoroquinolone bactericidal antibiotic that in-hibits bacterial DNA-gyrase, preventing DNA supercoiling and DNA synthesis. Fluoroquinolones have good activity against many gram-negative bacilli and some gram-positive cocci (Staphylococcus aureus and Staphylococcus intermedius). In general, ﬂuoroquinolo-nes have a dose or concentration dependant effect rather than a time-dependant bactericidal effect. MIC 90 values for Mannheimia (Pasturella) hemolytica and Pasturella multocida average 0. 06 mcg/m L and 0. 015 mcg/m L, respectively. Pharmacokinetics After subcutaneous injection in the neck in cattle, danoﬂoxacin is reportedly rapidly absorbed with high bioavailability (≈90%). Peak serum levels occur about 2-3 hours after dosing. Steady-state vol-ume of distribution is approximately 2. 7 L/kg; lung levels exceed those in plasma. T erminal elimination half-life ranges from 3-6 hours. In cattle, elimination is primarily unchanged drug into the urine. Other species may metabolize greater percentages of the drug into a desmethyl metabolite (desmethyldanoﬂoxacin). In horses, a research study on the pharmacokinetics of IM, IV and IG (intragastric) administration of danoﬂoxacin at 1. 25 mg/kg to healthy mature horses revealed favorable bioavailability with the IM route at 89% and poor bioavailability of the IG route at 22%. The authors reported good tolerability of the IG route (Fernandez-Varon, Ayala et al. 2006). In sheep, the drug quickly reaches high tissue concentrations. One hour after IM administration, the concentration peaks in lung tissue and interdigital skin. A study dosing sheep at 1. 25 mg/kg IV and IM resulted in similar levels for serum, exudates and transu-dates (Aliabadi, Landoni et al. 2003). In goats, a study of danoﬂoxacin administered at 1. 25 mg/kg IV or IM, revealed similar half-lives of 4. 67 and 4. 41 hours after IV and IM, respectively. Volume of distribution was high via either route with 100% bioavailability reported after IM administration. The drug's penetration into both exudates and transudates were slightly slower after IM administration (Aliabadi and Lees 2001). Another study found that goats challenged with E. coli endotoxin receiving danoﬂoxacin at 1. 25 mg/kg IV or IM had an altered clearance of the drug with signiﬁcant increases in plasma concentrations and AUC (Ismail 2006). In camels, IV administration of the drug at 1. 25mg/kg results in a high volume of distribution, a half-life of 5. 37 hours and rapid clearance. The IM administration of the drug at the same dose re-sulted in rapid and near complete absorption, with a half life of 5. 71 hours (Aliabadi, Badrelin et al. 2003). In pigs, the drug has been shown to reach a high concentration in lung tissue and gastrointestinal tissue, including mucosa. In the ﬁrst 24-hours after an intramuscular dose of 2 mg/kg, 43% of the dose is eliminated in the urine. Elimination half-life in swine is about 7 hours. Contraindications/Precautions/Warnings The FDA prohibits extra-label usage of this drug in food ani-mals. The manufacturer cautions use of danoﬂoxacin in animals with known or suspected CNS disorders as quinolones have rarely caused CNS stimulation. Adverse Effects Hypersensitivity reactions and lameness have been reported after administration to calves at labeled dosages. Incidence rates are not	pppbs.pdf
250 DANTROLENE SODIUM known, but they are believed to occur uncommonly. In cattle, sub-cutaneous injections can cause a local tissue reaction that may result in trim loss. Reproductive/Nursing Safety Studies documenting safety during pregnancy in cattle are not avail-able. In studies performed in rats (100 mg/kg/day), mice (50 mg/ kg/day) and rabbits (15 mg/kg/day), no teratogenic effects were ob-served. Danoﬂoxacin safety during nursing is not known, but it is pro-hibited from use in lactating dairy cattle where the milk is for hu-man consumption. Overdosage/Acute Toxicity Limited information is available for cattle. High dosages, 18-60 mg/ kg for 3-6 days in feeder calves reportedly can cause arthropathies/ lameness (consistent with other ﬂuoroquinolones), CNS stimulation (ataxia, nystagmus, tremors), inappetance, recumbency, depression, and exophthalmos. Some (3/6) 21-day-old calves receiving 18 mg/kg twice 48 hours apart developed nasal pad erythema. Studies performed in adult dogs given 2. 4 mg/kg/day PO for 90 days developed no observable effects. Drug Interactions No speciﬁc interactions have been reported when danoﬂoxacin is used in cattle. In humans: T ! THEOPHYLLINE (aminophylline ): Some injectable ﬂuoroquinolones (e. g., ciproﬂoxacin) can potentially increase serum concentra-tions; increased monitoring of theophylline concentrations is rec-ommended Laboratory Considerations No issues identiﬁed Doses T ! CATTLE: For labeled indications: a) 6 mg/kg (1. 5 m L per 100 lb body weight) SC. Repeat once in approximately 48 hours. Administered dosage volume should not exceed 15 m L. (Label directions; A180®—Pﬁzer) Monitoring T ! Clinical efﬁcacy Client Information T ! If clients are to administer this product to food animals, they should be advised on proper injection technique and the impor-tance of using the product per the label only Chemistry/Synonyms Danoﬂoxacin mesylate is a synthetic ﬂuoroquinolone that occurs as a white to off-white crystalline powder. Approximately 180 grams are soluble in 1 liter of water. Danoﬂoxacin may also be known by the following synonyms: CP-76136-27, danoﬂoxacine or danoﬂoxacino. Internationally registered trade names include: Advocin®, Advocine®, Danocin®, Advocid®, and Advovet ®. Storage/Stability/Compatibility Danoﬂoxacin mesylate for injection should be stored at or below 30° C and protected from light and freezing. The color of the injectable solution is yellow to amber and does not affect potency. Danoﬂoxacin injection for SC use should not be mixed with oth-er medications or diluents. Fluoroquinolone injectable products can be very sensitive to p H changes or chelation with cationic substances (calcium, magnesium, zinc, etc. ). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Danoﬂoxacin Mesylate 180 mg/m L (of danoﬂoxacin) in 100 & 250 m L multi-dose vials; A180® (Pﬁzer); (Rx). Approved for use in cattle only. Not for use in cattle intended for dairy product or calves to be processed for veal. When administered per the label directions, slaughter withdrawal is 4 days from the time of the last treatment. HUMAN-LABELED PRODUCTS: None DANTROLENE SODIUM (dan-troe-leen) Dantrium® SKELETAL MUSCLE RELAXANT Prescriber Highlights TT Direct acting muscle relaxant TT Primary indications: HORSES: post-anesthesia myositis/ acute rhabdomyolysis; DOGS & CATS: functional urethral obstruction; SWINE: malignant hyperthermia TT Extreme caution: Hepatic dysfunction TT Caution: Severe cardiac dysfunction or pulmonary disease TT Adverse Effects: Weakness, sedation, increased urinary frequency, GI effects; hepatotoxicity possible especially with chronic use. TT Injectable is very expensive Uses/Indications In humans, oral dantrolene is indicated primarily for the treatment associated with upper motor neuron disorders (e. g., multiple sclero-sis, cerebral palsy, spinal cord injuries, etc. ). In veterinary medicine, its proposed indications include: the prevention and treatment of malignant hyperthermia syndrome in various species, the treatment of functional urethral obstruction due to increased external urethral tone in dogs and cats, the prevention and treatment of equine post-anesthetic myositis (PAM), and equine exertional rhabdomyolysis. It has also been recommended for use in the treatment of bites from Black Widow Spiders in small animals and the treatment of porcine stress syndrome. Pharmacology/Actions Dantrolene exhibits muscle relaxation activity by direct action on muscle. While the exact mechanism is not well understood, it prob-ably acts on skeletal muscle by interfering with the release of calcium from the sarcoplasmic reticulum. It has no discernible effects on the respiratory or cardiovascular systems, but can cause drowsiness and dizziness. The reasons for these CNS effects are not known. Pharmacokinetics The bioavailability of dantrolene after oral administration in hu-mans is only about 35% and after intragastric administration to horses, approximately 39%. The drug is fairly slowly absorbed, with peak levels occurring about 5 hours after oral administration (hu-mans) and 1. 5 hours in horses. The drug is substantially bound to plasma proteins (principally albumin), but many drugs may displace it from such (see Drug Interactions). Dantrolene is rapidly eliminated from the horse (half-life≈130 minutes). The elimination half-life in humans is approximately 8 hours. Dantrolene is metabolized in the liver and the metabolites are	pppbs.pdf
DANTROLENE SODIUM 251 excreted in the urine. Only about 1% of the parent drug is excreted unchanged in the urine and bile. In horses, oral dantrolene absorption is affected by food and must be given to fasted horse orally to achieve therapeutic levels. Contraindications/Precautions/Warnings Because dantrolene can cause hepatotoxicity, it should be used with extreme caution in patients with preexisting liver disease. It should be used with caution in patients with severe cardiac dysfunction or pulmonary disease. Adverse Effects The most signiﬁcant adverse reaction with dantrolene therapy is hepatotoxicity. In humans, it is most commonly associated with high dose chronic therapy, but may also be seen after short high dose therapy. The incidence of this reaction is unknown in veteri-nary medicine, but monitor for its occurrence. More common, but less signiﬁcant are the CNS associated signs of weakness, sedation, dizziness, headache, and GI effects (nausea, vomiting, constipation). Also seen are increased urinary frequency and, possibly, hypotension. Reproductive/Nursing Safety The safe use of dantrolene during pregnancy has not been deter-mined. 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 labora-tory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the beneﬁt of therapy clearly outweighs the risks. ) Dantrolene is distributed into milk; safe use cannot be assured during nursing. Overdosage/Acute Toxicity There is no speciﬁc antidotal therapy to dantrolene overdoses, therefore, remove the drug from the gut if possible and treat sup-portively. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dantrolene and may be of signiﬁcance in veterinary patients: !TBENZODIAZEPINES & OTHER CNS DEPRESSANTS : Increased sedation may be seen if tranquilizing agents are used concomitantly with dantrolene !TCALCIUM-CHANNEL BLOCKERS : Rare reports of cardiovascular col-lapse in humans; concomitant use with dantrolene during malig-nant hyperthermia crises not recommended !TESTROGENS : Increased risks of hepatotoxicity from dantrolene have been seen in women >35 years of age who are also receiving estrogen therapy; veterinary signiﬁcance is unknown !TWARFARIN : Dantrolene may be displaced from plasma proteins by warfarin with increased effects or adverse reactions resulting Doses !TDOGS: For treatment of functional urethral obstruction due to in-creased external urethral tone: a) 1-5 mg/kg PO q8h (Polzin and Osborne 1985), (Chew, Di Bartola, and Fenner 1986) b) 1-5 mg/kg PO q8-12h (Lane 2000), (Coates 2004) c) 1 mg/kg PO q8h (Lulich 2004) For canine stress syndrome (CSS)/Malignant Hyperthermia (MH): a) T o treat an acute attack: 0. 2-3 mg/kg IV (Axlund 2004a) b) For MH-like syndrome associated with hops (Humulus lu-pulus) ingestion: 2-3 mg/kg IV or 3. 5 mg/kg PO as soon as possible after ingestion. (Wismer 2004) For adjunctive treatment of Black Widow Spider bite: a) 1 mg/kg IV; followed by 1 mg/kg PO q4h (Bailey 1986a) !TCATS: For treatment of functional urethral obstruction due to in-creased external urethral tone: a) 0. 5-2 mg/kg PO q8h OR 1 mg/kg IV (Lane 2000); (Osborne, Kruger et al. 2000) b) 0. 5-2 mg/kg PO three times daily (Coates 2004) c) 2-10 mg (total dose) PO three times daily with either pra-zosin (0. 5 mg/cat once to twice daily) or phenoxybenzamine (2. 5-7. 5 mg/cat once to twice daily) (Sparkes 2006b) !THORSES: For treatment of acute rhabdomyolysis: a) 15-25 mg/kg slow IV four times daily (Robinson 1987) b) 2-4 mg/kg PO via nasogastric tube once daily (Hanson 1999) For prevention of rhabdomyolysis: a) For prevention of recurrent exertional rhabdomyolysis in Thoroughbreds: 4 mg/kg PO in horses fasted (12-hour fast in study) prior to administration. (Mc Kenzie, Valberg et al. 2003) b) Several dosage regimens have been recommended, but take care as use and efﬁcacy are uncertain: 2 mg/kg PO once daily for 3-5 days and then every 3rd day for a month has been recommended. Drug is diluted in normal saline and given via stomach tube. Another dosage recommendation is 300 mg (total dose) PO once daily (may be preferable because the drug is hepatotoxic). Another recommendation is 500 mg (total dose) PO for 3-5 days and then 300 mg PO ev-ery third day. Monitor hepatic function and status. (Mac Leay 2004) For prevention of post-anesthetic myositis (PAM): a) 10 mg/kg PO (intragastric) 1. 5 hours before surgery. This should give peak levels at the time surgery begins and main-tain postulated therapeutic levels for an additional 2 hours. The intragastric preparation was made by dissolving/sus-pending the contents of oral capsules into 500 m L of normal saline. Should further doses be warranted, additional doses of 2. 5 mg/kg PO (intragastric) q60 minutes can be given. Alternatively, IV doses of 1. 9 mg/kg loading will give thera-peutic levels but will only persist for about 20 minutes. An IV dose of 4 mg/kg will maintain therapeutic levels for about 2 hours, but peak levels will be quite high. (Court et al. 1987) !TSWINE: Prevention or treatment of malignant hyperthermia: a) 3. 5 mg/kg IV (Booth 1988a)	pppbs.pdf
252 DAPSONE Monitoring Depending on the reason for use: DAPSONE T ! Baseline and periodic liver function tests (ALT, AST, Alk Phos, (dap-sone) DDSetc. ) if projecting to be used chronically or using high dosages T ! Body temperature (malignant hyperthermia) ANTIMYCOBACTERIAL ANTIBIOTIC T ! Urine volume, frequency, continence Prescriber Highlights Client Information TT Potentially useful for treating mycobacterial & some pro-T ! Dantrolene can cause GI upset (vomiting, lack of appetite), in-tozoal (Pneumocystis) infections creased urinary frequency, and sedation (drowsiness) T ! Rarely, dantrolene can cause liver toxicity; contact veterinarian TT May be used to treat Brown recluse spider bites & cuta-neous vasculitis if patient develops persistent vomiting, lack of appetite, unex-plained profound lethargy, or yellowish whites of eyes or mucous TT Relatively contraindicated in cats membranes TT Adverse effects: hepatotoxicity, anemia, thrombocytope-T ! Intravenous use of this drug should only be used by professionals nia, neutropenias, gastrointestinal effects, neuropathies, familiar with its use & cutaneous drug eruptions; photosensitivity reactions are possible Chemistry/Synonyms A hydantoin derivative that is dissimilar structurally and pharma-cologically from other skeletal muscle relaxant drugs, dantrolene Uses/Indicationssodium is a weak acid with a p K a of 7. 5. It occurs as an odorless, Dapsone may be useful as a second-line agent in the treatment of my-tasteless, orange, ﬁne powder that is slightly soluble in water. It rap-cobacterial diseases in dogs and, possibly, cats. It potentially may be idly hydrolyzes in aqueous solutions to the free acid form that pre-a useful treatment for Pneumocystis jiroveci (formerly Pneumocystis cipitates out of solution. carinii) infections. Dantrolene Sodium may also be known by the following syn-Because of its leukocyte inhibitory characteristics, dapsone onyms and internationally registered trade names: F-440, F-368, may be useful for adjunctive treatment of Brown recluse spider Danlene®, Dantamacrin®, Dantralen®, or Dantrolen®. (Loxosceles rectusa recluse) bites, or when an underlying etiology Storage/Stability/Compatibility causing cutaneous vasculitis cannot be determined. Dantrolene capsules should be stored in well-closed containers Pharmacology/Actions at room temperature. Dantrolene powder for injection should be The exact mechanism for dapsone's actions are not known. It prob-stored at temperatures less than 30°C and protected from prolonged ably has similar actions to that of the sulfonamides, primarily af-exposure to light. After reconstitution, the powder for injection fecting folic acid synthesis in susceptible organisms. Dapsone alsoshould be used within 6 hours when stored at room temperature decreases neutrophil chemotaxis, complement activation, antibody and should be protected from direct light. It is not compatible with production and lysosomal enzyme synthesis. The mechanisms for either normal saline or D 5W injection. these actions are not well understood. Dosage Forms/Regulatory Status Pharmacokinetics VETERINARY-LABELED PRODUCTS: None After oral administration to dogs, dapsone is rapidly and completely HUMAN-LABELED PRODUCTS: absorbed. Elimination half-life ranges from about 6-10 hours. In Dantrolene Sodium Capsules: 25 mg, 50 mg, & 100 mg; Dantrium® humans, the monoacetyl metabolite is almost completely bound to (Procter & Gamble Pharm. ); generic; (Rx) plasma proteins, but in dogs, it is only about 60% bound. Dapsone is primarily eliminated via the kidneys as conjugates and unidentiﬁed Dantrolene Sodium Powder for Injection: 20 mg/vial (approx. 0. 32 metabolites. Half-life in humans is widely variable and ranges from mg/m L after reconstitution; with mannitol 3 g/vial) in 70 m L vials; about 10-50 hours. Dantrium® Intravenous (Procter & Gamble Pharm. ); (Rx). Note: Be-cause of the expense, minimum order quantity, and non-returnable Contraindications/Precautions/Warnings nature of the commercially available intravenous product, it may Because of increased incidences of neurotoxicity and hemolytic ane-not be practical for veterinary use. mia, dapsone is generally not recommended for use in cats. Dapsone in contraindicated in patients hypersensitive to it or other sulfone drugs. It should not be used in patients with severe anemias or other preexisting blood dyscrasias. Because of its potential for causing he-patic toxicity, dapsone should be used with caution in animals with preexisting hepatic dysfunction. Adverse Effects Adverse effects include hepatotoxicity, hemolytic anemia, thrombo-cytopenia, neutropenias, gastrointestinal effects, neuropathies, and cutaneous drug eruptions. Photosensitivity is possible. Dapsone is a potential carcinogen. Reproductive/Nursing Safety In pregnant animals, dapsone should be used with caution. In hu-mans, the FDA categorizes dapsone as a category C drug for use during pregnancy (Animal studies have shown an adverse effect on	pppbs.pdf
DAPSONE 253 the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans). Animal studies have apparently not been performed with dapsone to determine its effects in pregnancy. Dapsone is excreted into milk in concentrations equivalent to those found in plasma; and hemolytic reactions have been seen in human neonates. Consider switching to milk replacer if dapsone is required in a nursing dam. Overdosage/Acute Toxicity Because of its toxicity potential, speciﬁc species differences in sen-sitivity, and pharmacokinetics, it is recommended to contact an animal poison control center in cases of dapsone overdoses. In humans, dapsone overdoses generally cause nausea, vomiting, and hyperexcitability which can occur within minutes of an overdose. Methemoglobinemia with associated depression, seizures, and cy-anosis can occur. Hemolysis may be delayed, occurring from 7-14 days after the overdose. Treatment in humans includes removal of drug from the gut, methylene blue for methemoglobinemia and, sometimes, hemodialysis to enhance removal of the drug and the monoacetyl metabolite. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dapsone and may be of signiﬁcance in veterinary patients: !TPROBENECID : May decrease the renal excretion of active metabo-lites of dapsone !TPYRIMETHAMINE : May increase risk of hematologic reactions oc-curring with dapsone !TRIFAMPIN : May decrease plasma dapsone concentrations (7-10 fold) !TTRIMETHOPRIM : May increase plasma dapsone concentrations (and vice versa) and potentially increase each other's toxicity Laboratory Considerations No speciﬁc laboratory interactions or considerations noted Doses !TDOGS: a) As an alternative treatment for pemphigus: Dapsone at 1 mg/ kg PO q8h; with sulfasalazine at 10-40 mg/kg q8h. (Rosenk-rantz 2004) b) For post-vaccination alopecia/vasculitis resistant to predni-sone therapy: 1 mg/kg PO q8h (Lemarie 2003c) c) For treating mycobacteriosis: 1. 1 mg/kg PO q6h until remis-sion, then 0. 3 mg/kg q8-12h after recovery (Greene and Watson 1998) d) For adjunctive therapy of vasculitis: 1 mg/kg PO q8h (Hillier 2006d) e) For adjunctive treatment of Brown Recluse spider (Loxosceles sp. ) bite: 1 mg/kg PO three times daily for 10 days (Peterson 2006d) !TCATS: CAUTION: Dapsone can potentially cause serious side effects in cats (e. g., blood dyscrasias, and hepatic or neuro toxicities); many consider its use relatively contraindicated in cats. If this drug is to be used, clients must accept the risks associated with its use; intensive monitoring for adverse effects must be performed. a) As an alternative to clofazimine for treating feline leprosy (see caution above): 1 mg/kg once daily PO. (Lemarie 2003a) b) For treating mycobacteriosis: 8 mg/kg PO once daily for 6 weeks (Greene and Watson 1998) c) For aural chondritis: 1 mg/kg PO q24h (Grifﬁn 2006) !THORSES: a) As an alternative treatment for Pneumocystis carinii pneu-monia: 3 mg/kg PO once daily (q24h). Note : From one case report of treatment of a foal; treatment period was 56 days. (Clark-Price, Cox et al. 2004) Monitoring !TCBC with platelets every 2-3 weeks during ﬁrst 4 months of treatment and then every 3-4 months !TLiver function tests !TOther adverse effects (GI, drug eruptions, neurotoxicity, etc. ) !TEfﬁcacy Client Information !TClients should understand that limited experience has occurred with dapsone in domestic animals and that toxicity may occur. !TBecause photosensitivity can occur, exposed skin should be pro-tected from prolonged exposure to sunlight. Chemistry/Synonyms A sulfone antimycobacterial/antiprotozoan, dapsone occurs as a white or creamy-white, odorless, crystalline powder. It is very slightly soluble in water, freely soluble in alcohol, and insoluble in ﬁxed or vegetable oils. Dapsone may also be known as: DADPS, dapsonum, DDS, di-aminodiphenylsulfone, NSC-6091, diaphenylsulfone, disulone, sulfonyldianiline, Avlosulfone®, Daps®, Dapsoderm-X®, Dopsan®, Novasulfone®, Servidapsone®, and Sulfona®. Storage/Stability Dapsone tablets should be stored protected from light at controlled room temperature (20-25°C, 68-77°F). Dapsone tablets may be compounded into a stable liquid dosage form. The simplest method is to use a 1:1 ratio of Ora-Plus®:Ora-Sweet® and use crushed tablets to make a concentration of 2 mg/ m L. This preparation is stable either stored refrigerated or at room temperature for 90 days. See the following reference for spe-ciﬁc information: Nahata, MC et al, Ann Pharmacotherapy 2000; 34:848-50. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Dapsone Tablets: 25 mg & 100 mg (scored); generic (Jacobus); (Rx)	pppbs.pdf
254 DARBEPOETIN ALFA TDARBEPOETIN ALFA (dar-beh-poe-eh-tin al-fah) Aranesp® ERYTHROPOIETIC AGENT Prescriber Highlights TT Biosynthetic erythropoietic agent potentially useful for treating anemia of chronic kidney disease in dogs & cats TT May be less immunogenic (not proven) in dogs or cats than epoetin alfa (r Hu EPO) TT Longer duration of effect, initially only dosed once per week TT Treatment expense may be formidable Uses/Indications Darbepoetin may potentially be useful in treating anemia of chronic kidney disease in dogs and cats. It may be less immunogenic than epoetin, but this is only theoretical and has not been documented. Another advantage is that doses may be administered less often to maintain PCV. Treatment costs may be higher than using epoetin, however. Pharmacology/Actions Darbepoetin is a recombinant DNA-produced protein related to erythropoietin. It stimulates erythropoiesis using the same mecha-nism as endogenous erythropoietin by interacting with progenitor stem cells to increase RBC production. Darbepoetin may be less im-munogenic in animals than epoetin secondary to its formulation utilizing carbohydrates as part of its structure. Theoretically, car-bohydrates may “shield” the sites on the drug of greatest antigenic potential from immune cell detection. Carbohydrates also increase the solubility and stability of the compound, causing less aggregate formation and, therefore, potentially less immunogenicity. Pharmacokinetics No information was located on the pharmacokinetics in dogs or cats. In humans with chronic renal failure after subcutaneous injection, bioavailability is about 37% and the drug is absorbed slowly with a distribution half-life of about 1. 4 hours. It is extensively metabolized and terminal elimination half-life averages 21 hours. T erminal half-life is about 3 times greater than that of epoetin alfa. Contraindications/Precautions/Warnings Darbepoetin should not be used in dogs or cats with documented anti-r Hu EPO antibodies. Antibody formation diagnosis is based upon high myeloid:erythroid ratio on bone marrow cytology and exclusion of other causes of anemia. In humans, darbepoetin is con-traindicated in patients hypersensitive to it or excipients in the for-mulation and in those with uncontrolled hypertension. Adverse Effects The adverse effect proﬁle for darbepoetin is unknown, but adverse effects reported with r Hu EPO (epoetin) therapy in animals include: anti-r Hu EPO antibody formation with resultant pure red blood cell aplasia (PRCA), hypertension, seizures, or iron deﬁciency. Reproductive/Nursing Safety Studies performed in pregnant rats and rabbits demonstrated no overt teratogenicity at IV dosages of up to 20 mg/kg/day. Decreased body weights were noted in some rat pups. It is unknown if darbepoetin is distributed into milk, but it is unlikely to pose much risk to animals nursing. Overdosage/Acute Toxicity Little information is available. Humans have received therapeutic dosages of up to 8 mcg/kg every week for 12 weeks. Polycythemia is possible and therapeutic phlebotomy may be required. Drug Interactions None have been identiﬁed. For epoetin (a related compound): T ! ANDROGENS : May increase the sensitivity of erythroid progenitors and this interaction has been used for therapeutic effect T ! DESMOPRESSIN : With EPO can decrease bleeding times Laboratory Considerations No speciﬁc lab issues were identiﬁed; see Contraindications and Monitoring for more information. Doses T ! DOGS /CATS: Doses and dosing intervals for darbepoetin in dogs and cats have not been well established. Anecdotally it has been suggested to use the initial human dose of 0. 45 mcg/kg of darbepoetin in dogs and cats and adjust using clinical judgment and careful monitoring. Alternatively, animals that have received epoetin alfa (RHu EPO) can have their total weekly dosages converted using the following guidelines: T otal weekly dose of epoetin in units divided by 200 = once weekly dose in mcg darbepoetin. Example: animal gets 400 Units of epoetin 3 times weekly = 1200 Units. Divide by 200 = 6 mcg of darbepoetin once weekly. Monitoring T ! Before re-dosing check PCV each time T ! Monitor patient's iron stores or supplement with iron T ! Blood pressure Client Information T ! Clients must be committed to the expense and associated moni-toring required for this treatment T ! herapeutic effects may not be noted for several weeks after start-ing treatment Chemistry/Synonyms Darbepoetin alfa is a 165-amino acid protein that is produced us-ing recombinant DNA technology in Chinese hamster ovary cells. Two additional N-linked oligosaccharide chains are added to human erythropoietin yielding a glycoprotein with an approximate molecu-lar weight of 37,000 daltons. Darbepoetin may also be known by the following synonyms: NESP, novel erythropoiesis stimulating protein, darbepoetina or darbepoetinum. Internationally registered trade names include: Aranesp® and Nespo®. Storage/Stability The commercially available injection solutions (polysorbate or al-bumin-based) should be stored at 2-8°C and protected from light. Do not freeze or shake. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None The ARCI (Racing Commissioners International) has designated this drug as a class 2 substance. It is also prohibited on the premises of a racing facility.	pppbs.pdf
DECOQUINATE 255 HUMAN-LABELED PRODUCTS: Darbepoetin Alfa Solution for Injection (preservative free); Aranesp® (Amgen); (Rx) Each size is available in polysorbate or albumin-based solutions: 25 mcg/0. 42 m L preﬁlled syringes 25 mcg per 1 m L single-dose vials 40 mcg/0. 4 m L preﬁlled syringes 40 mcg per 1 m L single-dose vials 60 mcg/0. 3 m L preﬁlled syringes 60 mcg per 1 m L single-dose vials 100 mcg/0. 5 m L preﬁlled syringes 100 mcg per 1 m L single-dose vials 150 mcg/0. 3 m L preﬁlled syringes 150 mcg per 1 m L single-dose vials 200 mcg/0. 4 m L preﬁlled syringes 200 mcg per 1 m L single-dose vials 300 mcg/0. 6 m L preﬁlled syringes 300 mcg per 1 m L single-dose vials 500 mcg per 1 m L single-dose vials and preﬁlled syringes DECOQUINATE (de-koe-kwin-ate) Deccox® ANTIPROTOZOAL/COCCIDIOSTAT Prescriber Highlights TT Coccidiostat TT Not approved for lactating dairy animals, laying chickens TT Not effective against adult coccidia; no effect on clinical coccidiosis Uses/Indications Decoquinate is labeled for use in cattle for the prevention of coccid-iosis in either ruminating or non-ruminating calves, cattle or young goats caused by the species E. christenseni or E. ninakohlyakimoviae. It is used for prevention of coccidiosis in broilers caused by E. tenel-la, E. necatrix, E. acervulina, E. mivati, E. maxima or E. burnetti. It may be useful in dogs as prophylactic treatment for coccidiosis and hepatozoonosis relapse. Pharmacology/Actions Decoquinate is 4-hydroxy quinolone agent that has anticoccidial activity. Decoquinate acts on the sporozoite stage of the life cycle. The sporozoite apparently can still penetrate the host intestinal cell, but further development is prevented. The mechanism of action for decoquinate is to disrupt electron transport in the mitochondrial cytochrome system of coccidia. Pharmacokinetics No information was located. Contraindications/Precautions/Warnings Decoquinate is not effective for treating clinical coccidiosis and has no efﬁcacy against adult coccidia. Decoquinate is not approved for use in animals producing milk for food or in laying chickens. Adverse Effects No adverse effects listed when given as directed. Overdosage/Acute Toxicity No speciﬁc information located. Decoquinate is considered to have a wide safety margin. Drug Interactions/Laboratory Considerations None noted Doses T ! DOGS: For coccidiosis prophylaxis: a) 50 mg/kg PO once daily (Matz 1995) For canine hepatozoonosis (Hepatozoon americanum): Note : When using decoquinate for this indication, obtain the decoqui-nate 6% (27. 2 gram/lb. ) powder. An approximate conversion is G teaspoonful is equivalent to approximately 45 mg decoquinate and 1 teaspoonful (5 m L) is equivalent to approximately 180 mg decoquinate. a) For 14 days: Use TMP/Sulfa 15 mg/kg PO q12h; Clindamy-cin 10 mg/kg PO q8h; Pyrimethamine 0. 25 mg/kg PO once daily); Then to prevent relapse after TCP therapy: Decoquinate at 20 mg/kg PO q12h long-term. Recommend treating for 2 years and then performing muscle biopsy. If negative, may discontinue. When using the 27. 2 gram/lb (6%) feed additive (Deccox®) the decoquinate powder can be administered at a rate of 1 teaspoon per 10 kg (22 lb) of body weight and fed twice daily. (Macintire, Vincent-Johnson et al. 2006), (Ma-cintire 2007) b) TMP/Sulfa 15 mg/kg PO daily for 14 days; Clindamycin 10 mg/kg PO q8h For 14 days; Pyrimethamine 0. 25 mg/kg PO once daily For 14 days; Then give Decoquinate: 10-20 mg/kg PO q12h for 24 months. (Blagburn 2005a) T ! CATTLE: a) For prophylaxis of coccidiosis: Using the 6% premix: 0. 5 mg/ kg per day in feed for at least 28 days (Penzhorn and Swan 1993) (Mc Dougald and Roberson 1988) T ! GOATS: For prophylaxis of coccidiosis: a) 0. 5 mg/kg per day in feed during periods of exposure (Bret-zlaff 1993) b) 0. 5-1 mg/kg of body weight PO (de la Concha 2002) T ! LLAMAS: a) For prophylaxis of coccidiosis: Using the 6% premix: 0. 5 mg/ kg per day in feed for at least 28 days (Johnson 1993) Client Information T ! Decoquinate should be used for at least 4 weeks when used for preventing coccidiosis outbreaks T ! When used in dogs for Hepatazoonosis treatment may be for up to two years T ! Mix well into food Chemistry/Synonyms A coccidiostat, decoquinate occurs as a cream to buff-colored ﬁne amorphous powder having a slight odor. It is insoluble in water. Decoquinate may also be known as HC-1528, M&B-15497, or Deccox®. Storage/Stability/Compatibility Decoquinate is reportedly incompatible with strong bases or ox-idizing material. Follow label storage directions; store in a cool, dry place, preferably in airtight containers.	pppbs.pdf
256 DEFEROXAMINE MESYLATE Deccox® is labeled as being compatible (and cleared for use) with bacitracin zinc (with or without roxarsone), chlortetracycline, and lincomycin. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Decoquinate 6% (27. 2 gram/lb. ) Feed Additive (with corn meal, soybean oil, lecithin and silicon dioxide) in 50 lb bags; Deccox® (Al-pharma); (OTC). Approved for use in cattle, sheep, goats (Do NOT feed to cows, goats or sheep producing milk for food), and chickens (not laying chickens). Decoquinate 0. 5% (2. 271 grams/lb) Feed Additive in 50 lb bags; Doccox®-L (Alpharma), (OTC). Approved for use in ruminating and non-ruminating calves and cattle. Do NOT feed to cows producing milk for food. Decoquinate 0. 8% (3. 632 grams/lb) in 5 lb and 50 lb bags. Deccox®M (Alpharma) (OTC). Approved for use in ruminating and non-rumi-nating calves including veal calves. Also available are calf milk replacers that contain 22. 7 mg decoqui-nate per pound. For the prevention of coccidiosis in non-ruminating and calves and cattle. Advance® Calvita® Supreme 20/21 (and 18/21) Medicated with Decoquinate (MS Specialty Nutrition); (OTC) HUMAN-LABELED PRODUCTS: None DEFEROXAMINE MESYLATE (de-fer-OX-a-meen) Desferal®, DFO Prescriber Highlights TT Parental iron chelating agent used primarily for treat-ment of iron or aluminum intoxication in dogs/cats; has been used as a ferric ion chelator in cardiac arrest/GDV TT Contraindications: Severe renal failure unless dialysis used TT Caution: Pregnancy TT Adverse Effects: Allergic reactions, auditory neurotoxicity, pain or swelling at injection sites, GI distress TT When used IV, must be given slowly Uses/Indications Deferoxamine is used for the treatment of either acute or chronic iron toxicity. It is being evaluated as an iron chelator for adjunctive treatment of acute cardiac ischemia and as a chelator for aluminum toxicity. Its efﬁcacy in treating reperfusion injuries has been disap-pointing. Pharmacology/Actions Deferoxamine (DFO) binds ferric (Fe+++) ions to its three hydroxam-ic groups forming ferrioxamine. This forms a stable, water-soluble compound that is readily excreted by the kidneys. DFO does not ap-pear to chelate other trace metals (except aluminum) or electrolytes in clinically signiﬁcant quantities. Pharmacokinetics DFO is poorly absorbed from the GI and is usually given parenteral-ly. The drug is widely distributed in the body. DFO and ferrioxamine are excreted primarily in the urine. Ferrioxamine will give the urine a reddish color (“vin rosé”) that indicates iron removal. Contraindications/Precautions/Warnings DFO is contraindicated in patients with severe renal failure, unless dialysis is used to remove ferrioxamine. Adverse Effects There is little veterinary experience with this drug. Potential adverse effects include, allergic reactions, auditory neurotoxicity (particu-larly with chronic, high-dose therapy), pain or swelling at injection sites, and GI distress. T oo rapid IV injection may cause rapid heart rates, convulsions, hypotension, hives, and wheezing. Oral administration of DFO is controversial. Some have recom-mended oral administration after oral iron ingestions, but DFO may actually increase the amount of iron absorbed from the gut. At pres-ent, oral sodium bicarbonate solution 5% given as a gastric lavage is probably a better treatment in reducing oral absorption of iron. Reproductive/Nursing Safety Because deferoxamine has caused skeletal abnormalities in animals at dosages just above those recommended for iron toxicity, it should be used during pregnancy only when its beneﬁts outweigh it 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. ) Overdosage/Acute Toxicity See Adverse Effects above. Chronic high dose use may also lead to hypocalcemia and thrombocytopenia. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving deferoxamine and may be of signiﬁcance in veterinary patients: T ! PROCHLORPERAZINE : Use with deferoxamine may cause temporary impairment of consciousness T ! VITAMIN C : May be synergistic with deferoxamine in removing iron, but could lead to increased tissue iron toxicity especially in cardiac muscle; it should be used with caution, particularly in pa-tients with preexisting cardiac disease Laboratory Considerations T ! DFO may interfere (falsely low values) with colorimetric iron assays T ! DFO may cause falsely high total iron binding capacity ( TIBC ) measurements Doses T ! DOGS & CATS: In dogs at risk for, or exhibiting signs of severe iron toxicosis; cat dosages not well established: a) Most effective within the ﬁrst 24 hours. Extrapolated animal dose is 40 mg/kg IM q4-8 hours. IM route is preferred as too rapid IV administration can cause hypotension and pul-monary edema. Efﬁcacy can be increased by giving ascorbic acid after the gut has been cleared of iron. Deferoxamine-iron complex gives a salmon pink (“vin rose”) color to urine. Con-tinue to chelate until urine clears or serum iron levels return to normal. (Wismer 2004) b) Initiate ASAP or at least within 12 hours of ingestion; give as a constant rate infusion at 15 mg/kg/hour. More rapid infu-sion may precipitate arrhythmias or aggravate hypotension. If constant rate infusion is not possible or are unable to monitor patient during infusion, give 40 mg/kg IM q4-8h, depend-ing on clinical status. Continue therapy until serum iron lev-els are below 300 microliters/dl or decrease below the TIBC,	pppbs.pdf
DERACOXIB 257 whichever is lower. Chelation therapy may require 2-3 days of therapy. Following recovery, monitor for signs of GI ob-struction, which may develop 4-6 weeks post-ingestion. (Greentree and Hall 1995) c) 10 mg/kg IM or IV q8h for 24 hours (Firth 2000) Experimentally, as a ferric ion chelator during treatment of car-diac arrest: a) 5-15 mg/kg IV, IM or SC (Muir 1994) b) 10 mg/kg IV, IM q2h twice, then three times daily for 24 hours (Hackett and Van pelt 1995) Monitoring For iron overload: T ! Efﬁcacy (serum ferritin, serum iron, TIBC are recommended to monitor iron overload) T ! Adverse effects (see above); additionally, if chronic iron overload: eye examinations (iron toxicity and its subsequent removal may adversely affect vision) Chemistry/Synonyms An iron-chelating agent, deferoxamine mesylate occurs as a white to off-white powder that is freely soluble in alcohol or water. Deferoxamine mesylate may also be known as: desferoxam-ine mesylate, DFO, Ba-33112, Ba-29837, deferoxamini mesilas, desferrioxamine mesylate, desferrioxamine methanesulphonate, NSC-527604, Desferal® or Desferin®. Storage/Stability/Compatibility Store at room temperature. After aseptic reconstitution (2-5 m L for 500 mg vial; 8-20 m L for 2 gram vial) with sterile water for injection, the solution may be stored for up 24 hours at room tem-perature and protected from light. It is recommended not to mix this agent with other drugs; do not use if solution is turbid. Di-lution in normal saline, lactated Ringer's or dextrose 5% has been recommended when administering as an intravenous infusion. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Deferoxamine Mesylate Powder for Injection (lyophilized): 500 mg & 2 g in vials; Desferal® (Novartis); Deferoxamine Mesylate (Hos-pira); (Rx) DERACOXIB (dare-a-cox-ib) Deramaxx® NON-STEROIDAL ANTIINFLAMMATORY AGENT Prescriber Highlights TT Coxib-class NSAID approved for use in dogs for treatment of post-operative pain (higher dose, 7 day maximum) & for treatment of pain & inﬂammation associated with osteoarthritis (lower dose, ongoing dosing) TT May be useful alternative to piroxicam in adjunctive treatment of transitional cell carcinoma of bladder TT At lower doses, appears to cause predominantly COX-2 inhibition TT Adverse effect proﬁle still being fully determined, but GI & renal effects are possible Uses/Indications Deracoxib is indicated for the treatment of post-operative pain (higher dose, 7 day maximum), and for the treatment of pain and inﬂammation associated with osteoarthritis (lower dose, ongoing dosing) in dogs. Like piroxicam, deracoxib is of interest in adjunctive treatment of transitional cell carcinoma of the bladder; investigations into this use are ongoing. Pharmacology/Actions Deracoxib is a coxib-class, nonsteroidal antiinﬂammatory drug (NSAID). It is believed to predominantly inhibit cyclooxygenase-2 (COX-2) and spare COX-1 at therapeutic dosages. This, theoreti-cally, would inhibit production of the prostaglandins that contrib-ute to pain and inﬂammation (COX-2) and spare those that main-tain normal gastrointestinal and renal function (COX-1). However, COX-1 and COX-2 inhibition studies are done in vitro and do not necessarily correlate perfectly with clinical effects seen in actual patients. Pharmacokinetics After oral administration to dogs, bioavailability is greater than 90%; the time to peak serum concentration occurs at approximate-ly 2 hours. The presence of food in the gut can enhance bioavail-ability. The drug has an apparent volume of distribution of 1. 5 L/ kg in dogs and is at least 90% bound to canine plasma proteins. Deracoxib is hepatically metabolized to four primary metabolites. These metabolites and unchanged drug are principally eliminated in the feces. Some excretion of metabolites occurs via renal mecha-nisms. T erminal elimination half-life in the dog is dependent upon dose. In dosages up to approximately 8 mg/kg, half-life is about 3 hours (clearance ≈ 5 m L/min/kg). Half-life at a dose of 20 mg/kg is approximately 19 hours (clearance ≈ 1. 7 m L/min/kg). Drug accu-mulation can occur with higher dosages, leading to increased toxic effects as increased COX-1 inhibition can occur at higher concen-trations. In cats, after 1 mg oral doses of deracoxib, peak levels (0. 28 mcg/ m L) occurred about 3. 6 hours after administration. Elimination half life was about 8 hours. Contraindications/Precautions/Warnings Deracoxib is contraindicated in patients known to be hypersensi-tive to it. It should be used with caution in patients with concurrent GI ulcerative diseases, renal or hepatic dysfunction, those in hypo-	pppbs.pdf
258 DERACOXIB Tproteinemic states, or with conditions that may predispose them to hypercoagulability. Adverse Effects In the majority of dogs treated, deracoxib appears to be well toler-ated, particularly when dosed as labeled and not in conjunction with other NSAIDs or corticosteroids. However, like other NSAIDs used in dogs, many adverse effects associated with deracoxib have been re-ported and include: gastrointestinal (vomiting, anorexia/weight loss, diarrhea, melena, hematemesis, hematochezia, GI ulceration/perfo-ration); urinary (azotemia, polydipsia, polyuria, UTI, hematuria, incontinence, renal failure); hematologic (anemia, thrombocytope-nia); hepatic (increased hepatic enzymes, changes in total protein, etc. ); neurologic (lethargy/weakness, seizures, etc. ); cardiovascular/ respiratory (tachypnea, bradycardia, cough); and dermatologic/im-munologic (fever, facial/muzzle edema, urticaria, dermatitis). Rare occurrences of death associated with these effects are possible. As additional clinical experience is gained with this agent, relative in-stances of these effects and the potential risk for them to occur in a given patient population should be clariﬁed. Reproductive/Nursing Safety No information on the drug's safety in pregnancy or in nursing pups was located. Use with caution in these animals. Overdosage/Acute Toxicity There is little data available regarding this drug's acute toxicity. A 14-day study in dogs demonstrated no clinically observable adverse effects in the dogs that received 10 mg/kg. Dogs who received 25 mg/kg, 50 mg/kg or 100 mg/kg per day for 10-11 days survived, but showed vomiting and melena; no hepatic or renal lesions were demonstrated in these dogs. There were 211 exposures to deracoxib reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org ) dur-ing 2005-2006. In these cases 204 were dogs with 19 showing clinical signs and the remaining 7 cases were cats with 2 showing clinical signs. Common ﬁndings in dogs recorded in decreasing fre-quency included vomiting, anorexia, diarrhea, lethargy and anemia. Common ﬁndings in cats recorded included vomiting. Because non-linear elimination occurs in dogs at dosages of 10 mg/kg and above, dogs acutely ingesting dosages above this amount should be observed for gastrointestinal erosion or ulceration and treated symptomatically for vomiting and GI bleeding. Dogs ingest-ing dosages above 100 mg/kg should be considered for gut evacua-tion techniques if ingested deracoxib can be safely removed before substantial absorption occurs. Although the manufacturer states that the drug was clinically well tolerated at doses up to 10 mg/kg/ day for 26 weeks, dose-dependent increases in BUN values and focal tubular degeneration/regeneration were seen at doses of 6 mg/kg/ day and greater. This medication is a NSAID. As with any NSAID, overdosage can lead to gastrointestinal and renal effects. Decontamination with emetics and/or activated charcoal is appropriate. For doses where GI effects are expected, the use of gastrointestinal protectants is war-ranted. If renal effects are also expected, ﬂuid diuresis is warranted. Drug Interactions No speciﬁc drug interactions were noted, but the manufacturer warns that use in conjunction with other NSAIDs or corticosteroids be avoided, or monitored carefully. If switching from one NSAID to another or replacing with/or subtracting corticosteroid treatment, it is recommended to observe a “wash out” period to reduce the chances of adverse effects occurring. It is also possible deracoxib may cause increased renal dysfunction if used with other drugs that can cause or contribute to renal dysfunction (e. g., diuretics, aminogly-cosides ), but the clinical signiﬁcance of this potential interaction is unclear. The following drug interactions have either been reported or are theoretical in humans or animals receiving coxib-class NSAIDs and may be of signiﬁcance in veterinary patients: !TACE INHIBITORS (e. g., enalapril, benazepril ): Some NSAIDs can re-duce effects on blood pressure !TASPIRIN : May increase the risk of gastrointestinal toxicity (e. g., ul-ceration, bleeding, vomiting, diarrhea) !TCORTICOSTEROIDS (e. g., prednisone ): May increase the risk of gastro-intestinal toxicity (e. g., ulceration, bleeding, vomiting, diarrhea) !TDIGOXIN : NSAIDS may increase serum levels !TFLUCONAZOLE : Administration has increased plasma levels of cele-coxib in humans and potentially could also affect ﬁrocoxib levels in dogs !TFUROSEMIDE : NSAIDs may reduce saluretic and diuretic effects !TMETHOTREXATE : Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate; use together with extreme caution !TNEPHROTOXIC DRUGS (e. g., furosemide, aminoglycosides, amphotericin B, etc. ): May enhance the risk of nephrotoxicity development !TNSAIDS, OTHER : May increase the risk of gastrointestinal toxicity (e. g., ulceration, bleeding, vomiting, diarrhea) Laboratory Considerations !TNo speciﬁc laboratory interactions were noted for deracoxib. De-racoxib does not appear to affect thyroid function tests in dogs. Doses !TDOGS: a) For the control of pain and inﬂammation associated with os-teoarthritis: 1-2 mg/kg PO once a day as needed. For treatment of post-operative pain: 3-4 mg/kg PO once a day as needed, not to exceed 7 days of therapy at this dosage. (Package insert; Deramaxx®) Monitoring !TBaseline and periodic CBC and serum chemistry (including BUN/ serum creatinine, and liver function assessment) !TBaseline history and physical !TEfﬁcacy of therapy !TAdverse effect monitoring via client Client Information Note : The manufacturer provides a client information sheet they rec-ommend be given with every prescription for this medication. !TSince dogs may ﬁnd the chewable tablets' taste desirable, the drug should be stored out of reach of animals and children !TOwners should immediately report to the veterinarian if any of the following adverse effects occur: bloody stool/diarrhea or vom-it, or allergic reaction (facial swelling face, hives, red, itchy skin) !TOwners should contact the veterinarian if any of the following adverse effects persist or are severe: loss of appetite, vomiting, change in bowel movements (e. g., stool color), change in behavior, decrease in water consumption, or urination !The manufacturer recommends that although the drug can be given on an empty stomach, it is preferable to be given with food; water should be available at all times to avoid dehydration !TOther drugs for pain or inﬂammation should not be used with this medication without the approval of the veterinarian !TDo not increase or alter the dose of this medication without the approval of the veterinarian.	pppbs.pdf
DESLORELIN ACETATE 259 Chemistry/Synonyms Deracoxib is a diaryl-substituted pyrazole that is chemically related to other coxib-class NSAIDs such as celecoxib. Its molecular weight is 397. 38. Deracoxib's chemical name is: 4-[3-(diﬂuoromethyl)-5-(3-ﬂuo-ro-4-methoxyphenyl)-1H-pyrazole-1-yl] benzenesulfonamide. Storage/Stability The commercially available chewable tablets for dogs should be stored at room temperature between 15-30°C (59-86°F). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Deracoxib Chewable (scored) Tablets: 25 mg, 75 mg, & 100 mg in bottles of 7, 30 and 90 tablets; Deramaxx® (Novartis) (Rx). Ap-proved for use in dogs. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None Dermcaps® — see Fatty Acids DES — see Diethylstilbestrol DESLORELIN ACETATE (dess-lor-a-lin) Ovuplant® HORMONAL A GENT Prescriber Highlights TT Synthetic Gn RH analog for estrual mares to induce & time ovulation TT No labeled contraindications TT Adverse Effects: May cause some local swelling, pain, etc; interovulatory period may be prolonged if implant not removed TT Availability may be an issue Uses/Indications Deslorelin is approved for inducing ovulation in estrual mares. There is also interest in developing dosages and dosage forms as a long-term, reversible contraceptive in a variety of animal species, as a treatment for prostatic disease in male dogs, and incontinence in ovariectomized dogs. At the time of writing, deslorelin in not avail-able in the USA, but is marketed in Canada. In humans, deslorelin has been investigated for treating children with precocious puberty, and in adults for prostate carcinoma, dys-menorrhea, ﬁbroids, and endometriosis. Pharmacology/Actions Deslorelin increases the levels of endogenous luteinizing hormone (LH), thereby inducing ovulation. When developing follicles are greater than 30 mm in diameter, deslorelin induces ovulation in ap-proximately 85% of mares within 48 hours of administration. Pharmacokinetics In horses after implantation of a 2. 1 mg pellet, concentrations of LH and FSH peak about 12 hours after implant and return to pre-treatment levels approximately 3-4 days after implantation. Oral dosing of 100 mcg/kg to Beagles, demonstrated no increase in LF or FSH. Contraindications/Precautions/Warnings When used as indicated, the manufacturer lists no contraindications. Adverse Effects Minor local swelling, sensitivity to touch, and elevated skin temper-ature at injection site may occur; these effects should resolve within 5 days of implantation. There is some evidence that deslorelin implants can suppress pi-tuitary FSH secretion and decrease follicular development in subse-quent diestrus, leading to a prolonged interovulatory period. Some clinicians (see the dose recommendation by Mc Cue 2003, below), recommend removing the implant to negate this possibility. Reproductive/Nursing Safety Abnormalities in foal viability or behavior related to the use of deslorelin have not been observed in foals born to treated mares. Overdosage/Acute Toxicity Overdosage is unlikely. If inadvertent administration of additional implant is done, it should be removed upon detection if within 96 hours of implant. Drug Interactions No speciﬁc interactions noted Laboratory Considerations None noted Doses T ! HORSES: For induction of ovulation: a) If follicle is greater than 30 mm in diameter (as determined by rectal palpation or ultrasound), and breeding is to take place within 48 hours, place one implant subcutaneously in the neck. Implant site should be midway between head and shoulder over the muscle mass of the neck and away for subcutaneous nerves and vessels. Thoroughly disinfect site of implant. Insert the entire length of needle SC and fully depress the implanter plunger. Slowly withdraw needle while pressing skin at injection site. Examine implanter to as-sure that implant has been administered. Do not reuse im-planter. Implant will be absorbed with time. (Package insert; Ovuplant®) b) As above, but because interovulatory interval may be pro-longed if implant is left in the mare, remove after approxi-mately 48 hours. Alternative dosing/removal method: Restrain mare and brieﬂy wash vulva with soap and water and then dry. One m L of lidocaine is infused into the edge of the vulva. The im-plant is inserted just beneath the epithelium in the blocked area. When the lidocaine is absorbed, the implant can be pal-pated. After ovulation, the implant can be gently “squeezed” out of the original opening created by the implant device. No treatment is required at the site after removal of the implant. (Mc Cue 2003a) Monitoring T ! None required	pppbs.pdf
260 DESMOPRESSIN ACETATE Chemistry/Synonyms Deslorelin acetate is a synthetic gonadotropin-releasing hormone (Gn RH, gonadorelin) analog. It is a nonapeptide and has chemi-cal modiﬁcations in the amino aide composition at positions 6 and 9/10. Storage/Stability Deslorelin implants should be stored refrigerated (2-8°C, 36-46°F). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None in the USA In Canada: Deslorelin 2. 1 mg cylindrical implant with implanter; 5 per box Ovuplant® (Wyeth. Approved for ovulation induction in mares. Not for use in horses intended for food. The FDA may allow legal importation of this medication for com-passionate use in animals; for more information, see the Instructions for Legally Importing Drugs for Compassionate Use in the USA found in the appendix. HUMAN-LABELED PRODUCTS: None DESMOPRESSIN ACETATE (des-moe-press-in) Stimate®, DDAVP® HORMONAL AGENT Prescriber Highlights TT Synthetic vasopressin analogue used to treat diabetes insipidus & Von Willebrand's disease (limited usefulness) TT Contraindications: Hypersensitivity to desmopressin, type IIB or platelet-type (pseudo) Von Willebrand's (German shorthair pointers?) TT Use caution in patients susceptible to thrombosis TT Adverse Effects: Eye irritation after conjunctival adminis-tration; hypersensitivity possible TT Overdoses can cause ﬂuid retention/hyponatremia Uses/Indications Desmopressin has been found to be useful in the treatment of cen-tral diabetes insipidus in small animals. It may be useful in treat-ing Von Willebrand's disease, but its short duration of activity (2-4 hours) in this condition, resistance development, and expense limit its usefulness for this disorder. Desmopressin may be useful periop-eratively to reduce lymph node involvement and metastatic disease in canine mammary gland cancer. Pharmacology/Actions Desmopressin is related structurally to arginine vasopressin, but it has more antidiuretic activity and less vasopressor properties on a per weight basis. Desmopressin increases water reabsorption by the collecting ducts in the kidneys, thereby increasing urine osmolality and decreasing net urine production. Therapeutic doses do not di-rectly affect either urinary sodium or potassium excretion. Desmopressin causes a dose-dependent increase in plasma factor VIII and plasminogen factor and also causes smaller increases in fac-tor VIII-related antigen and ristocetin cofactor activities. Pharmacokinetics Because desmopressin is destroyed in the GI tract, it usually is given parenterally or topically. Oral tablets have been used in those dogs that cannot tolerate ophthalmic administration, but bioavailability is very low. In humans, intranasal administration is commonly used, while in veterinary medicine topical administration to the conjunc-tiva is preferred. The onset of antidiuretic action in dogs usually oc-curs within one hour of administration, peaks in 2-8 hours, and may persist for up to 24 hours. Distribution characteristics of des-mopressin are not well described, but it does enter maternal milk. The metabolic fate is also not well understood. T erminal half lives in humans after IV administration are from 0. 4-4 hours. Contraindications/Precautions/Warnings Desmopressin is contraindicated in patients hypersensitive to it. It should not be used for treatment of type IIB or platelet-type (pseu-do) Von Willebrand's disease as platelet-aggregation and thrombo-cytopenia may occur. German shorthair pointers apparently can have this type of v WD. Desmopressin should be used with caution in patients susceptible to thrombotic events. When desmopressin is used to stimulate von Willebrand factor, with repeated administration tachyphylaxis (increasing lack of ef-ﬁcacy) will occur to a variable extent within 24 hours. Adverse Effects Side effects in small animals apparently are uncommon. Occasionally eye irritation may occur after conjunctival administration. Hypersensitivity reactions are possible. Humans using the drug have complained about increased headache frequency. Reproductive/Nursing Safety Safe use during pregnancy has not been established; however safe doses of up to 125 times the average human antidiuretic dose have been given to rats and rabbits without demonstration of fetal harm. 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. ) Desmopressin is likely safe to use during nursing. Overdosage/Acute Toxicity Oral doses of 0. 2 mg/kg/day have been administered to dogs for 6 months without any signiﬁcant drug-related toxicities reported. Dosages that are too high may lead to ﬂuid retention and hypona-tremia; dosage reduction and ﬂuid restriction may be employed to treat. Adequate monitoring should be performed. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving desmopressin and may be of signiﬁcance in veterinary patients: T ! CHLORPROPAMIDE, FLUDROCORTISONE, UREA : May enhance the an-tidiuretic effects of desmopressin Laboratory Considerations See Monitoring Parameters	pppbs.pdf
DESMOPRESSIN ACETATE 261 Doses Note : When doses listed below use “drops” of the nasal solution they are referencing the 0. 1 mg/m L product and NOT the 1. 5 mg/m L product (Stimate®). Do not confuse the two. !TDOGS: a) One drop placed twice daily in the conjunctival sac sufﬁ-ciently controls polyuria in most dogs with central DI. Using one drop three times a day usually returns urine production to normal. (Rijnberk 2005) b) For treatment of diabetes insipidus (central): 1-4 drops of the intranasal solution in the conjunctival sac once to twice daily; may use intranasal solution parenterally at 2-5 mcg SC once to twice daily (Nichols 2000) c) For treatment of complete and partial central diabetes insipi-dus: 1-4 drops of the intranasal solution in the conjunctival sac once a day to twice a day (Behrend 2003b) d) 1-2 drops into the conjunctival sac or 0. 01-0. 05 m L SC once a day to twice a day (Bruyette 2002b) e) As a trial in place of water deprivation test: one-half to one 0. 1 or 0. 2 mg DDA VP tablet PO q8h or 1-4 drops of nasal spray from an eye dropper into the conjunctival sac every 12 hours for 5-7 days. If central DI, owners should notice a decrease in PU/PD by the end of treatment period. Increase in urine speciﬁc gravity by 50% or more, compared with pre-treatment values, also support diagnosis of central DI. (Nel-son 2002b) For treatment of Von Willebrand's disease: a) 1 microgram/kg SC gives a duration of action of 3-4 hours; repeated dosages within 24 hours do not prolong response time (Brooks 1994) b) May be particularly useful to help prevent or control bleed-ing in association with surgery. Intranasal product is given subcutaneously at 1-4 mcg/kg. Onset of activity occurs in 30 minutes and duration of effect is approximately 2 hours. (Carr and Panciera 2000) c) For preoperative prophylaxis:1 mcg/kg SC one-half hour before surgery. Close monitoring needed to determine ex-tent and duration of response. Transfusion should be readily available. Desmopressin not effective for treatment or pre-operative prophylaxis of severe Types 2 and 3 v WD. (Brooks 2003) !TCATS: a) T o help differentiate central diabetes insipidus from the nephrogenic form: 1 drop into the conjunctival sac twice daily for 2-3 days; a dramatic reduction in water intake or a 50% or greater increase in urine concentration gives strong evidence for a deﬁcit in ADH production. For treatment of central DI: 1-2 drops into the conjunctival sac once or twice a day; duration of activity is 8-24 hours. (Bruyette 1991) b) For treatment of diabetes insipidus (central): 1-4 drops of the intranasal solution in the conjunctival sac once to twice daily; may use intranasal solution parenterally at 2-5 mcg SC once to twice daily (Nichols 2000) !THORSES: a) For diagnosis of diabetes insipidus: 20 mcg IV (Barnes, Schott II et al. 2002) Monitoring For Central DI: !TSerum electrolytes !TUrine osmolality and/or urine volume For Von Willebrand's disease: !TBleeding times Client Information !TKeep solutions refrigerated whenever possible. !TInstruct clients on the importance of compliance with adminis-tering this drug as directed. It is a treatment, not a cure for the condition. !TClients should be counseled on the expense associated with using this drug long-term. Chemistry/Synonyms A synthetic polypeptide related to arginine vasopressin (antidiuret-ic hormone), desmopressin acetate occurs as a ﬂuffy white powder with a bitter taste. The commercially available nasal solution has HCl added and the p H is approximately 4. This preparation also contains chlorobutonal 0. 5% as a preservative. Desmopressin Acetate may also be known as: 1-Deamino-8-D-Arginine Vasopressin, DDA VP®, Concentraid®, D-Void®, Deﬁrin®, Desmogalen®, Desmospray®, Desmotabs®, Emosint®, Minirin®, Minirin/DDA VP®, Minrin®, Minurin®, Nocutil®, Octim ®, Octostim®, Presinex®,or Stimate®. Storage/Stability The nasal solution should be refrigerated (2-8°C). It has an expira-tion date of one year after manufacture. While the nasal solution should be stored in the refrigerator, it is stable at room tempera-ture for 3 weeks in the unopened bottle. The product for injection should be stored refrigerated (4°C); do not freeze. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Desmopressin Acetate Nasal Solution: 0. 1 mg/m L (10 mcg/spray) in 5 m L nasal pump dispenser; Desmopressin Acetate (Bausch and Lomb); (Rx); 0. 1 mg/m L (0. 1 mg equals approx 400 units arginine vasopressin) in nasal spray pump: 7. 5 mg Na Cl/m L in 5 m L bottle (with 1. 7 mg citric acid monohydrate, 3 mg disodium phosphate dihyrdrate, 0. 2 mg benzalkonium chloride solution—50% per m L); & Rhinal tube delivery system: 9 mg Na Cl/m L (with 5 mg chlo-robutanol/m L) in 2. 5 m L vials; DDA VP® (Aventis); (Rx) Desmopressin Acetate Nasal Spray: 1. 5 mg/m L (150 mcg/spray) in 9 mg Na Cl/m L (with 5 mg chlorobutanol per m L) in 2. 5 m L bottle; Stimate® (ZLB Behring); (Rx); 0. 1 mg/m L (10 mcg/spray) in 5 m L (with 5 mg chlorobutanol, 9 mg sodium chloride & hydrochloric acid/m L); Minirin® (Ferring); (Rx) Desmopressin Acetate Injection: 4 mcg/m L (9 mg Na Cl/m L) in 1 m L single-dose amps and 10 m L multiple dose vials; DDA VP® (Aventis); (Rx); generic; (Rx) Desmopressin Acetate Tablets: 0. 1 mg & 0. 2 mg; DDA VP® (Aven-tis); Desmopressin Acetate (T eva); (Rx)	pppbs.pdf
262 DESOXYCORTICOSTERONE PIVALATE DESOXYCORTICOSTERONE PIVALATE DOCP (de-sox-ee-kor-ti-kost-er-ohn pih-vah-late) Percorten-V® MINERALOCORTICOID Prescriber Highlights TT Parenteral mineralocorticoid used to treat Addison's in dogs/cats TT Relative contraindications: congestive heart failure, se-vere renal disease, or edema; Caution: pregnancy TT Addison's patients must receive glucocorticoid supple-mentation in periods of high stress/illness TT May cause irritation at injection site TT Adjust dosage based upon monitoring parameters Uses/Indications DOCP is indicated for the parenteral treatment of adrenocortical in-sufﬁciency in dogs. It is also used in an extra-label manner in cats. Pharmacology/Actions Desoxycorticosterone pivalate (DOCP) is a long-acting mineralo-corticoid agent. The site of action of mineralocorticoids is at the renal distal tubule where it increases the absorption of sodium. Mineralocorticoids also enhance potassium and hydrogen ion ex-cretion. T o be effective, mineralocorticoids require a functioning kidney. Pharmacokinetics Little information is available. It is injected IM (or subcutaneously) as a microcrystalline depot for slow dissolution into the circulation. DOCP usually has a duration of action in dogs for 21-30 days after injection. Contraindications/Precautions/Warnings The drug is contraindicated in dogs suffering from congestive heart failure, severe renal disease, or edema. Because some animals may be more (or less) sensitive to the ef-fects of the drug, “cookbook” dosing without ongoing monitoring is inappropriate. Some animals may require additional supplementa-tion with a glucocorticoid agent on an ongoing basis that may cause polydipsia, polyuria, or polyphagia if doses are too high. All animals with hypoadrenocorticism should receive additional glucocorticoids (2-10 times basal) during periods of stress or acute illness. Do not administer DOCP IV; acute collapse and shock may re-sult. If given IV, treat immediately for shock with IV ﬂuids and glu-cocorticoids. Adverse Effects Occasionally, irritation at the site of injection may occur. Adverse effects of DOCP are generally a result of excessive dosage (see Overdosage below). Reproductive/Nursing Safety The manufacturer states that the drug should not be used in preg-nant dogs as safe use during pregnancy has not been established. Use in pregnant animals only when the potential beneﬁts outweigh the risks. DOCP should be safe for offspring when administered to nurs-ing dams. Overdosage/Acute Toxicity Overdosage may cause polyuria, polydipsia, hypernatremia, hyper-tension, edema, and hypokalemia. Cardiac enlargement is possible with prolonged overdoses. Excessive weight gain may be indica-tive of ﬂuid retention secondary to sodium retention. Electrolytes should be aggressively monitored and potassium may need to be supplemented. Discontinue the drug in patients until clinical signs associated with overdosage have resolved and then restart the drug at a lower dosage. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving DOCP and may be of signiﬁcance in veterinary patients: T ! AMPHOTERICIN B: Patients may develop hypokalemia if mineralo-corticoids are administered concomitantly with amphotericin B T ! ASPIRIN : DOCP may reduce salicylate levels T ! DIGOXIN : Because DOCP may cause hypokalemia, it should be used with caution and increased monitoring when used in pa-tients receiving digitalis glycosides T ! INSULIN : Potentially, DOCP could increase the insulin require-ments of diabetic patients T ! POTASSIUM-DEPLETING DIURETICS (e. g., furosemide, thiazides ): Pa-tients may develop hypokalemia if mineralocorticoids are admin-istered concomitantly with potassium-depleting diuretics; as di-uretics can cause a loss of sodium, they may counteract the effects DOCP Doses T ! DOGS: Note : Dosage requirements are variable and should be individual-ized to the patient. For hypoadrenocorticism: a) 2. 2 mg/kg IM every 25 days (Label information; Percorten®-V) b) Initially, inject 2. 2 mg/kg IM or SC every 25 days. Reevaluate at 12 and 25 days after initial injection. If hyponatremia and/ or hyperkalemia are noted at 12 days, increase dose by 10%. If they are noted at 25 days (but not on day 12), shorten dosing interval by 2 days. (Reusch 2000) c) 1. 5-2. 2 mg/kg IM q20-30 days (Lorenz and Melendez 2002c) d) Initially, 2. 2 mg/kg IM q25 days. If electrolytes remain in nor-mal range at 30 days, reduce dose by 10% a month. In our clinic, we have used a dose of DOCP as low as 1 mg/kg q30 days with good control of hypoadrenocorticism. (Scott-Mon-crieff 2006a)	pppbs.pdf
DETOMIDINE HCL 263 T ! CATS: For maintenance therapy of hypoadrenocorticism: a) 2. 2 mg/kg IM every 25 days plus prednisolone (0. 25-1 mg/ cat PO twice daily; if daily oral dosing not feasible, may give 10 mg of methylprednisolone acetate once a month IM) (Re-usch 2000) b) 10-12. 5 mg (total dose) IM per month. Adjust dose based-upon follow-up serum electrolyte concentrations monitored every 1-2 weeks during initial maintenance period. Normal electrolyte values 2 weeks following injection, suggests ad-equate dosing, but does not provide information regarding duration of action. Prednisone at 1. 25 mg PO once a day or IM methylprednisolone acetate 10 mg once a month can pro-vide long-term glucocorticoid supplementation. (Bruyette 2002c) Monitoring T ! Serum electrolytes, BUN, creatinine; initially every 1-2 weeks, then once stabilized, every 3-4 months T ! Weight, PE for edema Client Information T ! Clients should be familiar with the symptoms associated with both hypoadrenocorticism (e. g., weakness, depression, anorexia, vomiting, diarrhea, etc. ) and DOCP overdosage (e. g., edema) and report these to the veterinarian immediately. T ! If client is injecting the drug at home, instruct in proper tech-nique for IM administration. Vial should be shaken vigorously to suspend the macrocrystals. Chemistry/Synonyms A mineralocorticoid, desoxycorticosterone pivalate (DOCP) occurs as a white or creamy white powder that is odorless and stable in air. It is practically insoluble in water, slightly soluble in alcohol and vegetable oils. The injectable product is a white aqueous suspension and has a p H between 5-8. 5. Desoxycorticosterone pivalate may also be known as: deoxycor-ticosterone pivalate, deoxycorticosterone trimethyl-acetate, deoxy-cortone pivalate, deoxycortone trimethylacetate, desoxycorticoster-one pivalate, desoxycorticosterone trimethyl-acetate, Cortiron®,or Percorten-V®. Storage/Stability/Compatibility Store the injectable suspension at room temperature and protect from light or freezing. Do not mix with any other agent. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Desoxycorticosterone Pivalate Injectable Suspension: 25 mg/m L in 4 m L vials; Percorten-V® (Novartis); (Rx). Approved for use in dogs. The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None DETOMIDINE HCL (de-toe-ma-deen) Dormosedan® Prescriber Highlights TT Alpha 2 sedative analgesic used primarily in horses TT Contraindications: Heart block, severe coronary, cerebro-vascular, or respiratory disease, chronic renal failure TT Caution: Horses with endotoxic or traumatic shock or approaching shock, advanced hepatic or renal disease; stress due to temperature extremes, fatigue, or high alti-tude; patients treated for intestinal impactions; with sus-pected colic as it may mask abdominal pain or changes in respiratory & cardiac rates TT May respond ( i. e., kick) to external stimuli even after fully sedated; use caution, opioids may temper TT Adverse Effects: Initial blood pressure increase, then bra-dycardia/heart block, piloerection Uses/Indications At present, detomidine is only approved for use as a sedative analge-sic in horses, but it has been used clinically in other species. Pharmacology/Actions Detomidine, like xylazine, is an alpha 2-adrenergic agonist that produces a dose-dependent sedative and analgesic effect, but it also has cardiac and respiratory effects. For more information, re-fer to the xylazine monograph or the adverse effects section below. Detomidine is approximately 50-100 times as potent as xylazine. Pharmacokinetics Detomidine is well absorbed after oral administration, but is used only parenterally currently. The drug is apparently rapidly distrib-uted into tissues, including the brain after parenteral administra-tion and is extensively metabolized and then excreted primarily into the urine. Peak sedative actions can range from 5-20 minutes post injection in horses. Contraindications/Precautions/Warnings Detomidine is contraindicated in horses with preexisting A V or SA heart block, severe coronary insufﬁciency, cerebrovascular disease, respiratory disease or chronic renal failure. Use cautiously in ani-mals with endotoxic or traumatic shock or approaching shock, and advanced hepatic or renal disease. Horses who are stressed due to temperature extremes, fatigue, or high altitude should be given the drug carefully. Because this drug may inhibit gastrointestinal mo-tility, use with prudence in patients treated for intestinal impac-tions. In horses with suspected colic, the use of detomidine analge-sia should be used cautiously as it may mask abdominal pain and conceal changes in respiratory and cardiac rates, thereby making diagnosis more difﬁcult. Although animals may appear to be deeply sedated, some may respond (kick, etc. ) to external stimuli; use appropriate caution. The addition of opioids (e. g., butorphanol) may help temper this effect. The manufacturer recommends allowing the horse to stand quietly for 5 minutes prior to injection and for 10-15 minutes af-ter injection to improve the effect of the drug. After administering detomidine, protect the animal from temperature extremes. Adverse Effects Detomidine can cause an initial rise in blood pressure that is then followed by bradycardia and heart block. Atropine at 0. 02 mg/kg	pppbs.pdf
264 DETOMIDINE HCL TIV has been successfully used to prevent or correct the bradycardia that may be seen when the detomidine is used at labeled dosages. In addition, piloerection, sweating, ataxia, salivation, slight muscle tremors, and penile prolapse may all be noted after injection. When compared to xylazine, detomidine causes more pro-nounced bradycardia and bradyarrhythmias. Because the sedative and muscle-relaxing effects of detomidine in horses can persist for up to 90 minutes, it may inﬂuence the quality of recovery and con-tribute to post-anesthesia ataxia. Reproductive/Nursing Safety The manufacturer states that “Information on the possible effects of detomidine HCl in breeding horses is limited to uncontrolled clinical reports; therefore, this drug is not recommended for use in breeding animals. ” No other information was located. Overdosage/Acute Toxicity The manufacturer states that detomidine is tolerated by horses at doses 5X (0. 2 mg/kg) the high dose level (0. 04 mg/kg). Doses of 0. 4 mg/kg given daily for 3 consecutive days produced microscopic foci of myocardial necrosis in 1 of 8 horses tested. Doses of 10-40X rec-ommended can cause severe respiratory and cardiovascular changes that can become irreversible and cause death. Y ohimbine or atipam-ezole could be used to reverse some or all of the effects of the drug. Atipamezole, at a dose of 50-100 mcg/kg has been successfully used to treat inadvertent overdoses of detomidine in horses. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving detomidine and may be of signiﬁcance in veterinary patients: !TALPHA-2 AGONISTS, OTHER (e. g., xylazine, medetomidine, romiﬁdine, clonidine and including epinephrine ): Not recommended to be used together with detomidine as effects may be additive !TANESTHETICS, OPIATES, SEDATIVE/HYPNOTICS : Effects may be addi-tive; dosage reduction of one or both agents may be required; po-tential for increased risk for arrhythmias when used in combina-tion with thiopental, ketamine or halothane !TPHENOTHIAZINES (e. g., acepromazine ): Severe hypotension can result !TSEDATIVES OR ANALGESICS, OTHER : The manufacturer warns to use with extreme caution in combination with other sedative or an-algesic drugs !TSULFONAMIDES, POTENTIATED (e. g., trimethoprim/sulfa ): The manu-facturer warns against using this agent with intravenous potenti-ated sulfonamides (e. g., trimethoprim/sulfa) as fatal dysrhythmias may occur Doses !THORSES: (Note : ARCI UCGFS Class 3 Drug) For sedation/analgesia ( CAUTION : Do not confuse mcg/kg with mg/kg doses): a) 20-40 micrograms/kg (0. 02-0. 04 mg/kg) IV or IM (IV only for analgesia). Effects generally occur within 2-5 minutes. Lower dose will generally provide 30-90 minutes of sedation and 30-45 minutes of analgesia. The higher dose will gener-ally provide 90-120 minutes of sedation and 45-75 minutes of analgesia. Allow animal to rest quietly prior to and after injection. (Package insert; Dormosedan®—SKB) b) For horses with marked abdominal pain that are either not candidates for exploratory surgery or must be transported long distances for surgery: 0. 01-0. 02 mg/kg (10-20 mcg/kg) IV or IM (Moore 1999) c) Detomidine at 0. 01-0. 02 mg/kg IV or IM with or without butorphanol (0. 02-0. 03 mg/kg) (Taylor 1999) d) For adjunctive treatment of moderate pain: 0. 03-0. 04 mg/kg IV For caudal epidural analgesia: 0. 06 mg/kg, given between S4-S5; duration of analgesia is 2-3 hours or detomidine 0. 03 mg/kg with morphine (0. 2 mg mg/kg) given between S1-L6; duration of analgesia is >6 hours (Muir 2004) e) For oral administration when horse is not amenable to injec-tions: 0. 06 mg/kg PO; profound sedation occurs in about 45 minutes (Hubbell 2006) f) As a CRI for standing chemical restraint and analgesia: Two protocols have been described: 1) Loading dose of 7. 5 mcg/kg IV bolus, followed by a CRI rate of 0. 6 mcg/kg/minute for the ﬁrst 15 minutes; after this CRI rate is halved every 15 minutes. In many cases did not provide adequate analgesia alone and needed to be supple-mented by local anesthetics, epidural analgesia, or supple-mental detomidine and/or butorphanol. Average duration of procedures was 40 minutes. 2) Loading dose of 8. 4 mcg/kg IV bolus, then 0. 5 mcg/kg/ minute for 15 minutes, then 0. 3 mcg/kg/minute for 15 min-utes, then 0. 15 mcg/kg/minute thereafter. A butorphanol CRI was used if additional sedation and analgesia was required. (Mogg 2006) !TCATTLE: a) For sedation/analgesia: 30-60 micrograms/kg (0. 03-0. 06 mg/kg) IV or IM (Not approved) (Alitalo 1986) b) For analgesia: 0. 01 mg/kg IV; short (1/2 hour) duration of action. Appropriate withdrawal times are: Milk = 72 hours; Slaughter = 7 days. (Walz 2006b) !TSHEEP, GOATS: a) For anesthesia: Detomidine at 0. 01 mg/kg IM, followed by propofol at 3-5 mg/kg IV. For analgesia: 0. 005-0. 05 mg/kg IV or IM q3-6 hours (once) (Haskell 2005b) !TLLAMAS, ALPACAS: a) For analgesia: 0. 005-0. 05 mg/kg IV or IM q3-6 hours (once) (Haskell 2005b) !TBIRDS: a) For sedation/analgesia: 0. 3 mg/kg IM; limited data available on duration of effect, adverse effects, etc. (Clyde and Paul-Murphy 2000) Monitoring !TLevel of sedation, analgesia !TCardiac rate/rhythm; blood pressure if indicated Client Information !This drug should be used in a professionally supervised setting by individuals familiar with its properties. Chemistry/Synonyms An imidazoline derivative alpha 2-adrenergic agonist, detomidine HCl occurs as a white crystalline substance that is soluble in water. Detomidine HCl may also be known as: demotidini hydrochlo-ridum, MPV-253-AII, or Dormosedan®. Storage/Stability Detomidine HCl for injection should be stored at room temperature (15-30°C) and protected from light.	pppbs.pdf
DEXAMETHASONE 265 Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Detomidine HCl for Injection: 10 mg/m L in 5 and 20 m L vials; Dormosedan® (Pﬁzer); (Rx). Approved for use in mature horses and yearlings. The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: None DEXAMETHASONE DEXAMETHASONE SODIUM PHOSPHATE (dex-a-meth-a-zone) Azium®, Dexasone® GLUCOCORTICOID Prescriber Highlights TT Injectable, oral & ophthalmic glucocorticoid TT Long acting; 30X more potent than hydrocortisone; no mineralocorticoid activity TT If using for 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: endocrine conditions ( e. g., adrenal insufﬁciency), rheumatic diseases ( e. g., rheumatoid arthritis), collagen diseases ( e. g., systemic lupus), aller-gic states, respiratory diseases ( e. g., asthma), dermatologic diseases (e. g., pemphigus, allergic dermatoses), hematologic disorders ( e. g., thrombocytopenias, autoimmune hemolytic anemias), neoplasias, nervous system disorders (increased CSF pressure), GI diseases (e. g., ulcerative colitis exacerbations), and renal diseases (e. g., nephrotic syndrome). Some glucocorticoids are used topically in the eye and skin for various conditions or are injected intra-articularly or intra-lesionally. The above listing is certainly not complete. For speciﬁc dosages and indications refer to the Doses section. High dose dexamethasone use for shock or CNS trauma is con-troversial; recent studies have not demonstrated signiﬁcant beneﬁt and it actually may cause increased deleterious effects. Pharmacology/Actions Glucocorticoids have effects on virtually every cell type and system in mammals. An overview of the effects of these agents follows: CARDIOVASCULAR SYSTEM: Glucocorticoids can reduce capillary per-meability and enhance vasoconstriction. A relatively clinically in-signiﬁcant positive inotropic effect can occur after glucocorticoid administration. Increased blood pressure can result from both the drugs' vasoconstrictive properties and increased blood volume that may be produced. CELLS: Glucocorticoids inhibit ﬁbroblast proliferation, macrophage response to migration inhibiting factor, sensitization of lympho-cytes and the cellular response to mediators of inﬂammation. Glucocorticoids stabilize lysosomal membranes. CNS/AUTONOM IC NERVOUS SY STEM: Glucocorticoids can lower seizure threshold, alter mood and behavior, diminish the response to pyro-gens, stimulate appetite and maintain alpha rhythm. Glucocorticoids are necessary for normal adrenergic receptor sensitivity. ENDOCRINE SYSTEM: When animals are not stressed, glucocorti-coids will suppress the release of ACTH from the anterior pituitary, thereby reducing or preventing the release of endogenous corticos-teroids. Stress factors (e. g., renal disease, liver disease, diabetes) may sometimes nullify the suppressing aspects of exogenously admin-istered steroids. Release of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), prolactin, and luteinizing hor-mone (LH) may all be reduced when glucocorticoids are adminis-tered at pharmacological doses. Conversion of thyroxine (T 4) to triiodothyronine (T 3) may be reduced by glucocorticoids; plasma levels of parathyroid hormone increased. Glucocorticoids may in-hibit osteoblast function. Vasopressin (ADH) activity is reduced at the renal tubules and diuresis may occur. Glucocorticoids inhibit insulin binding to insulin-receptors and the post-receptor effects of insulin. HEMATOPOIETIC SYSTEM: Glucocorticoids can increase the numbers of circulating platelets, neutrophils and red blood cells, but platelet aggregation is inhibited. Decreased amounts of lymphocytes (pe-ripheral), monocytes and eosinophils are seen as glucocorticoids can sequester these cells into the lungs and spleen and prompt de-creased release from the bone marrow. Removal of old red blood cells becomes diminished. Glucocorticoids can cause involution of lymphoid tissue. GI TRACT AND H EPATIC SYSTEM: Glucocorticoids increase the secretion of gastric acid, pepsin, and trypsin. They alter the structure of mu-cin and decrease mucosal cell proliferation. Iron salts and calcium absorption are decreased while fat absorption is increased. Hepatic changes can include increased fat and glycogen deposits within he-patocytes,increased serum levels of alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT). Signiﬁcant increases can be seen in serum alkaline phosphatase levels. Glucocorticoids can cause minor increases in BSP (bromosulfophthalein) retention time. IMMUNE SYSTEM (also see Cells and Hematopoietic System): Gluco-corticoids can decrease circulating levels of T-lymphocytes; inhibit lymphokines; inhibit neutrophil, macrophage, and monocyte mi-gration; reduce production of interferon; inhibit phagocytosis and chemotaxis; antigen processing; and diminish intracellular killing. Speciﬁc acquired immunity is affected less than nonspeciﬁc im-mune responses. Glucocorticoids can also antagonize the comple-ment cascade and mask the clinical signs of infection. Mast cells are decreased in number and histamine synthesis is suppressed. Many of these effects only occur at high or very high doses and there are species differences in response.	pppbs.pdf
266 DEXAMETHASONE METABOLIC EFFECTS: Glucocorticoids stimulate gluconeogenesis. Lipogenesis is enhanced in certain areas of the body (e. g., abdomen) and adipose tissue can be redistributed away from the extremities to the trunk. Fatty acids are mobilized from tissues and their oxidation is increased. Plasma levels of triglycerides, cholesterol, and glycerol are increased. Protein is mobilized from most areas of the body (not the liver). MUSCULOSKELETAL: Glucocorticoids may cause muscular weakness (also caused if there is a lack of glucocorticoids), atrophy, and os-teoporosis. Bone growth can be inhibited via growth hormone and somatomedin inhibition, increased calcium excretion and inhibi-tion of vitamin D activation. Resorption of bone can be enhanced. Fibrocartilage growth is also inhibited. OPHTHALMIC: Prolonged corticosteroid use (both systemic or topi-cally to the eye) can cause increased intraocular pressure and glau-coma, cataracts, and exophthalmos. RENAL, FLUID, & ELECTROLY TES: Glucocorticoids can increase potas-sium and calcium excretion, sodium and chloride reabsorption, and extracellular ﬂuid volume. Hypokalemia and/or hypocalcemia rarely occur. Diuresis may develop following glucocorticoid ad-ministration. SKIN: Thinning of dermal tissue and skin atrophy can be seen with glucocorticoid therapy. Hair follicles can become distended and alo-pecia may occur. Pharmacokinetics Pharmacokinetics of dexamethasone do not translate into pharma-cologic effect. The half-life of dexamethasone in dogs is about 2-5 hours, but biologic activity can persist for 48 hours or more. Contraindications/Precautions/Warnings Because dexamethasone has negligible mineralocorticoid effect, it should generally not be used alone in the treatment of adrenal in-sufﬁciency. Do not administer the propylene glycol base injectable product rapidly intravenously; hypotension, collapse, and hemolytic anemia can occur. Many clinicians only use dexamethasone sodium phos-phate when giving the drug intravenously. Systemic use of glucocorticoids is generally considered contrain-dicated in systemic fungal infections (unless used for replacement therapy in Addison's), when administered IM in patients with idio-pathic thrombocytopenia and in patients hypersensitive to a partic-ular compound. Use of sustained-release injectable glucocorticoids is considered contraindicated for chronic corticosteroid therapy of systemic diseases. Animals that have received glucocorticoids systemically other than with “burst” therapy, should be tapered off the drugs. Patients who have received the drugs chronically should be tapered off slowly as endogenous ACTH and corticosteroid function may return slow-ly. Should the animal undergo a “stressor” (e. g., surgery, trauma, ill-ness, etc. ) during the tapering process or until normal adrenal and pituitary function resume, additional glucocorticoids should be ad-ministered. Adverse Effects Adverse effects are generally associated with long-term administra-tion of these drugs, especially if given at high dosages or not on an alternate day regimen. Effects generally are manifested as clinical signs of hyperadrenocorticism. Glucocorticoids can retard growth in young animals. Many of the potential effects, adverse and other-wise, are outlined above in the Pharmacology section. In dogs, polydipsia (PD), polyphagia (PP) and polyuria (PU), may all be seen with short-term “burst” therapy as well as with alternate-day maintenance therapy on days when giving the drug. Adverse effects in dogs can include: dull, dry haircoat, weight gain, panting, vomiting, diarrhea, elevated liver enzymes, pancreatitis, GI ulceration, lipidemias, activation or worsening of diabetes mel-litus, muscle wasting, and behavioral changes (depression, lethargy, viciousness). Discontinuation of the drug may be necessary; chang-ing to an alternate steroid may also alleviate the problem. With the exception of PU/PD/PP, adverse effects associated with antiinﬂam-matory therapy are relatively uncommon. Adverse effects associated with immunosuppressive doses are more common and, potentially, more severe. Cats generally require higher dosages than dogs for clinical effect, but tend to develop fewer adverse effects. Occasionally, polydipsia, polyuria, polyphagia with weight gain, diarrhea, or depression can be seen. Long-term, high dose therapy can lead to “Cushingoid” ef-fects, however. Administration of dexamethasone or triamcinolone may play a role in the development of laminitis in horses. Reproductive/Nursing Safety Corticosteroid therapy may induce parturition in large animal spe-cies during the latter stages of pregnancy. In humans, the FDA cat-egorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no ad-equate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the beneﬁt of therapy clearly outweighs the risks. ) Overdosage/Acute Toxicity Glucocorticoids when given short-term are unlikely to cause sig-niﬁcant harmful effects, even in massive dosages. One incidence of a dog developing acute CNS effects after accidental ingestion of glucocorticoids has been reported. Should clinical signs occur, use supportive treatment if required. Chronic usage of glucocorticoids can lead to serious adverse ef-fects. Refer to Adverse Effects above for more information. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dexamethasone and may be of signiﬁcance in veterinary patients: !TAMPHOTERICIN B : Administered concomitantly with glucocorti-coids may cause hypokalemia !TANTICHOLINESTERASE AGENTS (e. g., pyridostigmine, neostigmine, etc. ): In patients with myasthenia gravis, concomitant glucocorticoid and anticholinesterase agent administration may lead to profound muscle weakness. If possible, discontinue anticholinesterase med-ication at least 24 hours prior to corticosteroid administration !TASPIRIN : Glucocorticoids may reduce salicylate blood levels !TBARBITURATES : May increase the metabolism of glucocorticoids and decrease dexamethasone blood levels !TCYCLOPHOSPHAMIDE : Glucocorticoids may also inhibit the hepatic metabolism of cyclophosphamide; dosage adjustments may be required !TCYCLOSPORINE : Concomitant administration of glucocorticoids and cyclosporine may increase the blood levels of each, by mutu-ally inhibiting the hepatic metabolism of each other; the clinical signiﬁcance of this interaction is not clear !TDIAZEPAM : Dexamethasone may decrease diazepam levels	pppbs.pdf
DEXAMETHASONE 267 !TDIURETICS, POTASSIUM-DEPLETING (e. g., spironolactone, triamterene ): Administered concomitantly with glucocorticoids may cause hy-pokalemia !TEPHEDRINE : May reduce dexamethasone blood levels and interfere with dexamethasone suppression tests !TINDOMETHACIN : Can cause false negative test results in the dexam-ethasone suppression test !TINSULIN : Insulin requirements may increase in patients receiving glucocorticoids !TKETOCONAZOLE AND OTHER AZOLE ANTIFUNGALS : May decrease the metabolism of glucocorticoids and increase dexamethasone blood levels; ketoconazole may induce adrenal insufﬁciency when glucocorticoids are withdrawn by inhibiting adrenal cor-ticosteroid synthesis !TMACROLIDE A NTIBIOTICS (erythromycin, clarithromycin ): May de-crease the metabolism of glucocorticoids and increase dexam-ethasone blood levels !TMITOTANE : May alter the metabolism of steroids; higher than usu-al doses of steroids may be necessary to treat mitotane-induced adrenal insufﬁciency !TNSAIDS : Administration of ulcerogenic drugs with glucocorticoids may increase the risk of gastrointestinal ulceration !TPHENYTOIN : May increase the metabolism of glucocorticoids and decrease dexamethasone blood levels !TRIFAMPIN : May increase the metabolism of glucocorticoids and decrease dexamethasone blood levels !TVACCINES : Patients receiving corticosteroids at immunosuppres-sive dosages should generally not receive live attenuated-virus vaccines as virus replication may be augmented; a diminished immune response may occur after vaccine, toxoid, or bacterin administration in patients receiving glucocorticoids Laboratory Considerations !TGlucocorticoids may increase serum cholesterol !TGlucocorticoids may increase urine glucose levels !TGlucocorticoids may decrease serum potassium !TGlucocorticoids can suppress the release of thyroid stimulating hormone (TSH) and reduce T3 & T4 values. Thyroid gland atro-phy has been reported after chronic glucocorticoid administra-tion. Uptake of I131 by the thyroid may be decreased by gluco-corticoids. !TReactions to skin tests may be suppressed by glucocorticoids !TFalse-negative results of the nitroblue tetrazolium test for systemic bacterial infections may be induced by glucocorticoids !TGlucocorticoids may cause neutrophilia within 4-8 hours after dosing and return to baseline within 24-48 hours after drug dis-continuation !TGlucocorticoids can cause lymphopenia in dogs which can persist for weeks after drug discontinuation Doses !TDOGS: For labeled indications (antiinﬂammatory; glucocorticoid agent): a) Injection: 0. 5-1 mg IV or IM; may be repeated for 3-5 days; Tablets: 0. 25-1. 25 mg PO daily in single or two divided dos-es (Package Insert; Azium®— Schering) Low-Dose Dexamethasone Suppression T est: a) Draw pre-sample. Inject 0. 01-0. 015 mg/kg dexametha-sone IV (may dilute dexamethasone 1:10 with sterile saline to insure accurate dosing). Collect samples at 4 hrs. and 8 hrs. post dexamethasone. Usual pre-dose cortisol normals: 0. 5-4. 0 micrograms/dl; post-dexamethasone normals: less than 1. 5 micrograms/dl (Kemppainen and Zerbe 1989a) b) Draw pre-sample in AM. Inject 0. 01 mg/kg dexamethasone sodium phosphate IV. Draw sample 8 hours post injection. (Feldman 1989), (Morgan 1988), (Feldman, Schrader, and Twedt 1988) High-Dose Dexamethasone Suppression T est: a) Draw pre-dose sample. Inject 0. 1 or 1 mg/kg IV dexametha-sone. Draw post-dose samples at 4 hours and 8 hours. Use 1 mg/kg dose if not suppressed at lower dose (0. 1 mg/kg). Use 1 mg/kg dose with caution in patients with diabetes mel-litus and if cortisol values are greater than 12 micrograms/dl (Kemppainen and Zerbe 1989a) b) Draw pre-dose sample. Administer 0. 1 mg/kg IV dexametha-sone sodium phosphate. Draw second sample 8 hours post injection (Feldman 1989) c) Draw pre-dose sample. Administer 0. 1 mg/kg IV dexametha-sone sodium phosphate. Draw second sample 4 hours post injection (Morgan 1988) d) Draw pre-dose sample. Administer 0. 1 mg/kg IV dexametha-sone sodium phosphate. Draw second sample 4 or 8 hours post injection (Feldman, Schrader, and Twedt 1988) Combined Dexamethasone Suppression-ACTH Stimulation test: a) Draw pre-dose sample. Administer 0. 1 mg/kg IV dexametha-sone; collect post-dexamethasone sample 4 hours later. Im-mediately give ACTH (gel) 2. 2 IU/kg IM. Collect post-ACTH sample 2 hours later. (Kemppainen and Zerbe 1989a) For tentative diagnosis of Addison's disease: a) 1) Draw blood for hemogram, serum biochemistry and basal cortisol; 2) Begin IV ﬂuids and give 2-5 mg/kg dexametha-sone sodium phosphate; 3) Immediately give 0. 25 mg of cosyntropin IV or IM; 4) Draw a second blood sample for plasma cortisol 45-60 minutes later. Blood levels of <1 mcg/ d L are typical for hypoadrenocorticism, while those stimu-lating to only 2-3 mcg/d L are also suggestive. (Schaer 2006) For toy breed dogs with hydrocephalus: a) 0. 25 mg/kg three to four times daily; reduce dose slowly over 2-4 weeks (Simpson 1989) For adjunctive therapy of craniocerebral/spinal trauma: a) If patient's condition is not improved 30 minutes after re-ceiving water-soluble glucocorticoids: 2 mg/kg by slow IV in-fusion. If patient continues to deteriorate, additional therapy is warranted. (Shores 1989) b) Initially, 0. 2 mg/kg bolus, then 0. 2 mg/kg daily in 2-3 divid-ed doses. If animal is in shock, give 2 mg/kg initially. (Fenner 1986a) c) For spinal cord trauma: 2-3 mg/kg IV followed in 6-8 hours by 1 mg/kg SC or IV two to three times daily for 24 hours. Then 0. 2 mg/kg SC or IV two to three times daily for 2-3 days. Then 0. 1 mg/kg IV or SC two to three times daily for 3-5 days (Schunk 1988a) T o reduce intracerebral pressure and edema: a) In the palliative therapy of intracranial neoplasms: 0. 25-2 mg/kg q6h IV in acute episodes (Le Couteur and Turrel 1986) b) In the adjunctive therapy of status epilepticus: 2 mg/kg IV initially; repeat in 6-8 hours with 1 mg/kg. Follow with ta-pering doses. (Schunk 1988b)	pppbs.pdf
268 DEXAMETHASONE For adjunctive therapy of ﬁbrocartilaginous embolic myopathy: a) 2. 2 mg/kg IV, then 6-8 hours later give 1 mg/kg SC. Repeat 1 mg/kg SC in 12 hours, then give 0. 1 mg/kg SC twice daily for 3-5 days (Schunk 1988a) For patients with thoracolumbar intervertebral disk disease and acute onset of paraparesis: a) 2 mg/kg IV followed in 6-8 hours with 0. 5-1 mg/kg SC, two to three times daily for 24 hours, then 0. 1 mg/kg SC or PO twice daily for 3-5 days (Schunk 1988a) For medical therapy of cervical spondylopathy: a) With an acute onset or sudden worsening with moderate to marked tetraparesis: 2. 2 mg/kg IV once followed in 6-8 hours by 1 mg/kg SC twice daily for two doses. Then 0. 1-0. 2 mg/kg PO or SC twice a day for 3-5 days (Schunk 1988a) For adjunctive therapy of shock: a) Dexamethasone sodium phosphate: 4-6 mg/kg IV (Kemp-painen 1986) For initial adjunctive treatment of acute adrenocortical collapse: a) Dexamethasone: 0. 5-1 mg/kg IV or Dexamethasone Sodium phosphate 2-4 mg/kg IV (Schrader 1986), (Feldman, Schrad-er, and Twedt 1988) For treatment of acquired thrombocytopenia: a) 0. 25-0. 3 mg/kg IV or SC once, then 0. 1-0. 15 mg/kg SC or PO twice a day for 7 days. Decrease oral dose by H every 5-7 days for 3 weeks, then go to alternate day therapy for 6 weeks. (Dodds 1988) For adjunctive therapy of endotoxemia secondary to acute gastric dilatation-volvulus: a) 5 mg/kg slowly IV (Bellah 1988) For adjunctive therapy of cholecalciferol (Quintox®, Rampage®) toxicity: a) 1 mg/kg SC divided four times daily (Grauer and Hjelle 1988b) !TCATS: For labeled indications (antiinﬂammatory; glucocorticoid agent): a) Injection: 0. 125-0. 5 mg IV or IM; may be repeated for 3-5 days; Tablets: 0. 125-0. 5 mg daily in single or divided doses (Package Insert; Azium®— Schering) High-Dose Dexamethasone Suppression T est: a) As a screening test for feline hyperadrenocorticism: 0. 1 mg/kg IV. A dose of 1 mg/kg IV may differentiate pituitary-depen-dent hyperadrenocorticism (PDH) from an adrenal tumor. (Zerbe 1989) Combined Dexamethasone Suppression-ACTH Stimulation T est: a) Collect blood sample, then give dexamethasone 0. 1 mg IV, collect sample 2 hours after dexamethasone. Immediately give ACTH (2. 2 IU/kg) and collect samples 1 and 2 hours post ACTH. (Zerbe 1989) For endotoxic or septicemic shock: a) Dexamethasone sodium succinate: 5 mg/kg IV (Jenkins 1985) As adjunctive therapy for feline neoplasias (lymphosarcoma, acute lymphoid leukemia, mast cell neoplasms): a) 2-6 mg/m2 q24-48h PO, SC or IV (Couto 1989) For adjunctive emergency treatment of feline asthma: a) 1 mg/kg IV (sodium phosphate salt) (Noone 1986) For chronic therapy of feline allergic bronchitis: a) 0. 25 mg PO one to three times daily. Once patient stabilizes, attempt to reduce dose; keep on alternate-day therapy for at least 1-2 months after symptoms have initially resolved. (Bauer 1988) For alternative therapy for idiopathic feline miliary dermatitis: a) 1 mg PO once daily for 7 days, then 1 mg PO twice a week. May need to add progestational agent. (Kwochka 1986) !TRABBITS/RODENTS/SMALL MAMMALS: a) Mice, Rats, Gerbils, Hamsters, Guinea pigs, Chinchillas: 0. 6 mg/kg IM (as an antiinﬂammatory) (Adamcak and Otten 2000) !TCATTLE: For adjunctive therapy of insect bites or stings: a) 2 mg/kg IM or IV q4h (use epinephrine if anaphylaxis devel-ops) (Fowler 1993) For adjunctive therapy of cerebral edema secondary to polioen-cephalomalacia: a) 1-2 mg/kg intravenously (Dill 1986) For adjunctive therapy of radial nerve injury, or femoral nerve paralysis: a) Adult cattle (400-800 kg and not pregnant): 20-40 mg IM or IV; Calves: 10 mg IM or IV. Taper or discontinue therapy in 2-3 days. Many cases require only a single dose. (Rebhun 1986) For adjunctive therapy of obturator nerve paralysis: a) 10-40 mg parenterally once daily for 2-3 days, then discon-tinue (Rebhun 1986) For adjunctive therapy of peroneal nerve injuries: a) 10-30 mg parenterally for acute cases when not contraindi-cated due to pregnancy or infection (Rebhun 1986) For elective inducement of parturition or termination of pregnancy: a) For abortion: 25 mg parenterally with 25 mg prostaglandin F2alpha after 150 days of gestation. For inducement or par-turition from 8th month of gestation on: 20 mg IM. (Drost 1986) b) For inducement of parturition when given within 2 weeks of normal term: 20-30 mg IM (Barth 1986) For adjunctive therapy of aseptic laminitis: a) 5-20 mg IM or IV; continue therapy for 2-3 days (Berg 1986) For primary bovine ketosis: a) 5-20 mg IV or IM (Package Insert; Azium®— Schering) !THORSES: (Note : ARCI UCGFS Class 4 Drug) For labeled indications (antiinﬂammatory; glucocorticoid agent): a) Dexamethasone Injection: 2. 5-5 mg IV or IM (Package In-sert; Azium®— Schering) Dexamethasone sodium phosphate injection: 2. 5-5 mg IV (Package Insert; Azium® SP— Schering) For recurrent airway obstruction (heaves): a) For a 500 kg horse give 40 mg IM once every other day for 3 treatments, followed by 35 mg IM once every other day for 3 treatments, followed by 30 mg IM once every other day for 3 treatments, etc., until horse is weaned off dexamethasone. Corticosteroid use may be contraindicated in horses predis-posed to laminitis or exhibiting endocrinopathies. (Ains-worth and Hackett 2004) For glucocorticoid therapy: a) 0. 05-0. 2 mg/kg once daily IV, IM or PO (Robinson 1987) Dexamethasone suppression test: a) 20 mg IM. Normal values: Cortisol levels decrease 50% in 2 hours, 70% in 4 hours, and 80% at 6 hours. At 24 hours, levels are still depressed about 30% of original value. (Beech 1987b)	pppbs.pdf
DEXAMETHASONE 269 T!TSWINE: For glucocorticoid therapy: a) 1-10 mg IV or IM (Howard 1986) !TLLAMAS: For adjunctive therapy of anaphylaxis: a) 2 mg/kg IV (Smith 1989) !TBIRDS: For shock, trauma, gram-negative endotoxemia: a) Dexamethasone 2 mg/m L injection: 2-4 mg/kg IM or IV once, twice or three times daily. Taper off drug when using long-term. (Clubb 1986) !TREPTILES: For septic shock in most species: a) Using Dexamethasone Sodium Phosphate: 0. 1-0. 25 mg/kg IV or IM (Gauvin 1993) Monitoring Monitoring of glucocorticoid therapy is dependent on its reason for use, dosage, agent used (amount of mineralocorticoid activity), dosage schedule (daily versus alternate day therapy), duration of therapy, and the animal's age and condition. The following list may not be appropriate or complete for all animals; use clinical assess-ment and judgment should adverse effects be noted: !TWeight, appetite, signs of edema !TSerum and/or urine electrolytes !Total plasma proteins, albumin !TBlood glucose !TGrowth and development in young animals !TACTH stimulation test if necessary Client Information !TClients should carefully follow the dosage instructions and should not discontinue the drug abruptly without consulting with vet-erinarian beforehand. !TClients should be briefed on the potential adverse effects that can be seen with these drugs and instructed to contact the veterinar-ian should these effects become severe or progress. Chemistry/Synonyms A synthetic glucocorticoid, dexamethasone occurs as an odorless, white to practically white, crystalline powder that melts with some decomposition at about 250°C. It is practically insoluble in water and sparingly soluble in alcohol. Dexamethasone sodium phos-phate occurs as an odorless or having a slight odor, white to slightly yellow, hygroscopic powder. One gram is soluble in about 2 m L of water; it is slightly soluble in alcohol 1. 3 mg of dexamethasone sodium phosphate is equivalent to 1 mg of dexamethasone; 4 mg/m L of dexamethasone sodium phosphate injection is approximately equivalent to 3 mg/m L of dexamethasone. Dexamethasone may also be known as: desamethasone, dexam-etasone, dexamethasonum, 9alpha-Fluoro-16alpha-methylpredni-solone; hexadecadrol; many trade names are available. Storage/Stability/Compatibility Dexamethasone is heat labile and should be stored at room tem-perature (15-30°C) unless otherwise directed by the manufacturer. Dexamethasone sodium phosphate injection should be protected from light. Dexamethasone tablets should be stored in well-closed containers. Dexamethasone sodium phosphate for injection is reportedly compatible with the following drugs: amikacin sulfate, aminophyl-line, bleomycin sulfate, cimetidine HCl, glycopyrrolate, lidocaine HCl, nafcillin sodium, netilmicin sulfate, prochlorperazine edisy-late and verapamil. Dexamethasone sodium phosphate is reportedly incompatible with: daunorubicin HCl, doxorubicin HCl, metaraminol bitartrate, and vancomycin. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more speciﬁc information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Dexamethasone Injection: 2 mg/m L; Amtech® Dexamethasone So-lution (Phoenix Scientiﬁc), Azium® Solution (Schering-Plough), Dexamethasone 2 mg Injection (Vedco, RXV), Dexamethasone Injection (Bimeda, Pro Labs, Vet T ek, Dexamethasone Solution (As-pen, Butler, Phoenix Pharmaceutical), Dexasone® (RXV); (Rx). Ap-proved for use in dogs, cats, horses (those not intended for food) and cattle. There are no withdrawal times required when used in cattle. A withdrawal period has not been established for this prod-uct in preruminal calves; do not use in veal calves. Dexamethasone Oral Powder: 10 mg crystalline in 10 mg pack-ets. Approved for use in cattle and horses (not horses intended for food). Azium® Powder (Schering-Plough); (Rx) Dexamethasone Sodium Phosphate Injection: 4 mg/m L (equiva-lent to 3 mg/m L dexamethasone); Dexaject SP® (Vetus), Dexame-thasone Sodium Phosphate Injection (Butler, Vedco); generic; (Rx). Approved for use in horses. Dexamethasone 5 mg and trichlormethiazide 200 mg oral bolus: in boxes of 30 and 100 boluses; Naquasone® Bolus (Schering-Plough); (Rx). Approved for use in cattle. Milk withdrawal = 72 hours. The ARCI (Racing Commissioners International) has designated dexamethasone as a class 4 substance. See the appendix for more information. HUMAN-LABELED PRODUCTS: Dexamethasone Tablets: 0. 25 mg, 0. 5 mg, 0. 75 mg, 1 mg, 1. 5 mg, 2 mg, 4 mg, & 6 mg; Decadron® (Merck); generic; (Rx) Dexamethasone Oral Elixir/Solution: 0. 5 mg/5 m L in 100 m L, 237 m L, 500 m L and UD 5 and UD 20 m L, 1 mg/m L (concentrate) in 30 m L with dropper; Dexamethasone Intensol® (Roxane); generic; (Rx) Dexamethasone Sodium Phosphate Injection: 4 mg/m L (as sodium phosphate solution) in 1, 5, 10 and 30 m L vials, 1 m L syringe and 1 m L ﬁll in 2 m L vials; generic; (Rx); 10 mg/m L (as sodium phos-phate solution) in 1m L and 10 m L vials and 1 m L syringes; generic; (Rx); 20 mg/m L (as sodium phosphate solution) in 5 m L vials (IV) (with sodium sulﬁte & benzyl alcohol); Hexadrol® Phosphate (Or-ganon), (Rx) Dexamethasone is also available in topical ophthalmic (see ophthal-mic products in the appendix) and inhaled aerosol dosage forms.	pppbs.pdf
270 DEXMEDETOMIDINE DEXMEDETOMIDINE (deks-mee-deh-toe-mih-deen) Dexdomitor® ALPHA-2 ADRENERGIC AGONIST Prescriber Highlights TT Alpha-2 agonist similar to medetomidine used as a pre-anesthetic & for sedation, analgesia in dogs & cats TT Contraindications: cardiac disease, liver or kidney dis-eases, shock, severe debilitation, or animals stressed due to heat, cold or fatigue; caution in very old or young animals, animals with seizure disorders, respiratory, renal or kidney disorders 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 Dosed in dogs based upon body surface area, not weight TT Effects may be reversed with atipamezole Note : This compound has been approved for use in dogs in the USA, but at the time of writing (Autumn 2007) it had not yet been marketed in the USA and the package insert was not available for review. The fol-lowing should be considered a preliminary monograph. Uses/Indications In the USA, dexmedetomidine for dogs is approved for use as a seda-tive and analgesic to facilitate clinical examinations, clinical proce-dures, minor surgical procedures, and minor dental procedures, and as a preanesthetic to general anesthesia. In Europe, dexmedetomidine is additionally indicated for use in cats similarly to dogs above, but when used as premed it is indicated for use prior to ketamine general anesthesia. Pharmacology/Actions Dexmedetomidine is the dextrorotatory enantiomer of the alpha-2 adrenergic agonist, medetomidine. The other enantiomer, levome-detomidine is thought to be pharmacologically inactive so dexme-detomidine is about two times more potent than medetomidine. Dexmedetomidine is much more speciﬁc than xylazine for al-pha2 receptors versus alpha 1 receptors. The pharmacologic effects of dexmedetomidine include: depression of CNS (sedation, anxioly-sis), analgesia, GI (decreased secretions, varying affects on intestinal muscle tone) and endocrine functions, peripheral and cardiac va-soconstriction, bradycardia, respiratory depression, diuresis, hypo-thermia, analgesia (somatic and visceral), muscle relaxation (but not enough for intubation), and blanched or cyanotic mucous mem-branes. Effects on blood pressure are variable, but dexmedetomidine can cause hypertension longer than does xylazine. Pharmacokinetics In dogs after IM administration, dexmedetomidine is absorbed (bioavailability 60%) and reaches peak plasma levels in about 35 minutes. Volume of distribution is 0. 9 L/kg and elimination half-life is approximately 40-50 minutes. The drug is primarily metabolized in the liver via glucuronidation and N-methylation. No metabolites are active and they are eliminated primarily in the urine and to lesser extent in the feces. In cats after IM administration, dexmedetomidine is absorbed and reaches peak plasma levels of about 17 ng/m L occur in about 15 minutes. Volume of distribution is 2. 2 L/kg and elimination half-life is approximately 1 hour. Metabolites are eliminated primarily in the urine and to lesser extent in the feces. In humans after IV administration, dexmedetomidine is rapidly distributed, undergoes almost complete biotransformation via both glucuronidation and CY-450 enzymes systems and has a terminal elimination half-life of about 2 hours. Metabolites are eliminated in the urine and feces. Contraindications/Precautions/Warnings The European labeling states not to use in puppies less than 6 months old or in kittens less than 5 months old; in animals with cardiovascular disorders; in animals with severe systemic disease or that are moribund; or in animals known to be hypersensitive to the active substance or any of the excipients. Use with caution in animals with, or prone to developing, sei-zures. Dexmedetomidine lowered the seizure threshold in cats un-dergoing anesthesia with enﬂurane. Adverse Effects The adverse effects reported with medetomidine or dexmedetomi-dine are essentially extensions of their pharmacologic effects includ-ing bradycardia, muscle tremors, transient hypertension, occasional A V blocks, decreased respiration, hypothermia, urination, vomiting, hyperglycemia, and pain on injection (IM). Rare effects that have been reported, include: prolonged sedation, paradoxical excitation, hypersensitivity, pulmonary edema, apnea, and death from circula-tory 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. However, no teratogenic effects were ob-served when rats were given up to 200 mcg/kg SC from days 5-16 of gestation or when rabbits were given up 96 mcg/kg IV from days 6-18 of gestation. In humans, the FDA categorizes this drug as cat-egory C for use during pregnancy ( Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in hu-mans; or there are no animal reproduction studies and no adequate studies in humans. ) Dexmedetomidine is distributed into the milk of lactating rats; safe use during nursing has not been established. Overdosage/Acute Toxicity Single doses of up to 5X (IV) and 10X (IM) were tolerated in dogs, but adverse effects can occur (see above). Because of the poten-tial of additional adverse effects occurring (heart block, PVC's, or tachycardia), treatment of medetomidine-induced bradycardia with anticholinergic agents (atropine or glycopyrrolate) is usually not recommended. Atipamezole is probably a safer choice to treat any medetomidine-induced effect. Drug Interactions Note : Before attempting combination therapy with dexmedetomi-dine, it is strongly advised to access references from veterinary anes-thesiologists familiar with the use of this product. T ! ANESTHETICS, OPIATES, SEDATIVE/HYPNOTICS : Effects may be addi-tive; dosage reduction of one or both agents may be required The following drug interactions have either been reported or are theoretical in humans or animals receiving medetomidine (a related compound) and may be of signiﬁcance in veterinary patients: T ! ATROPINE, 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	pppbs.pdf
DEXPANTHENOL 271 Timportant when using higher doses of medetomidine and con-comitant use is discouraged. T ! YOHIMBINE : May reverse the effects of medetomidine; but atipam-ezole is preferred for clinical use to reverse the drug's effects Laboratory Considerations T ! Medetomidine (and presumably dexmedetomidine) can inhibit ADP-induced platelet aggregation in cats. Doses T ! DOGS: a) For sedation and analgesia: 375 mcg/m2 body surface area (BSA) IV; 500 mcg/m2 BSA IM. The mcg/kg dosage decreases as body weight increases. As a preanesthetic: Depending on duration and severity of the procedure and anesthetic regimen: 125-375 mcg/m2 IM. DEXPANTHENOL D-PANTHENOL (dex-pan-the-nole) Ilopan® Prescriber Highlights TT Precursor to Coenzyme A that ostensibly aids in produc-tion of acetylcholine TT Potentially may be useful in the prevention of post-surgi-cal ileus, but efﬁcacy is in doubt TT Contraindications: Ileus secondary to mechanical ob-struction or in cases of colic caused by the treatment of cholinergic anthelmintics (FOI Summar y; Dexdomitor®—Orion) T ! CATS: a) For sedation and analgesia, or as a preanesthetic: 40 mcg/ kg IM. Expected sedative and analgesic effects are reached within 15 minutes and maintained for up to 60 minutes. (Dexdomitor®—Pﬁzer U. K. ) 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 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 Dexmedetomidine is the dextrorotatory enantiomer of medetomidine. Dexmedetomidine HCl may also be known as (S)-medetomidine, (+)-medetomidine, MPV 1440, MPV 295, or MPV 785. Trade names include: Precedex® or Dexdomitor®. Storage/Stability/Compatibility Store the injection at room temperature (15-30°C); do not freeze. Dexmedetomidine is not compatible with butorphanol when mixed in the same syringe. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Dexmedetomidine HCl 0. 5 mg/m L (500 mcg/m L) in 10 m L mul-tidose vials; Dexdomitor® (Orion); (Rx). Note : At time of writing, approved but not marketed in the USA. HUMAN-LABELED PRODUCTS: Dexmedetomidine HCl 100 mcg/m L, preservative free in 2 m L vi-als; Precedex® (Abbott); (Rx) Uses/Indications Dexpanthenol has been suggested for use in intestinal atony or dis-tension, postoperative retention of ﬂatus and feces, prophylaxis and treatment of paralytic ileus after abdominal surgery or traumatic injuries, equine colic (not due to mechanical obstruction) and any other condition when there is an impairment of smooth muscle function. Controlled studies are lacking with regard to proving the efﬁcacy of the drug for any of these indications. Pharmacology/Actions A precursor to pantothenic acid, dexpanthenol acts as a precursor to coenzyme A that is necessary for acetylation reactions to occur during gluconeogenesis and in the production of acetylcholine. It has been postulated that post-surgical ileus can be prevented by giving high doses of dexpanthenol, thereby assuring adequate lev-els of acetylcholine. However, one study in normal horses (Adams, Lamar, and Masty 1984) failed to demonstrate any effect of dexpan-thenol on peristalsis. Pharmacokinetics Dexpanthenol is rapidly converted to pantothenic acid in vivo, which is widely distributed throughout the body, primarily as co-enzyme A. Contraindications/Precautions/Warnings Dexpanthenol is contraindicated in ileus secondary to mechanical obstruction, or in cases of colic caused by the treatment of cholin-ergic anthelmintics. It is also contraindicated in humans with he-mophilia as it may exacerbate bleeding. Adverse Effects Adverse reactions are reportedly rare. Hypersensitivity reactions have been reported in humans, but may have been due to the pre-servative agents found in the injectable product. Potentially, GI cramping and diarrhea are possible. Reproductive/Nursing Safety Safety in use during pregnancy has not been established. In hu-mans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity The drug is considered non-toxic even when administered in high doses.	pppbs.pdf
272 DEXRAZOXANE Drug Interactions The following drug interactions have either been reported or are DEXRAZOXANE theoretical in humans or animals receiving dexpanthenol and may (dex-ra-zox-ane) Zinecard®be of signiﬁcance in veterinary patients: T ! NEOSTIGMINE; SUCCINYLCHOLINE : The manufacturers have recom-ANTIDOTE mended that dexpanthenol not be administered within 12 hours of neostigmine or other parasympathomimetic agents or within Prescriber Highlights 1 hour of patients receiving succinylcholine. The clinical signiﬁ-TT May be useful in attenuating the cardiotoxic effects of cance of these potential interactions has not been documented, doxorubicin in patients (dogs) showing signs of anthra-however. cycline cardiotoxicity, have cardiac disease, or are at Doses maximum cumulative dosages of doxorubicin; also T ! DOGS & CATS: used to treat extravasation injuries associated with doxorubicin a) 11 mg/kg IM; repeat if indicated at 4-6 hour intervals (Ros-soff 1974) TT Potentially may reduce efﬁcacy of doxorubicin & increase b) 11 mg/kg IM; may be repeated in 2 hours after initial injection myelosuppression and followed every 6-8 hours until condition is alleviated. TT For extravasation treatment, must be administered The time interval and duration of therapy will depend upon within hours of injury the degree of severity that the animal is exhibiting from the TT Very expensive clinical standpoint. (Label Instructions; d-Panthenol® Inject-able—Vedco) T ! HORSES: Uses/Indications a) 2. 5 grams IV or IM; repeat if indicated at 4-6 hour intervals Dexrazoxane may be useful to attenuate the cardiotoxic effects of (Rossoff 1974), (Label Instructions; d-Panthenol® Injectable— doxorubicin in patients who are showing signs of anthracycline Vedco) cardiotoxicity, have cardiac disease, or are at maximum cumulative dosages of doxorubicin. It is also used to treat extravasation injuries Monitoring associated with doxorubicin. T ! Clinical efﬁcacy While dexrazoxane has been shown to be cardioprotective when Client Information given at dosages of 10 times the doxorubicin dose, there is evidence T ! Should be used in a professionally monitored situation where gas-that it may also partially protect the cancer cells being treated. trointestinal motility can be monitored. Pharmacology/Actions Dexrazoxane is hydrolyzed to an active metabolite that chelates Chemistry/Synonyms intracellular iron that is believed to prevent the formation of an The alcohol of D-pantothenic acid, dexpanthenol occurs as a slightly anthracycline-iron complex thought to be the primary cause of an-bitter-tasting, clear, viscous, somewhat hygroscopic liquid. It is freely thracycline-induced cardiomyopathy. soluble in water or alcohol. Dexpanthenol may also be known as: D-panthenol, dexpanthe-Pharmacokinetics nolum, dextro-pantothenyl alcohol, pantothenol; many trade names In dogs, dexrazoxane's pharmacokinetics ﬁt a two compartment are available. open model. Steady-state volume of distribution is 0. 67 L/kg, ter-Storage/Stability/Compatibility minal half life is about 1. 2 hours, and clearance about 11 m L/min/ Dexpanthenol should be protected from both freezing and excessive kg. Clearance was dose-independent and the drug showed low tissue heat. It is incompatible with strong acids and alkalis. and protein binding. Dexrazoxane is primarily excreted in the urine as unchanged drug and metabolites. Dosage Forms/Regulatory Status Contraindications/Precautions/Warnings VETERINARY-LABELED PRODUCTS: Dexrazoxane should not be used unless an anthracycline antine-Dexpanthenol Injection: 250 mg/m L in 100 m L vials; Amtech® D-oplastic agent is being used. Panthenol Injection (IVX), D-Panthenol® Injectable (Vedco), generic Efﬁcacy and safety for use in cats is not known. (Butler, Phoenix Pharmaceutical); (Rx). Labeled for use in dogs, cats, and horses. Adverse Effects Dexrazoxane may cause additive myelosuppression when used with HUMAN-LABELED PRODUCTS: other myelosuppressive agents. There is some evidence in humans, Dexpanthenol Injection: 250 mg/m L in 2 m L and 10 m L vials, UD that dexrazoxane may reduce the efﬁcacy of anthracycline antitu-Stat-Pak 2 m L disp syringes; Ilopan® (Adria); generic; (Rx) mor agents. Clinical signiﬁcance in veterinary patients is unknown. Wear gloves when handling and use normal procedures for han-Dextrose — see the Tables of Parenteral Fluids in the dling and disposal of anti-cancer medications. If unreconstituted Appendix powder contacts skin or mucous membranes, wash off thoroughly with soap and water. Reproductive/Nursing Safety Dexrazoxane has been shown to cause testicular atrophy in dogs when administered at usual doses for 13 weeks. In humans, the FDA categorizes dexrazoxane as a category C drug for use during preg-nancy (Animal studies have shown an adverse effect on the fetus, but	pppbs.pdf
DEXTRAN 70 273 there are no adequate studies in humans; or there are no animal re-production studies and no adequate studies in humans). In rats and rabbits, dexrazoxane was teratogenic at doses lower than those ad-ministered to humans. It is unknown if dexrazoxane enters maternal milk; human mothers are advised to discontinue nursing if given the drug. Overdosage/Acute Toxicity Because of the method of administration and drug expense, over-doses are unlikely in veterinary medicine. As there is no known an-tidote, treatment would be supportive. Potentially, the drug could be removed via hemodialysis. Drug Interactions Dexrazoxane does not inﬂuence the pharmacokinetics of doxorubicin. The following drug interactions have either been reported or are theoretical in humans or animals receiving dexrazoxane and may be of signiﬁcance in veterinary patients: T ! MYELOSUPPRESSIVE AGENTS, OTHER : Additive myelo-suppression may occur when used with other myelosuppressive agents. Laboratory Considerations No speciﬁc laboratory interactions or considerations were noted. Doses T ! DOGS: For treatment of anthracycline (doxorubicin, epirubicin, etc. ) extravasation: a) T erminate doxorubicin infusion immediately, and infuse in-travenously 1000 mg/m2 of dexrazoxane in a separate infu-sion within 6 hours and again on day 2. Infuse 500 mg/m2 on day 3. Acute surgical evaluation is performed. Note : Dosage recommendations are for human patients, but may apply to veterinary patients. (Langer, Sehested et al. 2000) b) Anecdotally; IV administration of dexrazoxane at 10 times the doxorubicin dose with 3 hours and again at 24 and 48 hours after extravasation signiﬁcantly reduces local tissue in-jury. (Vail 2006) For prevention of doxorubicin-induced cardiomyopathy: a) Dexrazoxane to doxorubicin dose ratio is 10:1 (e. g., 300 mg/ m2 of dexrazoxane to 30 mg/m2 doxorubicin) given as slow IV bolus, starting 30 minutes of, and prior to the doxorubicin dose (as a short, IV bolus. ) (Selting 2005) b) Use can be considered in breeds at risk (Shelties, Collies, Australian Shepherds, etc. ), dogs that are exceeding the usual cumulative dose cut-off, and in cases where there is preex-isting cardiac disease and no effective chemo options exist: Dexrazoxane to doxorubicin dose ratio is 10:1 (e. g., 300 mg/ m2 of dexrazoxane to 30 mg/m2 doxorubicin) given as slow IV bolus, starting 30 minutes before doxorubicin is adminis-tered. (Vail 2006) Monitoring T ! CBC T ! If used for cardioprotection: echocardiogram, ECG, etc Client Information T ! Clients should understand and accept the potential costs associ-ated with this drug and that when used for extravasation injuries, may not be fully effective. Chemistry/Synonyms A derivative of EDTA, dexrazoxane occurs as a white crystalline powder that is soluble in water and slightly soluble in ethanol and practically insoluble in nonpolar organic solvents. It has a p Ka of 2. 1 and degrades rapidly at p H's above 7. Dexrazoxane may also be known as: 2,6-Piperazinedione, ADR-529, ICRF-187, NSC-169780, Zinecard®, Cardioxane® or Eucardion®. Storage/Stability/Compatibility Unreconstituted dexrazoxane vials should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Once reconstituted with the supplied diluent, it is stable for 6 hours at room tempera-ture or refrigerated. Unused solutions after that time should be dis-carded. After reconstitution, the resulting solution may be diluted with either 0. 9% sodium chloride injection or D 5W in concentra-tions of 1. 3-5 mg/m L. Inspect visually for particulate matter and discoloration prior to administering. The manufacturer states that it should not be mixed with any other drug. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Dexrazoxane Lyophilized Powder for Injection: 250 mg (10 mg/m L when reconstituted in vials with 25 m L sodium lactate injection); and 500 mg (10 mg/m L when reconstituted with 50 m L sodium lactate injection); Zinecard® (Pﬁzer); Dexrazoxane (Bedford); (Rx) DEXTRAN 70 (dex-tran) PLASMA VOLUME EXPANDER Note : Dextran is also available as Dextran 40 and Dextran 75. As Dextran 70 is the most commonly used version in veterinary medicine, the fol-lowing monograph is limited to it alone. Prescriber Highlights TT Branched polysaccharide plasma volume expander TT Contraindications: Preexisting coagulopathies TT Caution: Patients susceptible to circulatory overload (severe heart or renal failure), thrombocytopenia TT Adverse Effects: Quite rare in dogs. Increased bleeding times, acute renal failure & anaphylaxis possible (but very rare) TT Must monitor for ﬂuid overload Uses/Indications Dextran 70 is a relatively low cost colloid for the adjunctive treat-ment of hypovolemic shock. Hetastarch is the more commonly em-ployed synthetic colloid used today. Pharmacology/Actions Dextran 70 has osmotic effects similarly to albumin. Dextran's col-loidal osmotic effect draws ﬂuid into the vascular system from the interstitial spaces, resulting in increased circulating blood volume.	pppbs.pdf
274 DEXTRAN 70 Pharmacokinetics After IV infusion, circulating blood volume is increased maximal-ly within one hour and effects can persist for 24 hours or more. Approximately 20-30% of a given dose remains in the intravascular compartment at 24 hours and it may be detected in the blood 4-6 weeks after dosing. Dextran 70 is slowly degraded to glucose by dex-tranase in the spleen and then metabolized to carbon dioxide and water. A small amount may be excreted directly into the gut and eliminated in the feces. Contraindications/Precautions/Warnings Patients overly susceptible to circulatory overload (severe heart or renal failure) should receive dextran 70 with great caution. Dextran 70 is contraindicated in patients with severe coagulopathies and should be used with caution in patients with thrombocytopenia as it can interfere with platelet function. Do not give dextran IM. Patients on strict sodium restriction should receive dextran cautiously as a 500 m L bag contains 77 m Eq of sodium. Adverse Effects Dextran 70 may increase bleeding time and decrease von Willebrand's factor antigen and factor VIII activity. This does not usually cause clinical bleeding in dogs. While anaphylactoid reactions are not rare in humans, they do occur rarely in dogs, but at a higher rate than with hetastarch. Unlike dextran 40, dextran 70 has rarely been associated with acute renal failure. In humans, GI effects (abdominal pain, nausea/vomiting) have been reported with use of dextran 70. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity The drug should be dosed and monitored carefully as volume over-load may result. Drug Interactions Dextran reportedly has no drug interactions that are clinically sig-niﬁcant. Laboratory Considerations !TDextran 70 may interfere with blood cross-matching as it can cross-link with red blood cells and appear as rouleaux formation. Iso-tonic saline may be used to negate this effect. !!Blood glucose levels may be increased as dextran is degraded. !TFalsely elevated bilirubin levels may be noted; reason unknown. Doses !TDOGS: a) Up to 40 m L/kg/day; not to be infused faster than 5 m L/kg/hr (Haskins 1992) b) 20 m L/kg; bolus to effect (Eastlake and Snyder 1998) c) 20 m L/kg/day; when acute resuscitation is required, may be given as a slow bolus over 30 minutes to an hour. May also be given as a constant rate infusion over a longer period to augment colloid oncotic pressure or decrease the volume of crystalloids infused, thereby reducing hemodilution. (Martin 2004) !TCATS: a) 10 m L/kg/day; when acute resuscitation is required. May be given as a slow bolus over 30 minutes to an hour. May also be given as a constant rate infusion over a longer period to augment colloid oncotic pressure or decrease the volume of crystalloids infused, thereby reducing hemodilution. (Martin 2004) !TCATTLE: a) For dehydrated (secondary to diarrhea) calves given as 6% Dextran 70 in 7. 2% sodium chloride: T o prepare solution, add 31. 6 g sodium chloride into the barrel of a 60 m L syringe. Draw 60 m L of 6% dextran 70 in 0. 9% Na Cl from the bag/ bottle to dilute the Na Cl crystals. Re-inject the dissolved solu-tion into the bag/bottle through a 0. 22 micron ﬁlter giving a 6% dextran 70 in 7. 2% Na Cl solution. Resultant solution may be refrigerated for up to 3 months. Inject IV 4-5 m L/ kg of this solution over 4-5 minutes, followed immediately by oral administration of isotonic electrolyte solution. Give dextran 70 solution one time only or hypernatremia may re-sult and follow-up with isotonic ﬂuids (oral or IV) are critical. (Sweeney 2003) Monitoring !TOther than the regular monitoring performed in patients that would require volume expansion therapy, there is no inordinate monitoring required speciﬁc to dextran therapy. Chemistry/Synonyms A branched polysaccharide used intravenously as a plasma volume expander, dextran 70 occurs as a white to light yellow amorphous powder. It is freely soluble in water and insoluble in alcohol. Dextran 70 contains (on average) molecules of 70,000 daltons. Each 500 m L of the commercially available 6% dextran 70 in normal saline pro-vides 77 m Eq of sodium. Dextran 70 in normal saline has a viscosity of 3. 68 centipose (blood is 3 centipose) and a colloid osmotic pres-sure of 65. 8 mm Hg (blood is 25-30 mm Hg). Dextran 70 may also be known as: dextranum 70, polyglu-cin, Dextran 70®, Fisiodex 70®, Gentran 70®, Hyskon®, Lomodex 70®, Longasteril 70®, Macrodex®, Macrohorm 70®, Neodextril 70®, Plander®, Rescue Flow®, or Solplex 70®. Storage/Stability/Compatibility Dextran 70 injection should be stored at room temperature; prefer-ably in an area with little temperature variability. While only clear solutions should be used, dextran ﬂakes can form but may be resol-ubolized by heating the solution in a boiling water bath until clear, or autoclaving at 110°C for 15 minutes. Dextran 70 is compatible with many other solutions and drugs; refer to specialized references or a hospital pharmacist for more information. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Dextran High Molecular Weight Injection: 6% dextran 70 in 0. 9% sodium chloride in 500 m L; Dextran 70® (Mc Gaw); (Rx), Gen-tran70® (Baxter); (Rx), Macrodex® (Medisan); (Rx) Dextran High Molecular Weight Injection: 6% dextran 70 in 5% dextrose in 500 m L; Macrodex® (Medisan); (Rx)	pppbs.pdf
DIAZEPAM 275 DIAZEPAM (dye-az-e-pam) Valium®, Diastat® BENZODIAZEPINE Prescriber Highlights TT Benzodiazepine used for a variety of indications (anxiolytic, muscle relaxant, hypnotic, appetite stimulant, & anticonvulsant) in several species TT Contraindications: Hypersensitivity to benzodiazepines, cats exposed to chlorpyrifos, signiﬁcant liver disease (especially in cats) TT Caution: hepatic or renal disease, aggressive, debilitated or geriatric patients; patients in coma, shock or with sig-niﬁcant respiratory depression TT Adverse Effects: Sedation & ataxia most prevalent. DOGS: CNS excitement; CATS: Hepatic failure or behavior changes; HORSES: Muscle fasciculations TT Inject IV slowly TT May be teratogenic TT Drug interactions TT Controlled substance (C-IV) Uses/Indications Diazepam is used clinically for its anxiolytic, muscle relaxant, hyp-notic, appetite stimulant, and anticonvulsant activities. Refer to the Dosage section for those and other suggested indications and doses for each species. Pharmacology/Actions The subcortical levels (primarily limbic, thalamic, and hypotha-lamic), of the CNS are depressed by diazepam and other benzo-diazepines thus producing the anxiolytic, sedative, skeletal muscle relaxant, and anticonvulsant effects seen. The exact mechanism of action is unknown, but postulated mechanisms include: antago-nism of serotonin, increased release of and/or facilitation of gam-ma-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. In all species studied, receptors are lacking in the white matter. Pharmacokinetics Diazepam is rapidly absorbed following oral administration. Peak plasma levels occur within 30 minutes to 2 hours after oral dosing. The drug is slowly (slower than oral) and incompletely absorbed following IM administration. In dogs, rectally administered diaz-epam has an average bioavailability of 50%, but signiﬁcant inter-patient variation occurs. When administered intranasally to dogs, bioavailability is about 80%. Diazepam is highly lipid soluble and is widely distributed throughout the body. It readily crosses the blood-brain barrier and is fairly highly bound to plasma proteins. In the horse at a serum concentration of 75 ng/m L, 87% of the drug is bound to plasma proteins. In humans, this value has been reported to be 98-99%. Diazepam is metabolized in the liver to several metabolites, in-cluding desmethyldiazepam (nordiazepam), temazepam, and ox-azepam, all of which are pharmacologically active. These are even-tually conjugated with glucuronide and eliminated primarily in the urine. Because of the active metabolites, serum values of diazepam are not useful in predicting efﬁcacy. Serum half-lives (approximat-ed) have been reported for diazepam and metabolites in dogs, cats, and horses: DOGS CATS HORSES HUMANS Diazepam 2. 5-3. 2 hrs 5. 5 hrs 7-22 hrs 20-50 hrs Nordiazepam 3 hrs 21. 3 hrs 30-200 hrs Contraindications/Precautions/Warnings Inject intravenously slowly. This is particularly true when using a small vein for access or in small animals; diazepam may cause sig-niﬁcant thrombophlebitis. Rapid injection of intravenous diazepam in small animals or neonates may cause cardiotoxicity secondary to the propylene glycol in the formulation. Intra-carotid artery injec-tions must be avoided. Use cautiously in patients with hepatic or renal disease and in debilitated or geriatric patients. The drug should be administered to patients in coma, shock, or with signiﬁcant respiratory depres-sion very cautiously. It is contraindicated in patients with known hypersensitivity to the drug. Diazepam should be used very cau-tiously, if at all, in aggressive patients, as it may disinhibit the anxi-ety that may help prevent these animals from aggressive behavior. Benzodiazepines may impair the abilities of working animals. If ad-ministering the drug IV, be prepared to administer cardiovascular or respiratory support. It is recommended not to use diazepam for seizure control in cats exposed to chlorpyrifos as organophosphate toxicity may be potentiated. Adverse Effects In horses, diazepam may cause muscle fasciculations, weakness and ataxia at doses sufﬁcient to cause sedation. Doses greater than 0. 2 mg/kg may induce recumbency as a result of its muscle relaxant properties and general CNS depressant effects. Cats may exhibit changes in behavior (irritability, depression, aberrant demeanor) after receiving diazepam. There have been reports of cats developing hepatic failure after receiving oral di-azepam (not dose dependent) for several days. Clinical signs (an-orexia, lethargy, increased ALT/AST, hyperbilirubinemia) have been reported to occur 5-11 days after beginning oral therapy. Cats that receive diazepam should have baseline liver function tests. These should be repeated and the drug discontinued if emesis, lethargy, inappetence or ataxia develops. Dogs may exhibit a contradictory response (CNS excitement) following administration of diazepam. The effects with regard to sedation and tranquilization are extremely variable with each dog. Because of this individual variation, diazepam is not an ideal sedat-ing agent for this species. Reproductive/Nursing Safety Diazepam has been implicated in causing congenital abnormalities in humans if administered during the ﬁrst trimester of pregnancy. Infants born of mothers receiving large doses of benzodiazepines shortly before delivery have been reported to suffer from apnea, impaired metabolic response to cold stress, difﬁculty in feeding, hyperbilirubinemia, hypotonia, etc. Withdrawal symptoms have occurred in infants whose mothers chronically took benzodiaz-epines during pregnancy. The veterinary signiﬁcance of these ef-fects is unclear, but the use of these agents during the ﬁrst trimester of pregnancy should only occur when the beneﬁts clearly outweigh the risks associated with their use. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, but the potential beneﬁts from the use of the drug	pppbs.pdf
276 DIAZEPAM in pregnant women may be acceptable despite its potential risks. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should be used cautiously as a last resort when the beneﬁt of therapy clearly outweighs the risks. ) Benzodiazepines and their metabolites are distributed into milk and may cause CNS effects in nursing neonates. Overdosage/Acute Toxicity When administered alone, diazepam overdoses are generally limited to signiﬁcant CNS depression (confusion, coma, decreased reﬂexes, etc. ). Hypotension, respiratory depression, and cardiac arrest have been reported in human patients, but apparently are quite rare. Treatment of acute toxicity consists of standard protocols for re-moving and/or binding the drug in the gut if taken orally, and sup-portive systemic measures. The use of analeptic agents (CNS stimu-lants such as caffeine) is generally not recommended. Flumazenil may be considered for adjunctive treatment of overdoses of benzo-diazepines. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving diazepam and may be of signiﬁcance in veterinary patients: !TAMITRIPTYLINE : Diazepam may increase levels !TANTACIDS : May decrease oral diazepam absorption !TANTIFUNGALS, AZOLE (itraconazole, ketoconazole, etc. ): May increase diazepam levels !TCIMETIDINE : May decrease metabolism of benzodiazepines !TCNS DEPRESSANT D RUGS (barbiturates, narcotics, anesthetics, etc. ): If diazepam administered with other CNS depressant agents addi-tive effects may occur !TDEXAMETHASONE : May decrease diazepam levels !TDIGOXIN : Diazepam may increase digoxin levels !TERYTHROMYCIN : May decrease the metabolism of benzodiazepines !TMINERAL OIL : May decrease oral diazepam absorption !TPHENOBARBITAL : May decrease diazepam concentrations !TPHENYTOIN : May decrease diazepam concentrations !TQUINIDINE : May increase diazepam levels !TRIFAMPIN : May induce hepatic microsomal enzymes and decrease the pharmacologic effects of benzodiazepines Laboratory Considerations !TPatients receiving diazepam, may show false negative urine glucose results if using Diastix® or Clinistix® tests. Doses !TDOGS: For treatment of seizures: a) For cluster seizures or status epilepticus (for client treatment at home): If on phenobarbital, use diazepam at 2 mg/kg (us-ing diazepam parenteral solution) per rectum. Administer at the onset of seizure and up to 3 times in a 24-hour period, but should not be given within 10 minutes of the prior dose. Owners should stay with dog for one hour after administra-tion. (Podell 2000), (Podell 2006b) b) For refractory status epilepticus using constant rate IV infu-sion: 0. 1-0. 5 mg/kg diluted in D5W. Rate administered per hour should be equal to the maintenance ﬂuid requirement for the patient. Use with caution as diazepam can crystallize in solution and adsorb to PVC tubing. For status or cluster seizure treatment at home: 0. 5-2 mg/kg per rectum (Platt and Mc Donnell 2000) c) For status epilepticus: 0. 5-1 mg/kg IV, 1-2 mg/kg per rec-tum; may need to be re-dosed, a long-acting anticonvulsant (e. g., phenobarbital) must be administered to gain complete control. (Knipe 2006b) d) For metaldehyde, strychnine, or brucine induced seizures/ tremors: 2-5 mg/kg IV (Bailey 1986a) e) For methylxanthine (e. g., theophylline) induced seizures: 0. 5-2 mg/kg IV (if unsuccessful, use phenobarbital at 6 mg/ kg IV q6-12h) (Hooser and Beasley 1986) f) For salicylate toxicity induced seizures: 2. 5-20 mg (total dose) IV or PO (Handagama 1986) g) Seizures secondary to CNS trauma: 0. 25-0. 5 mg/kg IV (Fenner 1986) For white shaker dog syndrome: a) 0. 25 mg/kg PO three to four times daily (Morgan 1988) For Scotty cramp: a) 0. 5-2 mg/kg IV to effect or PO three times daily (Morgan 1988) As a preanesthetic: a) 0. 1 mg/kg IV slowly (Morgan 1988) For irritable colon syndrome: a) 0. 15 mg/kg PO three times daily (Morgan 1988) For functional urethral obstruction/urethral sphincter hypertonus: a) 2-10 mg q8h (Polzin and Osborne 1985); (Lane 2000) b) 2-10 mg PO three times a day; 0. 5 mg/kg IV (Chew, Di Bar-tola, and Fenner 1986) c) 0. 2 mg/kg PO q8h or 2-10 mg (total dose) PO q8h (Bartges 2003a) As a restraining agent/sedative: a) 0. 2-0. 6 mg/kg IV (Morgan 1988) b) 0. 25 mg/kg PO q8h (Davis 1985a) For separation anxiety: a) 0. 5-2. 2 mg/kg PO as needed (Morgan 1988) For adjunctive treatment of metronidazole toxicity (CNS): a) Doses of diazepam averaged 0. 43 mg/kg in the study and were given as an IV bolus once, and then PO q8h for 3 days. (Evans, Levesque et al. 2002) !TCATS: As an appetite stimulant: a) 0. 05-0. 15 mg/kg IV once daily to every other day or 1 mg PO once daily (Morgan 1988) b) 0. 05-0. 4 mg/kg IV, IM or PO. After IV administration, eat-ing may begin in a few seconds; have food readily available. (Booth 1988a) Urine marking and anxiety: a) 0. 2-0. 4 mg/kg PO q12-24h (start at 0. 2 mg/kg PO q12h) (Overall 2000) b) For spraying: 1-2. 5 mg per cat PO q8-12h; sedation and ataxia should abate within several days (Reisner and Houpt 2000) For adjunctive treatment of feline psychogenic alopecia and dermatitis: a) 1-2 mg PO twice daily (Walton 1986)	pppbs.pdf
DIAZEPAM 277 For treatment of seizure disorders: a) 0. 25-0. 5 mg/kg PO q8-12h. T o halt an ongoing seizure, di-azepam may be administered at 0. 5-1 mg/kg IV. If cat has a history of receiving insulin, glucose may be more beneﬁcial. Do not use if cat has been exposed to chlorpyrifos as organo-phosphate toxicity may be potentiated. (Shell 2000) b) For oral maintenance therapy of seizures: As a second choice drug (after phenobarb): 0. 5-1 mg/kg PO q12h (Quesnel 2000) c) 0. 5-1 mg/kg/day PO dose is divided every 8-12 hours. Drug has a wide margin of safety and dosages as high as 2 mg/kg may be required in some cats. (Munana 2004c) d) For salicylate toxicity induced seizures: 2. 5-5 mg IV or PO (Handagama 1986) Functional urethral obstruction/urethral sphincter hypertonus: a) 1-2. 5 mg (total dose) PO q8h (Osborne, Kruger et al. 2000) b) 1-2. 5 mg (total dose) PO q8h OR 0. 5 mg/kg IV (Lane 2000) c) 2. 5-5 mg (total dose) PO q8h or as needed, or 0. 5 mg/kg IV (Bartges 2003a) !TFERRETS: For premedication/sedation: a) 1-2 mg/kg IM; may be given with ketamine (10-20 mg/kg) (Morrisey and Carpenter 2004) !TRABBITS/RODENTS/SMALL MAMMALS: a) Rabbits: Pre-anesthetic: 2-10 mg/kg IM; 1-5 mg/kg IM or IV. Give IV to effect for seizures. (Ivey and Morrisey 2000) b) Rabbits: As a tranquilizer (to increase relaxation of lightly anesthetized animals and permit ET intubation): 1 mg/kg IV as needed (Huerkamp 1995) c) Hamsters, Gerbils, Mice, Rats: 3-5 mg/kg IM. Guinea pigs: 0. 5-3 mg/kg IM (Adamcak and Otten 2000) !TCATTLE: a) Sedative in calves: 0. 4 mg/kg IV (Booth 1988a) b) As a tranquilizer: 0. 55-1. 1 mg/kg IM (Lumb and Jones 1984) c) Treatment of CNS hyperactivity and seizures: 0. 5-1. 5 mg/kg IM or IV (Bailey 1986b) !THORSES: (Note : ARCI UCGFS Class 2 Drug) For ﬁeld anesthesia: a) Sedate with xylazine (1 mg/kg IV; 2 mg/kg IM) given 5-10 minutes (longer for IM route) before induction of anesthe-sia with ketamine (2 mg/kg IV). Horse must be adequately sedated (head to the knees) before giving the ketamine (ket-amine can cause muscle rigidity and seizures). If adequate sedation does not occur, either 1) Redose xy-lazine: up to half the original dose; 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; 3) Diazepam (0. 03 mg/kg IV). Mix the diazepam with the ketamine. This combination will improve induction when sedation is marginal, improve muscle re-laxation during anesthesia and prolong anesthesia by about 5-10 minutes; 4) Guaifenesin (5% solution administered IV to effect) can also be used to increase sedation and muscle relaxation. (Mathews 1999) For seizures: a) Foals: 0. 05-0. 4 mg/kg IV; repeat in 30 minutes if necessary b) Adults: 25-50 mg IV; repeat in 30 minutes if necessary (Sweeney and Hansen 1987) Treatment of seizures secondary to intra-arterial injection of xy-lazine or other similar agents: a) 0. 10-0. 15 mg/kg IV (Thurmon and Benson 1987) As an appetite stimulant: a) 0. 02 mg/kg IV; immediately after dosing, offer animal food. Keep loud noises and distractions to a minimum. If effective, usually only 2-3 treatments in a 24-48 hour period are re-quired. (Ralston 1987) !TSWINE: For tranquilization: a) 5. 5 mg/kg IM (will develop posterior ataxia in 5 minutes and then recumbency within 10 minutes) (Booth 1988a) b) 0. 55-1. 1 mg/kg IM (Lumb and Jones 1984) c) For sedation prior to pentobarbital anesthesia: 8. 5 mg/kg IM (maximized at 30 minutes; reduces pentobarbital dose by 50%) (Booth 1988a) For treatment of CNS hyperactivity and seizures: a) 0. 5-1. 5 mg/kg IM or IV (Howard 1986) !TSHEEP: As a tranquilizer: a) 0. 55-1. 1 mg/kg IM (Lumb and Jones 1984) !TGOATS: For Bermuda grass induced toxicosis and tremors: a) 0. 8 mg/kg IV (Booth 1988a) T o stimulate appetite: a) 0. 04 mg/kg IV; offer food immediately, duration of effect may last up to 45 minutes (Booth 1988a) !TBIRDS: For adjunctive therapy of pain control (with analgesics): a) 0. 5-2 mg/kg IV or IM (Clyde and Paul-Murphy 2000) Monitoring !THorses should be observed carefully after receiving this drug. !TCats receiving diazepam should have baseline liver function tests. Repeat and discontinue drug if emesis, lethargy, inappetence, or ataxia develop. When used for seizure control in cats, one author (Quesnel 2000) recommends obtaining serum level 5 days after beginning therapy. Goal is to achieve levels in the therapeutic range of 500-700 nmol/L (500-700 ng/m L). Client Information !TKeep out of reach of children and in tightly closed containers !TCats: If patient develops lack of appetite, vomits, or yellowish whites of eyes contact veterinarian immediately Chemistry/Synonyms A benzodiazepine, diazepam is a white to yellow, practically odor-less crystalline powder with a melting point between 131°-135°C and p K a of 3. 4. Diazepam is tasteless initially, but develops a bitter after-taste. One gram is soluble in 333 m L of water, 25 m L of alco-hol, and it is sparingly soluble in propylene glycol. The p H of the commercially prepared injectable solution is adjusted with benzoic acid/sodium benzoate to 6. 2-6. 9. It consists of a 5 mg/m L solution with 40% propylene glycol, 10% ethanol, 5% sodium benzoate/ benzoic acid buffer, and 1. 5% benzyl alcohol as a preservative. Diazepam may also be known as: diazepamum, LA-III, NSC-77518, or Ro-5-2807; many trade names are available.	pppbs.pdf
278 DIAZOXIDE Storage/Stability/Compatibility All diazepam products should be stored at room temperature (15°-30°C). The injection should be kept from freezing and pro-tected from light. The oral dosage forms (tablets/capsules) should be stored in tight containers and protected from light. Because diazepam may adsorb to plastic, it should not be stored drawn up into plastic syringes. The drug may also signiﬁcantly ad-sorb to IV solution plastic (PVC) bags and to the infusion tubing. This adsorption appears to be dependent on several factors (tem-perature, concentration, ﬂow rates, line length, etc. ). The manufacturers of injectable diazepam do not recommend the drug be mixed with any other medication or IV diluent. The drug has been successfully diluted to concentrations of 5 mg/50 m L or 5 mg/100 m L in normal saline, lactated Ringer's and D 5W. Differing results have occurred with different manufacturer's prod-ucts. Do not administer if a precipitate forms and does not clear. While mixing diazepam with ketamine in a single syringe is not recommended, it is often done in veterinary medicine with apparent success; however, it should be used immediately after mixing and excess medication should not be saved. Do not use if a visible pre-cipitate forms. 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: Diazepam Tablets: 2 mg, 5 mg, & 10 mg; Valium® (Roche); generic; (Rx, C-IV) Diazepam Oral Solution: 1 mg/m L in 30 m L with dropper, 500 m L, and 5 mg and 10 mg patient cups; generic, Diazepam Intensol® (Rox-ane); (Rx, C-IV) Diazepam Injection: 5 mg/m L in 2 m L Carpuject cartridges; generic; (Rx, C-IV) Diazepam Rectal Gel: 2. 5 mg, 10 mg, 20 mg; Diastat® (Xcel); (Rx, C-IV) DIAZOXIDE, ORAL (di-az-ok-side) Proglycem®, Hyperstat IV® DIRECT V ASODILATOR/HYPERGLYCEMIC Prescriber Highlights TT Orally administered drug used to treat insulinomas in small animals TT Contraindications/Cautions: Functional hypoglycemia or hypoglycemia secondary to insulin overdosage (diabet-ics); hypersensitive to thiazide diuretics; CHF or renal disease TT Adverse Effects: Most likely are anorexia, vomiting &/ or diarrhea (may be reduced by giving with food). Less likely: tachycardia, hematologic abnormalities, diabetes mellitus, cataracts, & sodium & water retention. Adverse effects are more likely in dogs with hepatic disease. TT Availability & expense issues Uses/Indications Oral diazoxide is used in canine and ferret medicine for the treat-ment of hypoglycemia secondary to hyperinsulin secretion (e. g., in-sulinoma). Insulinomas are apparently very rare in the cat; there is little experience with this drug in that species. In human medicine, intravenous diazoxide is sometimes used for treating severe hypertension. Pharmacology/Actions Although related structurally to the thiazide diuretics, diazoxide does not possess any appreciable diuretic activity. By directly caus-ing a vasodilatory effect on the smooth muscle in peripheral arte-rioles, diazoxide reduces peripheral resistance and blood pressure. T o treat malignant hypertension, intravenous diazoxide is generally required for maximal response. Diazoxide exhibits hyperglycemic activity by directly inhibiting pancreatic insulin secretion. This action may be a result of the drug's capability to decrease the intracellular release of ionized calcium, thereby preventing the release of insulin from the insulin granules. Diazoxide does not apparently affect the synthesis of insulin, nor does it possess any antineoplastic activity. Diazoxide also enhances hyperglycemia by stimulating the beta-adrenergic system thereby stimulating epinephrine release and inhibiting the uptake of glucose by cells. Pharmacokinetics The serum half-life of diazoxide has been reported to be about 5 hours in the dog; other pharmacokinetic parameters in the dog ap-pear to be unavailable. In humans, serum diazoxide (at 10 mg/kg PO) levels peaked at about 12 hours after dosing with capsules. It is unknown what blood levels are required to obtain hyperglyce-mic effects. Highest concentrations of diazoxide are found in the kidneys with high levels also found in the liver and adrenal glands. Approximately 90% of the drug is bound to plasma proteins and it crosses the placenta and into the CNS. It is not known if diazoxide is distributed into milk. Diazoxide is partially metabolized in the liver and is excreted as both metabolites and unchanged drug by the kidneys. Serum half-life of the drug is prolonged in patients with renal impairment. Contraindications/Precautions/Warnings Diazoxide should not be used in patients with functional hypo-glycemia or for treating hypoglycemia secondary to insulin overdos-age in diabetic patients. Unless the potential advantages outweigh the risks, do not use in patients hypersensitive to thiazide diuretics. Because diazoxide can cause sodium and water retention, use cautiously in patients with congestive heart failure or renal disease. Adverse Effects When used to treat insulinomas in dogs, the most commonly seen adverse reactions include hypersalivation, anorexia, vomiting and/ or diarrhea; these effects may be lessened by administering the drug with food. Other effects that may be seen include: tachycar-dia, hematologic abnormalities (agranulocytosis, aplastic anemia, thrombocytopenia), diabetes mellitus, cataracts (secondary to hy-perglycemia?), and sodium and water retention. Administering the drug with meals or temporarily reducing the dose may alleviate the gastrointesti nal side effects. Adverse effects may be more readily noted in dogs with concurrent hepatic disease. Adverse effects reported with diazoxide use in ferrets include: in-appetence, vomiting, diarrhea, and bone marrow suppression. The drug is reportedly very bitter.	pppbs.pdf
DIAZOXIDE 279 Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) It is unknown if diazoxide enters milk. Overdosage/Acute Toxicity Acute overdosage may result in severe hyperglycemia and ketoaci-dosis. Treatment should include insulin (see insulin monograph), ﬂuids and electrolytes. Intensive and prolonged monitoring is rec-ommended. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving diazoxide and may be of signiﬁcance in veterinary patients: !TALPHA-ADRENERGIC AGENTS (e. g., phenoxybenzamine ): May decrease the effectiveness of diazoxide in increasing glucose levels !THYPOTENSIVE AGENTS, OTHER (e. g., hydralazine, prazosin, etc. ): Diaz-oxide may enhance the hypotensive actions of other hypotensive agents !TPHENOTHIAZINES (e. g., acepromazine, chlorpromazine ): May enhance the hyperglycemic effects of diazoxide !TPHENYTOIN : Diazoxide may increase the metabolism, or decrease the protein binding of phenytoin !TTHIAZIDE DIURETICS : May potentiate the hyperglycemic effects of oral diazoxide. Some clinicians have recommended using hydro-chlorothiazide (2-4 mg/kg/day PO) in combination with diaz-oxide, if diazoxide is ineffective alone to increase blood glucose levels; Caution: hypotension may occur Laboratory Considerations !TDiazoxide will cause a false-negative insulin response to the glu-cagon-stimulation test. !TDiazoxide may displace bilirubin from plasma proteins Doses !TDOGS: For hypoglycemia secondary to insulin secreting islet cell tumors: a) 10 mg/kg divided twice daily PO with meals; may increase dose up to 60 mg/kg to alleviate signs of hypoglycemia, if tolerated (Lothrop 1989) b) Initially, 5 mg/kg PO twice daily; increase to a maximum of 30 mg/kg PO twice daily to control clinical signs (Meleo and Caplan 2000) c) If after frequent feedings (4-6 small meals per day) and glu-cocorticoids (prednisone 1. 1-4. 4 mg/kg/day) alone fail to control hypoglycemia or dog develops “Cushingoid” appear-ance, add diazoxide (reduce prednisone dose if “Cushin-goid”) initially at 10 mg/kg divided twice a day. May gradu-ally increase dosage to 60 mg/kg/day as tolerated and add hydrochlorothiazide (2-4 mg/kg/day). (Feldman and Nel-son 1987c) For adjunctive therapy of hypoglycemia secondary to insulin se-creting non-islet cell (extra-pancreatic) tumors: a) Diazoxide 5-13 mg/kg PO three times daily (may add hy-drochlorothiazide 2-4 mg/kg/day) (Weller 1988) !TCATS: For hypoglycemia secondary to insulin secreting islet cell tumors: a) Initially, 5 mg/kg PO twice daily; increase to a maximum of 30 mg/kg PO twice daily to control clinical signs (Meleo and Caplan 2000) !TFERRETS: For hypoglycemia secondary to insulin secreting islet cell tumors: a) Initially, 5 mg/kg PO twice daily; increase to a maximum of 30 mg/kg PO twice daily to control clinical signs (Meleo and Caplan 2000) b) Ferrets: 5 mg PO twice daily to start; increase as needed up to 30 mg twice daily. Expensive; use with prednisone (0. 5-2 mg/kg PO or IM) (Williams 2000) c) After surgical resection of pancreatic nodules or partial pan-createctomy: Prednisone at 0. 5-2 mg/kg PO q12h will usu-ally control mild to moderate clinical signs. Begin at lowest dose and gradually increase as needed. Add diazoxide when clinical signs cannot be controlled with prednisone alone. Begin at 5-10 mg/kg PO q12h. At same time prednisone dosage may be lowered. (Johnson 2006c) Monitoring !TBlood (serum) glucose !TCBC (at least every 3-4 months) !TPhysical exam (monitor for clinical signs of other adverse ef-fects—see above) Client Information !TClients should be instructed to monitor for symptoms of hyper- or hypoglycemia, abnormal bleeding, GI disturbances, etc. Chemistry/Synonyms Related structurally to the thiazide diuretics, diazoxide occurs as an odorless, white to creamy-white, crystalline powder with a melting point of about 330°. It is practically insoluble to sparingly soluble in water and slightly soluble in alcohol. Diazoxide may also be known as: diazoxidum, NSC-64198, Sch-6783, SRG-95213, Eudemine®, Glicemin®, Hypertonalum®, Hyperstat IV®, Proglicem®, Sefulken®, or Tensuril®. Storage/Stability/Compatibility Diazoxide capsules and oral suspensions should be stored at 2-30°C and protected from light. Protect solutions/suspensions from freezing. Do not use darkened solutions/suspensions, as they may be subpotent. 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: Finding a supply of oral dosage forms for this medication may be a problem, it may be available from compounding pharmacies. Diazoxide Injection: 15 mg/m L in 20 m L amps; Hyperstat IV® (Schering); (Rx) Also available as 50 mg tablets in the U. K. as Eudemine® (Allan and Hanburys)	pppbs.pdf
280 DICHLORPHENAMIDE DICHLORPHENAMIDE (dye-klor-fen-a-mide) Daranide® CARBONIC ANHYDRASE INHIBITOR Prescriber Highlights TT Used primarily for open angle glaucoma TT Contraindicated in patients with signiﬁcant hepatic, renal, pulmonary or adrenocortical insufﬁciency, hyponatremia, hypokalemia, hyperchloremic acidosis or electrolyte imbalance TT Give oral doses with food if GI upset occurs TT Monitor with tonometry for glaucoma; check electrolytes TT Availability issues; may need to be obtained from a com-pounding pharmacy Uses/Indications Dichlorphenamide is used for the medical treatment of glaucoma. Because of availability issues and toxic effects associated with sys-temic therapy, human (and many veterinary) ophthalmologists are using topical carbonic anhydrase inhibitors (e. g., dorzolamide or brinzolamide) in place of acetazolamide, dichlorphenamide or met-hazolamide. 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; and anticonvulsant activity, which is independent of its diuretic effects (mechanism not fully understood, but may be due to carbonic anhydrase or a metabolic acidosis ef-fect). Pharmacokinetics The pharmacokinetics of this agent have apparently not been stud-ied in domestic animals. One report (Roberts 1985) states that after a dose of 2. 2 mg/kg, the onset of action is 30 minutes, maximal ef-fect in 2-4 hours, and duration of action is 6-12 hours in small animals. 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. 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, CNS effects (sedation, depression, excitement, etc. ), hema-tologic effects (bone marrow depression), renal effects (crystalluria, dysuria, renal colic, polyuria), hypokalemia, hyperglycemia, hy-ponatremia, hyperuricemia, hepatic insufﬁciency, dermatologic ef-fects (rash, etc. ), and hypersensitivity reactions. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category C for use dur-ing pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Overdosage/Acute Toxicity 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 dichlorphenamide and may be of signiﬁcance in veterinary patients: T ! ANTIDEPRESSANTS, TRICYCLIC : Alkaline urine cause by dichlo-rphenamide may decrease excretion T ! ASPIRIN (or other salicylates ): Increased risk of dichlorphenamide accumulation and toxicity; increased risk for metabolic acidosis; dichlorphenamide increases salicylate excretion T ! DIGOXIN : As dichlorphenamide may cause hypokalemia, increased risk for toxicity T ! INSULIN : Rarely, carbonic anhydrase inhibitors interfere with the hypoglycemic effects of insulin T ! METHENAMINE COMPOUNDS : Dichlorphenamide may negate effects in the urine T ! POTASSIUM, DRUGS AFFECTING (corticosteroids, amphotericin B, cor-ticotropin, or other diuretics ): Concomitant use may exacerbate potassium depletion T ! PHENOBARBITAL : Increased urinary excretion, may reduce pheno-barbital levels T ! PRIMIDONE : Decreased primidone concentrations T ! QUINIDINE : Alkaline urine cause by dichlorphenamide may de-crease excretion Laboratory Considerations T ! By alkalinizing the urine, carbonic anhydrase inhibitors may cause false positive results in determining urine protein using bromphe-nol blue reagent (Albustix®, Albutest®, Labstix®), sulfosalicylic acid (Bumintest®, Exton's T est Reagent), nitric acid ring test, or heat and acetic acid test methods. T ! Carbonic anhydrase inhibitors may decrease iodine uptake by the thyroid gland in hyperthyroid or euthyroid patients. Doses T ! DOGS: For adjunctive treatment of glaucoma: a) 2. 2-4. 4 mg/kg PO two to three times daily (q8-12h) (Nasisse 2005), (Milller 2005) b) 10-15 mg/kg per day divided 2-3 times daily (Brooks 2002b) c) 2-5 mg/kg PO q8-12h (Wilkie 2003) T ! CATS: For adjunctive treatment of glaucoma: a) 0. 5-1. 5 mg/kg PO two to three times daily (Powell 2003) b) 1-2 mg/kg PO q8-12h (Milller 2005)	pppbs.pdf
DICHLORVOS 281 Monitoring T ! Intraocular pressure/tonometry T ! Serum electrolytes T ! Baseline CBC with differential and periodic retests if using chronically T ! Other adverse effects Client Information T ! If GI upset occurs, give with food. T ! Notify veterinarian if abnormal bleeding or bruising occurs or if animal develops tremors or a rash. Chemistry/Synonyms A carbonic anhydrase inhibitor, dichlorphenamide occurs as a white or nearly white, crystalline powder with a melting range of 235-240°C, and p K as of 7. 4 and 8. 6. It is very slightly soluble in water and soluble in alcohol. Dichlorphenamide may also be known as: dichlorphenamide, diclofenamidum, Antidrasi®, Fenamide®, Glaucol®, Glauconide®, Glaumid®, Oralcon®, Oratrol®, or Tensodilen®. Storage/Stability Store tablets in well-closed containers and at room temperature. An expiration date of 5 years after the date of manufacture is assigned to the commercially available tablets. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: None Dichlorphenamide availability has been an issue and it may not be available commercially; if not, contact a compounding pharmacy for information. DICHLORVOS (dye-klor-vose) Atgard® ORGANOPHOSPHATE ANTIPARASITIC Prescriber Highlights TT Organophosphate used orally as a wormer (primarily roundworms) in pigs & as ectoparasiticide (“No Pest Strip”) for small mammals, etc. TT Contraindications: Anticholinesterase drugs; do not allow fowl access to medicated feed or manure from treated animals TT Adverse Effects (dose related): Vomiting, tremors, brady-cardia, respiratory distress, hyperexcitability, salivation, & diarrhea TT Drug Interactions Uses/Indications Dichlorvos is effective in swine against Ascaris, Trichuris, Ascarops strongylina and Oesophagostomum spp. Dichlorvos as a “No Pest Strip” is used as an ectoparasiticide for small mammals. It is also used as a premise spray to keep ﬂy popu-lations controlled. In horses, dichlorvos is labeled as being effective for the treat-ment and control of bots, pinworms, large and small bloodworms, and large roundworms, but no systemic equine products are cur-rently being marketed in the USA. Dichlorvos was available for use internally in dogs and cats for the treatment of roundworms and hookworms, but no products are currently being marketed since newer, safer and more effective anthelmintics have replaced dichlorvos. Pharmacology/Actions Like other organophosphate agents, dichlorvos inhibits acetylcho-linesterase interfering with neuromuscular transmission in suscep-tible parasites. Pharmacokinetics Speciﬁc information was not located for this agent. Contraindications/Precautions/Warnings For the product (Atgard®) for use in swine, no absolute contrain-dications are labeled, but it should not be used within a few days of any other cholinesterase inhibiting drug, pesticide or chemical. Do not allow fowl access to medicated feed or manure from treated animals. Unused medication or medicated feed should be buried 18 inch-es below the ground and covered so that it is unavailable to any other animal. Avoid contact with the skin and keep out of reach of children. Adverse Effects When used as labeled, the are no listed adverse effects in swine. Adverse effects are generally dose-related and may include those listed below in the Overdosage/Acute T oxicity section. Reproductive/Nursing Safety Studies performed in target species have demonstrated no terato-genic effects at usual doses. In pigs, no effects have been noted on reproductive capability, performance or litter survivability. Overdosage/Acute Toxicity If overdoses occur, vomiting, tremors, bradycardia, respiratory dis-tress, hyperexcitability, salivation, and diarrhea may occur. Atropine (see atropine and pralidoxime monographs for more information) may be antidotal. Use of succinylcholine, theophylline, amino-phylline, reserpine, or respiratory depressant drugs (e. g., narcotics, phenothiazines) should be avoided in patients with organophos-phate toxicity. If ingestion occurs by a human, contact a poison control center, physician, or hospital emergency room. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dichlorvos and may be of signiﬁcance in veterinary patients: T ! ACEPROMAZINE or other phenothiazines : Should not be given with-in one month of worming with an organophosphate agent as their effects may be potentiated T ! ANTICHOLINESTERASE DRUGS (e. g., neostigmine, physostigmine, and pyridostigmine ): Avoid use when using organophosphates as they can inhibit cholinesterase T ! DMSO : Because of its anticholinesterase activity, avoid the use of organophosphates with DMSO T ! MORPHINE : Avoid use when using organophosphates as it can in-hibit cholinesterase T ! PYRANTEL PAMOATE (or tartrate ): Adverse effects could be intensi-ﬁed if used concomitantly with an organophosphate	pppbs.pdf
282 DICLAZURIL T ! SUCCINYLCHOLINE : Patients receiving organophosphate anthelm-intics should not receive succinylcholine or other depolarizing DICLAZURIL muscle relaxants for at least 48 hours (dye-klaz-yoor-il) Protazil®, Clinicox® Doses ANTIPROTOZOAL T ! RABBITS/RODENTS/SMALL MAMMALS: a) Mice, Rats, Gerbils, Hamsters, Guinea pigs, Chinchillas: Hang 5 cm of a dichlorvos strip (e. g., Vapona No Pest Strip) 6 inches Prescriber Highlights above cage for 24 hours, twice weekly for 3 weeks (Anderson TT Approved (in USA) for EPM in horses & as a coccidiostat 1994); (Adamcak and Otten 2000) or hang in room for 24 in broiler chickens hours once a week for 6 weeks or a 1 inch square laid on cage TT Adverse effect proﬁle not well known for 24 hours once a week for 6 weeks (Adamcak and Otten 2000) T ! SWINE: Uses/Indicationsa) For Atgard® Swine Wormer: Dosing for pigs is accomplished by Diclazuril is indicated for the treatment of equine protozoal myelo-adding to feed (crumble-type or dry meal). Speciﬁc amounts encephalitis (EPM) caused by Sarcocystis neurona and as a coccid-of feed per packet are dependent on pig weight. See the label iostat in broiler chickens. for speciﬁc recommendations. Diclazuril could potentially be useful in treating coccidiosis, Neospora caninum and T oxoplasma infections in dogs or cats. Monitoring T ! Efﬁcacy Pharmacology/Actions T ! Adverse effects The triazine class of antiprotozoals are believed to target the “plas-tid” body, an organelle found in the members of the Apicomplexa Client Information phylum, including Sarcocystis neurona. The actual mechanism of ac-T ! Keep out of reach of children. Handling of dichlorvos liquid prep-tion is not well described. In vitro levels required to inhibit (95%) arations (e. g., premise spray) must be done with extreme care; fol-Sarcocystis neurona are about 1 ng/m L. low all label directions! T ! Oral pellets are non-digestible and may be seen in the animals' Pharmacokinetics feces. In horses, oral bioavailability is about 5%. CSF levels are approxi-mately 1-5% of those found in plasma. Elimination half-life is Chemistry/Synonyms prolonged (43-65 hours). Doses of 1 mg/kg/day should give mean An organophosphate insecticide, dichlorvos may also known as: steady-state plasma levels of about 2-2. 5 mg/m L with correspond-2,2,-dichlorovinyl dimethyl phosphate DDVP, NSC-6738, OMS-14, ing CSF levels of 20-70 ng/m L which is in excess of the in vitro IC95SD-1750, Atgard®, or Ravap E. C. ®. (1 ng/m L). Storage/Stability Contraindications/Precautions/Warnings Store Atgard® swine wormer at less than 80°F. Dichlorvos feed addi-The drug is contraindicated in patients known to be hypersensitive tives should not be stored at temperatures below freezing. Dichlorvos to diclazuril. is sensitive to hydrolysis if exposed to moisture or oxidizing agents. The safe use of Protazil® in horses used for breeding purposes, during pregnancy, in lactation, or with other therapies has not been Dosage Forms/Regulatory Status evaluated. VETERINARY-LABELED PRODUCTS: Adverse Effects Dichlorvos Feed Additives: Atgard® C (Boehringer Ingelheim); The adverse effect proﬁle in horses is not well known. In ﬁeld trials, (OTC); Atgard® Swine Wormer (Boehringer Ingelheim); (OTC). no adverse effects could be ascribed to the drug. When used as labeled there are no slaughter withdrawal times re-quired in swine. Reproductive/Nursing Safety Dichlorvos with T etrachlorvinphos (Rabon®) Premise and T opical The manufacturer states that the safe use of Protazil® in horses used Insecticide: Ravap E. C. ® (Boehringer Ingelheim); (OTC) for breeding purposes, during pregnancy, or in lactation has not been evaluated. Dichlorvos may also be found in premise insecticidal products. HUMAN-LABELED PRODUCTS: None Overdosage/Acute Toxicity Limited information is available, but the drug appears to have large safety margin in normal horses. Normal horses dosed up to 50 mg/ kg/day (50X) for 42 days developed only marginal effects (decreased weight gain, increased creatinine, BUN). Drug Interactions None were noted. The manufacturer states that the safety of Protazil® with concomitant therapies in horses has not been evaluated. Laboratory Considerations None were noted.	pppbs.pdf
DICLOFENAC SODIUM 283 Doses T ! HORSES: a) For treatment of equine protozoal myeloencephalitis (S. neurona): Using the oral pellets and the provided cup: T op dress at the rate of 1 mg/kg bodyweight for 28 days. If horse's bodyweight is in between two graduations on the dosing cup, ﬁll the cup to the higher of the two marks. (Label informa-tion; Protazil®—Schering-Plough) T ! DOGS /CATS: a) For coccidiosis: 25 mg/kg PO once. (Greene, Hartmannn et al. 2006) Monitoring T ! Clinical efﬁcacy (neuro exams) Client Information T ! Must be dosed daily as prescribed to be effective T ! Will not necessarily return a horse to “normal” Chemistry/Synonyms Diclazuril occurs as a white to light yellow powder. It is practically insoluble in water and alcohol. Diclazuril may also be known as diclazurilo, diclazurilum, R 64433 and by the trade names, Clinicox®, Protazil®, and Vecoxan®. Storage/Stability/Compatibility Diclazuril pellets should be stored at room temperature (15-30°C). Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Diclazuril Oral Pellets 1. 56% in 2 lb. and 10 lb. containers: Protazil® (Schering-Plough); (Rx) Approved for use in horses not intended for food. One 2 lb. bucket will treat an 1100 lb. horse for 28 days. Note : At the time this monograph was written (Summer 2007), this product was approved, but not yet marketed. Diclazuril 0. 2% Type A Medicated Feed Article in 50 lb. containers; Clinicox® (Schering-Plough). Approved for use in broiler chickens. HUMAN-LABELED PRODUCTS: None DICLOFENAC SODIUM (dye-kloe-fen-ak) Surpass® NON-STEROIDAL ANTIINFLAMMATORY (NSAID) Prescriber Highlights TT NSAID approved for topical use in horses for local control of joint pain & inﬂammation TT Appears well-tolerated at recommended dosage Uses/Indications The equine topical cream (Surpass®) is labeled for the control of pain and inﬂammation associated with osteoarthritis in tarsal, car-pal, metacarpophalangeal, metarsophalangeal, and proximal inter-phalangeal (hock, knee, fetlock, pastern) joints for use up to 10 days duration. While, theoretically, diclofenac could be used systemically (orally) in other veterinary species, there are approved and safer alternatives. Pharmacology/Actions Diclofenac is a non-speciﬁc inhibitor of cyclooxygenase (both COX-1 and COX-2). It may also have some inhibitory effects on li-pooxygenase. By inhibiting COX-2 enzymes, diclofenac reduces the production of prostaglandins associated with pain, hyperpyrexia, and inﬂammation. Pharmacokinetics When diclofenac is administered topically to horses via the 1% li-posomal cream, it is absorbed locally, but speciﬁc bioavailability data was not located. Peak levels in transudate obtained from tissue cages were about 80 ng/m L; levels stay increased from 6 hours to at least 18 hours after administration. At the dosages recommended for the topical cream, most of the drug remains in the tissues local to the administration point, but detectable levels in the systemic circulation may occur. In humans, diclofenac is more than 99% bound to plasma proteins. It is metabolized in the liver and the me-tabolites are excreted primarily into the urine. Contraindications/Precautions/Warnings T opical diclofenac should not be used in horses hypersensitive to it or any component of the cream. It has not been evaluated in horses less than one year old. Exceeding the recommended dosage or treating multiple joints may cause adverse effects. Adverse Effects The topical cream in horses appears to be well tolerated. One case of a horse developing colic during therapy has been reported. Other adverse effects that may be seen include weight loss, gastric ulcers, diarrhea, or uterine discharge. In the FDA 's adverse reaction data-base local reactions (inﬂammation, swelling, alopecia) have been reported. Reproductive/Nursing Safety Reproductive safety for topical diclofenac has not been investigated in breeding, pregnant or lactating horses. Overdosage/Acute Toxicity When overdoses are administered topically to horses, adverse ef-fects may occur including weight loss, gastric ulcers, colic, diarrhea, and uterine discharge. Treatment is supportive. For small animals, there were 255 exposures to diclofenac sodi-um reported to the ASPCA Animal Poison Control Center (APCC; www. apcc. aspca. org ) during 2000-2006. In these cases 241 were dogs with 24 showing clinical signs, 12 reported cat exposures with no reported clinical signs, and the remaining 2 cases were birds with no reported clinical signs. Common ﬁndings in dogs recorded in decreasing frequency included vomiting, diarrhea, bloody diarrhea, melena and polydipsia. This medication is a NSAID. As with any NSAID, overdosage can lead to gastrointestinal and renal effects. Decontamination with emetics and/or activated charcoal is appropriate. For doses where GI effects are expected, the use of gastrointestinal protectants is warrant-ed. If renal effects are also expected, ﬂuid diuresis is warranted. Drug Interactions When used topically at recommended dosages, there are no report-ed drug interactions in horses. Laboratory Considerations No speciﬁc laboratory interactions or considerations were noted.	pppbs.pdf
284 DICLOXACILLIN SODIUM Doses HORSES:T ! DICLOXACILLIN SODIUM a) For the control of pain and inﬂammation associated with osteoarthritis in tarsal, carpal, metacarpophalangeal, metar-(di-klox-a-sill-in) Dynapen® sophalangeal, and proximal interphalangeal (hock, knee, fet-ANTI-STAPHYLOCOCCAL PENICILLIN lock, pastern) joints using Surpass® topical cream: Apply a ﬁve inch ribbon twice daily over the affected joint for up to 10 Prescriber Highlights days. Wear rubber gloves and rub cream thoroughly into the hair covering the joint until cream disappears. (Label infor-Oral isoxazolyl (anti-staphylococcal) penicillin TT mation; Surpass®—Idexx) Contraindications: hypersensitivity to penicillins; do not TT Monitoring Efﬁcacy T ! use oral medications in critically ill patients Most predominant adverse effects are GI in nature TT Adverse effects T ! Must dose orally quite often (q6TT-8h); expense, efﬁcacy & owner compliance may be issues Client Information Clients should be instructed to use as directed, not to increase the T ! dose (area applied) or duration (not too exceed 10 days), or ad-Uses/Indications verse effects may occur. The veterinary use of dicloxacillin has been primarily in the PO Clients should wear protective gloves (non-permeable) when ap-T ! treatment of bone, skin, and other soft tissue infections in small plying the cream. animals when penicillinase-producing Staphylococcus species have A client information sheet is supplied with the medication and T ! been isolated. Because of its low oral bioavailability and short half-should be given to the client. life, other drugs with good staph coverage are usually employed. Chemistry/Synonyms Pharmacology/Actions A phenyl-acetic acid derivative non-steroidal antiinﬂammatory Cloxacillin,dicloxacillin and oxacillin have nearly identical spectrums agent, diclofenac sodium occurs as a white to off-white, hygroscopic, of activity and can be considered therapeutically equivalent when crystalline powder. It is sparingly soluble in water, soluble in alcohol comparing in vitro activity. These penicillinase-resistant penicillins and practically insoluble in chloroform and ether. have a narrower spectrum of activity than the natural penicillins. Diclofenac may also be known as: GP-45840, diclofenacum or Their antimicrobial efﬁcacy is aimed directly against penicillinase-diclophenac; many trade names are available for diclofenac products producing strains of gram-positive cocci, particularly Staphylococcal outside of the USA. species. They are sometimes called anti-staphylococcal penicillins. There are documented strains of Staphylococcus that are resistant Storage/Stability/Compatibility to these drugs (so-called methicillin-resistant Staph, MRSA), but Unless otherwise labeled, diclofenac sodium products should be these strains have not yet been a major problem in veterinary spe-stored in airtight containers and protected from light. The commer-cies. While this class of penicillins does have activity against some cially available 1% cream (Surpass®) should be stored at tempera-other gram-positive and gram-negative aerobes and anaerobes, tures up to 25°C (77°F); protect from freezing. other antibiotics (penicillins and others) are usually better choices. Dosage Forms/Regulatory Status The penicillinase-resistant penicillins are inactive against Rickettsia, mycobacteria, fungi, Mycoplasma and viruses. VETERINARY-LABELED PRODUCTS: Diclofenac sodium (liposomal) 1% topical cream in 124 gram tubes, Pharmacokinetics Surpass® (Idexx); (Rx). Approved for use in horses. Dicloxacillin is only available in oral dosage forms. Dicloxacillin so-dium is resistant to acid inactivation in the gut but is only partially HUMAN-LABELED PRODUCTS: absorbed. The bioavailability after oral administration in dogs is Diclofenac Tablets: 50 mg (as potassium); Cataﬂam® (Novartis); ge-only about 23% and in humans has been reported to range from neric; (Rx) 35-76%. If given with food, both the rate and extent of absorption Diclofenac Delayed-release Tablets: 25 mg, 50 mg, 75 mg & 100 mg is decreased. (as sodium); Voltaren-XR® (Novartis); generic; (Rx) The drug is distributed to the liver, kidneys, bone, bile, pleural, Diclofenac Sodium Gel: 3% (1 g contains 30 mg diclofenac sodium) with benzyl alcohol in 25 g & 50 g; Solaraze® (Skye Pharma); (Rx) synovial and ascitic ﬂuids. However, one manufacturer states that levels of the drug that are achieved in ascitic ﬂuid are not clinically therapeutic. As with the other penicillins, only minimal amounts are Diclofenac Sodium/Misoprostol Tablets: (each tablet consists of an distributed into the CSF. In humans, approximately 95-99% of the enteric-coated core containing diclofenac sodium surrounded by an drug is bound to plasma proteins. outer mantle containing misoprostol) 50 mg/misoprostol 200 mcg Dicloxacillin is partially metabolized to both active and inactive & 75 mg/misoprostol 200 mcg; Arthrotec® (Searle) (Rx) metabolites. These metabolites and the parent compound are rap-Diclofenac sodium is also approved as a topical ophthalmic agent idly excreted in the urine via both glomerular ﬁltration and tubular (see the ophthalmology drug appendix). secretion mechanisms. A small amount of the drug is also excreted in the feces via biliary elimination. The serum half-life in humans with normal renal function ranges from about 24-48 minutes. In dogs, 20-40 minutes to 2. 6 hours have been reported as the elimi-nation half-life.	pppbs.pdf
DICLOXACILLIN SODIUM 285 Contraindications/Precautions/Warnings Penicillins are contraindicated in patients with a history of hyper-sensitivity to them. Because there may be cross-reactivity, use peni-cillins cautiously in patients who are documented hypersensitive to other beta-lactam antibiotics (e. g., cephalosporins, cefamycins, carbapenems). Do not administer systemic antibiotics orally in patients with septicemia, shock, or other grave illnesses as absorption of the medi-cation from the GI tract may be signiﬁcantly delayed or diminished. Parenteral (preferably IV) routes should be used for these cases. Adverse Effects Adverse effects with the penicillins are usually not serious and have a relatively low frequency of occurrence. Hypersensitivity reactions unrelated to dose can occur with these agents and can manifest as rashes, fever, eosinophilia, neutropenia, agranulocytosis, thrombocytopenia, leukopenia, anemias, lymph-adenopathy, or full-blown anaphylaxis. In humans, it is estimated that 1-15% of patients hypersensitive to cephalosporins will also be hypersensitive to penicillins. The incidence of cross-reactivity in veterinary patients is unknown. When given orally, penicillins may cause GI effects (anorexia, vomiting, diarrhea). Because the penicillins may also alter gut ﬂora, antibiotic-associated diarrhea can occur and allow the proliferation of resistant bacteria in the colon (superinfections). Neurotoxicity (e. g., ataxia in dogs) has been associated with very high doses or very prolonged use. Although the penicillins are not considered hepatotoxic, elevated liver enzymes have been reported. Other effects reported in dogs include tachypnea, dyspnea, edema, and tachycardia. Reproductive/Nursing Safety Penicillins have been shown to cross the placenta and safe use of them during pregnancy has not been ﬁrmly established, but neither have there been any documented teratogenic problems associated with these drugs. However, use only when the potential beneﬁts outweigh the risks. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although speciﬁc studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) Dicloxacillin is distributed into milk. While safety cannot be as-sured (may alter neonatal gut ﬂora or cause hypersensitivity), it is unlikely to pose much risk to nursing offspring. Overdosage/Acute Toxicity Acute oral penicillin overdoses are unlikely to cause signiﬁcant problems other than GI distress, but other effects are possible (see Adverse Effects). In humans, very high dosages of parenteral peni-cillins, especially in patients with renal disease, have induced CNS effects. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving dicloxacillin and may be of signiﬁcance in veterinary patients: !TAMINOGLYCOSIDES : In vitro evidence of synergism with dicloxacil-lin against S. aureus strains !TCYCLOSPORINE : Dicloxacillin may reduce levels !TPROBENECID : Competitively blocks the tubular secretion of di-cloxacillin, thereby increasing serum levels and serum half-lives !TTETRACYCLINES : Theoretical antagonism; use together usually not recommended !TWARFARIN : Dicloxacillin may cause decreased warfarin efﬁcacy Laboratory Considerations !TAs penicillins and other beta-lactams can inactivate aminoglyco-sides in vitro (and in vivo in patients in renal failure), serum con-centrations of aminoglycosides may be falsely decreased if the patient is also receiving beta-lactam antibiotics and the serum is stored prior to analysis. It is recommended that if the assay is delayed, samples be frozen and, if possible, drawn at times when the beta-lactam antibiotic is at a trough. Doses !TDOGS /CATS: For susceptible infections: a) For localized soft tissue infections or skin infections caused by susceptible (non-beta-lactamase producers) bacteria: 25 mg/kg PO q6h for 14-84 days. (Greene, Hartmannn et al. 2006) b) 27. 5-33 mg/kg PO q8h (Aronson and Aucoin 1989) c) Dogs: For dermatologic infections: 22 mg/kg PO q8h (White 2003a) d) Dogs: For recurrent skin infections: 20-30 mg/kg PO three times daily; food may decrease absorption (Logas 2005b) Monitoring !TBecause penicillins usually have minimal toxicity associated with their use, monitoring for efﬁcacy is usually all that is required unless toxic clinical signs develop. Serum levels and therapeutic drug monitoring are not routinely done with these agents. Client Information !TOwners should be instructed to give oral penicillins to animals with an empty stomach, unless using amoxicillin or if GI effects (anorexia, vomiting) occur. !TCompliance with the therapeutic regimen should be stressed. !TReconstituted oral suspensions should be kept refrigerated and discarded after 14 days. Chemistry/Synonyms An isoxazolyl-penicillin, dicloxacillin sodium is a semisynthetic, penicillinase-resistant penicillin. It is available commercially as the monohydrate sodium salt that occurs as a white to off-white, crystalline powder that is freely soluble in water and has a p K a of 2. 7-2. 8. One mg of dicloxacillin sodium contains not less than 850 micrograms of dicloxacillin. Dicloxacillin Sodium may also be known as: sodium dicloxacillin, dichlorphenylmethyl isoxazolyl penicillin sodium, methyldichloro-phenyl isoxazolyl penicillin sodium, dicloxacilina sodica, dicloxacil-linum natricum, or P-1011; many trade names are available. Storage/Stability Dicloxacillin sodium capsules should be stored at temperatures less than 40°C and preferably at room temperature (15-30°C).	pppbs.pdf
286 DIETHLY CARBAMAZINE CITRATE Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: Dicloxacillin Sodium Capsules: 250 mg & 500 mg; generic; (Rx) DIETHYLCARBAMAZINE CITRATE (dye-ethel-kar-bam-a-zeen) Hetrazan®, DEC Prescriber Highlights TT Piperazine-derivative antiparasiticide used for daily heart-worm prevention & at higher dosages for other parasites TT No veterinary-labeled commercial preparations in USA available TT Contraindications: Dogs with microﬁlaria TT Adverse Effects: Rarely, GI effects; combination product with oxibendazole (no longer marketed) was implicated in causing hepatopathy in dogs Uses/Indications Once the hallmark agent for heartworm disease prophylaxis in dogs, DEC is no longer commercially available in the USA (in oral veteri-nary dosage forms). DEC is approved for use for the prophylaxis of heartworm disease (D. immitis), and/or the treatment of ascariasis in dogs. The drug is also used in ferrets and zoo animals susceptible to heartworm. DEC is used in dogs at higher dosages as alternative therapy for several other parasites (see Dosage section below). Some products were labeled for use in cats to treat ascarid infections. In cats, DEC may help alleviate the course (preventing lympho-ma development) of Fe LV infection. In the U. K., DEC is used as an injectable product to control para-sitic bronchitis (Dictyocaulus viviparous) in sheep and cattle. In humans, DEC is indicated as a ﬁlaricidal for the treatment of Wucheria bancrofti, Brugia malayi, Loa loa, and Onchocerca volvulus. Pharmacology/Actions The exact mechanism of how DEC exerts its anti-ﬁlaricidal (early larval stages of D. immitis) and anti-nematodal effects is not clearly understood. It is believed that DEC acts on the parasite's nervous system in a nicotinic-like fashion, thereby paralyzing it. DEC also has immunomodulatory effects via an unknown mechanism. Pharmacokinetics DEC is rapidly absorbed after oral administration, with peak se-rum levels occurring in about 3 hours. The drug is distributed to all tissues and organs except fat. DEC is rapidly metabolized and is primarily excreted in the urine (70% of a dose within 24 hours) as metabolites or unchanged drug (10-25% of a dose). Contraindications/Precautions/Warnings Diethylcarbamazine is contraindicated in dogs with microﬁlaria, as a shock-like reaction can occur in dogs with microﬁlaria that are treated with DEC. This effect may only be seen in 0. 3-5% of dogs, but the potential seriousness of the reaction precludes its use in all dogs with microﬁlaria. Dogs cleared of adult worms and microﬁ-laria may be started on DEC therapy for prophylaxis. Microﬁlaria detected in dogs that have undergone adulticide and microﬁlaricide therapy, and are receiving DEC prophylaxis, should have the DEC stopped until existing microﬁlaria are eliminated. DEC has been reported to cause infertility problems in male dogs, but these reports are rare. Controlled studies have not found any ad-verse effects on semen volume, p H, sperm counts, or motility. Adverse Effects When used at recommended doses for heartworm prophylaxis, adverse effects are very uncommon for DEC. Some dogs develop diarrhea or vomiting while on the drug, which may necessitate dis-continuation. GI effects are more predominant when used at higher dosages for the treatment of ascarids or other susceptible parasites. Giving with food or soon after eating may alleviate GI disturbances. Case reports of ﬁxed drug eruptions after DEC have also been re-ported in dogs. In microﬁlaria positive dogs that receive DEC, an anaphylactoid reaction can be seen within 20 minutes of dosing. Systems affected or clinical signs seen may include GI (salivation, diarrhea, emesis), CNS (depression, ataxia, prostration, lethargy), shock (pale mucous membranes, weak pulses, tachycardia, dyspnea), hepatic (increased liver enzymes) or DIC. The reaction generally peaks within 1-2 hours after the dose and death can occur. Treatment is basically sup-portive, using ﬂuid therapy and intravenous corticosteroids. Cats have reportedly developed hepatic injury from DEC. Reproductive/Nursing Safety DEC alone is reportedly safe to use in pregnant dogs throughout the gestational period. 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: A (Probably safe. Although speciﬁc studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) Overdosage/Acute Toxicity DEC is considered a relatively non-toxic compound, but quantitative data regarding its toxicity was not found. In dogs, large overdoses generally result in vomiting or depression. Inducement of vomiting or absorption reduction measures (activated charcoal, cathartics) could be considered for very large ingestions. Clinical signs, should they occur, should be handled in a supportive manner. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving DEC and may be of sig-niﬁcance in veterinary patients: T ! NICOTINE-LIKE C OMPOUNDS, OTHER (e. g., pyrantel, morantel, levami-sole): If used with diethylcarbamazine, other nicotine-like com-pounds could theoretically enhance the toxic effects of each other; use with DEC only with intensiﬁed monitoring Doses T ! DOGS: For heartworm prophylaxis: a) 6. 6 mg/kg PO once a day preceding infection and for 60 days following last exposure to mosquitoes. In dogs that become microﬁlaremic while on DEC, may continue, but do not in-terrupt daily DEC therapy. (Knight 1988) b) 6. 6 mg/kg PO daily from beginning of mosquito season and for two months thereafter. Should be given year-round in areas where mosquitoes are active throughout the year. Re-examine 3 months after starting therapy and at 6-month in-tervals for microﬁlaria. (T odd, Paul, and Di Pietro 1985)	pppbs.pdf
DIETHYLSTILBESTROL 287 c) 2. 5-3 mg/kg PO daily; begin prior to mosquito season (Raw-lings and Calvert 1989) d) 5-7 mg/kg PO daily. Begin before infection is likely and con-tinue 60 days after mosquito season. Some areas will require year-round treatment. (Calvert and Rawlings 1986) For treatment of susceptible parasites (other than heartworm— must not be used in microﬁlaria positive patients): a) For ascarids: 55-110 mg/kg PO; may be used as a preven-tative for ascaridiasis when dosed at 6. 6 mg/kg PO per day (T odd, Paul, and Di Pietro 1985) b) For lungworms (Crenosoma vulpis): 80 mg/kg PO q12h for 3 days (T odd, Paul, and Di Pietro 1985) T ! CATS: a) For Ascarids: 55-110 mg/kg PO (T odd, Paul, and Di Pietro 1985) T ! FERRETS: a) For heartworm prophylaxis: 5. 5 mg/kg PO once a day (Ran-dolph 1986) T ! CATTLE: a) For the treatment of early stages of Dictyocaulus viviparous infestations: 22 mg/kg IM for 3 successive days; or 44 mg/kg IM once. ( Note : DEC is available in an injectable dosage form containing 400 mg/m L in the U. K., no approved injectable form is available in the U. S. A. ) (Brander, Pugh, and Bywater 1982) Monitoring T ! Microﬁlaria, when used for heartworm prophylaxis T ! Clinical efﬁcacy, when used as an anthelmintic Client Information T ! Give all doses as directed T ! Dogs must be checked for microﬁlaria before restarting DEC in the spring. Dogs receiving DEC year around should be checked every six months Chemistry/Synonyms A piperazine derivative, diethylcarbamazine citrate (DEC) occurs as a white, slightly hygroscopic, crystalline powder that is either odorless or has a slight odor and a melting point of approximately 138°C. It is very soluble in water and slightly soluble (1 gram in 35 m L) in alcohol. Diethylcarbamazine citrate may also be known as: diethylcar-bamazine acid citrate, diethylcarbamazini citras; ditrazini cit-ras, RP-3799, Banocide®, Diethizine®, Filarcidan®, Hetrazan®, or Notezine®. Storage/Stability/Compatibility Unless otherwise speciﬁed by the manufacturer, diethylcarbamazine products should be stored in tight containers at room temperature and protected from light. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None in the USA HUMAN-LABELED PRODUCTS: Diethylcarbamazine Citrate Tablets: 50 mg; Hetrazan® (Wyeth-Ayerst); (Rx) Note : This product is available from the manufacturer without charge for compassionate use (in humans) only. DIETHYLSTILBESTROL DES (dye-ethel-stil-bes-tral) HORMONAL AGENT Prescriber Highlights TT Synthetic estrogen used in dogs primarily for estrogen responsive incontinence & other estrogen indications (prostatic hypertrophy, estrus induction, etc. ) TT Prohibited for use in food animals (potential carcinogen) TT Teratogen TT Many potential adverse effects: blood dyscrasias, GI effects, cystic endometrial hyperplasia & pyometra (non-spayed females), feminization (males), neoplasia TT Availability issues; must be obtained via a compounding pharmacy Uses/Indications DES has been used in estrogen responsive incontinence in spayed female dogs and in the medical treatment of benign prostatic hy-pertrophy in male dogs. It has also been used for the prevention of pregnancy after mismating in female dogs and cats. Its use alone for prevention of mismating is controversial as its efﬁcacy is in doubt. DES is used in canine medicine for the treatment of certain estro-gen-responsive neoplasias (see Pharmacology and Doses below). The use of DES for these conditions is controversial because of the risks associated with therapy. Pharmacology/Actions Estrogens are necessary for the normal growth and development of the female sex organs and in some species contribute to the devel-opment and maintenance of secondary female sex characteristics. Estrogens cause increased cell height and secretions of the cervical mucosa, thickening of the vaginal mucosa, endometrial prolifera-tion, and increased uterine tone. Estrogens have effects on the skeletal system. They increase cal-cium deposition, accelerate epiphyseal closure and increase bone formation. Estrogens have a slight anabolic effect and can increase sodium and water retention. Estrogens affect the release of gonadotropins from the pituitary gland, which can cause inhibition of lactation, inhibition of ovula-tion, and inhibition of androgen secretion. Excessive estrogen will delay the transport of the ovum and pre-vent it from reaching the uterus at the appropriate time for implan-tation. DES also possesses antineoplastic activity against some types of neoplasias (perianal gland adenoma and prostatic hyperplasia). It affects m RNA and protein synthesis in the cell nucleus and is cell cycle nonspeciﬁc. The mechanism of action for estrogen-responsive urinary in-continence is thought due to increasing sphincter sensitivity to norepinephrine. Pharmacokinetics DES is well absorbed from the GI tract of monogastric animals. It is slowly metabolized by the liver, primarily to a glucuronide form and then excreted in the urine and feces.	pppbs.pdf
288 DIETHYLSTILBESTROL Contraindications/Precautions/Warnings DES is prohibited by the FDA for use in food animals. Because of potential effects on bone marrow, DES should be used with extreme caution in patients with preexisting anemias or leu-kopenias. DES is contraindicated in females with estrogen-sensitive neoplasms. Adverse Effects While adverse effects with estrogen therapy can be serious (see be-low) in small animals, when used for estrogen-responsive inconti-nence at the lowest effective dose, it is usually well-tolerated. In cats and dogs, estrogens are considered toxic to the bone marrow and can cause blood dyscrasias. Blood dyscrasias are more prevalent in older animals and if higher dosages are used. Initially, a thrombocytosis and/or leukocytosis may be noted, but thrombo-cytopenia/leukopenias will gradually develop. Changes in a periph-eral blood smear may be apparent within two weeks after estrogen administration. Chronic estrogen toxicity may be characterized by a normochromic, normocytic anemia, thrombocytopenia, and neu-tropenia. Bone marrow depression may be transient and begin to resolve within 30-40 days or may persist or progress to a fatal aplas-tic anemia. Doses of 2. 2 mg/kg per day have caused death in cats secondary to bone marrow toxicity. Estrogens may induce mammary neoplasias. In cats, daily administration of DES has resulted in pancreatic, hepatic, and cardiac lesions. Estrogens may cause cystic endometrial hyperplasia and pyo-metra. After therapy is initiated, an open-cervix pyometra may be noted 1-6 weeks after therapy. When used chronically in male animals, feminization may occur. In females, signs of estrus may occur and persist for 7-10 days. Experimental administration of DES to female dogs as young as 8 months of age have induced malignant ovarian adenocarcinomas. Doses ranging from 60 to 495 mg given over 1 month to 4 years were implicated in causing these tumors. Reproductive/Nursing Safety DES is contraindicated during pregnancy, as it can cause fetal mal-formations of the genitourinary system. Estrogens have been documented to be carcinogenic at low levels in some laboratory animals. Because of the potential for danger to the public health, DES must not be used in animals to be used for human consumption. Overdosage/Acute Toxicity Acute overdosage in humans with estrogens has resulted in nausea, vomiting and withdrawal bleeding in females. No information was located regarding acute overdose in veterinary patients, however, the reader is referred to the warnings and adverse effects listed above. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving DES and may be of sig-niﬁcance in veterinary patients: !TANTIFUNGALS, AZOLE (itraconazole, ketoconazole, etc. ): May increase estrogen levels !TCIMETIDINE : May decrease metabolism of estrogens !TCORTICOSTEROIDS : Enhanced glucocorticoid effects may result if estrogens are used concomitantly with corticosteroid agents. It has been postulated that estrogens may either alter the protein binding of corticosteroids and/or decrease their metabolism. Cor-ticosteroid dosage adjustment may be necessary when estrogen therapy is either started or discontinued. !TERYTHROMYCIN, CLARITHROMYCIN : May decrease the metabolism of estrogens !!PHENOBARBITAL : May decrease estrogen concentrations !!PHENYTOIN : May decrease estrogen concentrations !TRIFAMPIN : May induce hepatic microsomal enzymes and decrease estrogen levels !TWARFARIN : Oral anticoagulant activity may be decreased if estro-gens are administered concurrently; increases in anticoagulant dosage may be necessary if adding estrogens Laboratory Considerations !TEstrogens in combination with progestins ( e. g., oral contracep-tives) have been demonstrated in humans to increase thyroxine-binding globulin (TBG) with resultant increases in total circulat-ing thyroid hormone. Decreased T3 resin uptake also occurs, but free T4 levels are unaltered. Doses !TDOGS: For treatment of estrogen-responsive incontinence: a) Initially 0. 1-1 mg PO daily for 3-5 days, followed by main-tenance therapy of approximately 1 mg PO per week. Some animals may require much higher initial dosages to obtain a response. Maximum initial doses of 0. 1-0. 3 mg/kg once daily for 7 days, then reduce to once weekly. All maintenance doses should be gradually reduced to the lowest effective dose. (Polzin and Osborne 1985) b) In females: 0. 1-1 mg (total dose) PO once daily for 5 days, then 1 mg once a week (Labato 2002a) c) 0. 5-1 mg (0. 02 mg/kg; maximum dose of 1 mg) for 3-5 days as an induction dose and then periodically decreased to ev-ery other day and then to the lowest dose that will maintain continence. In difﬁcult cases, may be used with phenylpropa-nolamine. (Chew and Di Bartola 2006) Note : Because of the unavailability of commercial DES products, some clinicians have used conjugated estrogens ( e. g., Premarin®) as a substitute: Example doses include: 20 mcg/kg PO every 4 days (Grauer 2000); 20 mcg/kg PO once daily for 5-7 days, then every 2-3 days as needed. (Lane 2006a) For estrus induction: a) DES at 5 mg/day for a tentative 7 days. The ﬁrst day of vulvar swelling is designated as Day 1. Continue DES on DAY 1 and Day 2. If no effect is seen in 7 days, give DES at 10 mg/day for another tentative 7 days. If vulvar swelling and bleeding detected, DES is continued on Day 1 and Day 2. If no effect seen in these 14 days, discontinue and restart in 30 days. Once proestrus initiated, on Day 5 give 5 mg of Luteinizing hor-mone (LH) if obtainable. If LH unavailable, give Gn RH 3. 3 mcg/kg IM and FSH 10 mg IM in its place. Bitch is bred on Day 13. Note : Adjust dosages of LH and FSH for animal size— the above dosages are for a dog weighing 50-60 lbs. (Purswell 1999) For pregnancy termination: Note : Most theriogenologists no lon-ger recommend estrogens for mismating. a) After mismating: 0. 1-1 mg PO for 5 days if animal is present-ed 24-48 hours after coitus. If animal is presented later than 5 days post-coitus: 1-2 mg PO for 5 days after ECP therapy (0. 044 mg/kg (ECP) IM once during 3-5 days of standing heat or within 72 hours of mismating) (Woody 1988)	pppbs.pdf
DIFLOXACIN HCL 289 For treatment of perianal gland adenomas and prostatic hyperplasias: a) 0. 1-1 mg PO q24-48h (Thompson 1989) b) For benign prostatic hypertrophy: 0. 2-1 mg total dose PO for 5 days (Root Kustritz and Klausner 2000) T ! CATS: For treatment of estrogen-responsive incontinence: a) In females: 0. 1-1 mg (total dose) PO once daily for 5 days, then 1 mg once a week (Labato 2002a) Monitoring When therapy is either at high dosages or chronic; see Adverse Effects for more information. Perform at least monthly: T ! Packed Cell Volumes (PCV) T ! White blood cell counts T ! Platelet counts T ! Perform liver function tests at baseline, and one month after therapy begins, repeat in 2 months after cessation of therapy if abnormal. Client Information T ! Contact veterinarian if signs of lethargy, diarrhea, vomiting, ab-normal discharge from vulva, excessive water consumption and urination or abnormal bleeding occur. Chemistry/Synonym A synthetic nonsteroidal estrogen agent, diethylstilbestrol occurs as an odorless, white, crystalline powder with a melting range of 169°-175°C. It is practically insoluble in water; soluble in alcohol or fatty oils. Diethylstilbestrol may also be known as: DES, diethylstilbe-strolum, diethylstilboestrol, NSC-3070, stilbestrol, stilboestrol, Apstil®, Boestrol®, Destilbenol®, or Distilbene®. Storage/Stability/Compatibility All commercially available DES tablets (plain tablets, enteric-coated tablets) should be stored at room temperature (15-30°C) in well-closed containers. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None HUMAN-LABELED PRODUCTS: No commercially available regular oral DES products are available in the USA, however, compounded preparations may be available from compounding pharmacies. DIFLOXACIN HCL (dye-ﬂox-a-sin) Dicural® FLU OROQUINOLONE ANTIBIOTIC Prescriber Highlights TT Veterinary-labeled ﬂuoroquinolone antibiotic for dogs TT Labeled for once daily administration TT Contraindications: Hypersensitivity. Relatively contra-indicated for young, growing animals due to cartilage abnormalities TT Caution: Seizure disorders, hepatic or renal insufﬁciency, dehydration. TT Adverse Effects: GI distress, CNS stimulation, or hypersensitivity TT Administer PO preferably on an empty stomach, unless GI upset Uses/Indications Diﬂoxacin is indicated for treatment in dogs for bacterial infections susceptible to it. In dogs with moderate to severe renal failure, di-ﬂoxacin may have an advantage over the other approved ﬂuoroqui-nolones as it has more extensive hepatobiliary excretion and may be less likely to accumulate to toxic levels. Diﬂoxacin tablets are not labeled for use in cats or other species. Pharmacology/Actions Like other drugs in its class, diﬂoxacin is a concentration-depen-dent bactericidal agent. It acts by inhibiting bacterial DNA-gyrase (a type-II topoisomerase), thereby preventing DNA supercoiling and DNA synthesis. The net result is disruption of bacterial cell replication. Diﬂoxacin has good activity against many gram-negative and gram-positive bacilli and cocci, including most species and strains of Klebsiella spp., Staphylococcus spp., E. coli, Enterobacter, Campylobacter, Shigella, Proteus, and Pasturella species. Some strains of Pseudomonas aeruginosa and Pseudomonas species are resistant and most Enterococcus spp. are resistant. Like other ﬂuo-roquinolones, diﬂoxacin has weak activity against most anaerobes and is not a good choice when treating known or suspected anaero-bic infections. Development of bacterial resistance to 4-ﬂuoroquinolones can occur. Pharmacokinetics After oral administration in dogs, diﬂoxacin serum levels peak about 3 hours post dosing. The drug is well absorbed (bioavailabil-ity >80%) and distributed (V d=2. 8-4. 7 L/kg) in dogs and mar-ginally bound to plasma proteins (16-52% in dogs). Diﬂoxacin is eliminated by excretion in the bile and more than 80% of a dose is eliminated in the feces. Elimination half-life is about 9. 3 hours. While excretion by the kidneys may only account for 5% of the total dose, urine levels remain well above MIC's for susceptible organ-isms for at least 24 hours after dosing. In horses, oral bioavailability after intragastric administration of a 5 mg/kg oral suspension (100 mg/m L; in simple syrup:deionized water at 60:40) was approximately 70%. Peak levels were about 0. 73 mg/L. After IV administration, volume of distribution (steady-state) was about 1 L/kg and terminal elimination half-life about 2. 7 hours. Elimination half-life after IM injection was about 5. 7 hours; after intragastric administration about 10. 8 hours.	pppbs.pdf
290 DIFLOXACIN HCL Contraindications/Precautions/Warnings Diﬂoxacin, like other ﬂuoroquinolones can cause arthropathies in immature, growing animals. Because dogs appear to be more sensi-tive to this effect, the manufacturer states that the drug is contrain-dicated in immature dogs during the rapid growth phase (between 2-8 months in small and medium-sized breeds and up to 18 months in large and giant breeds). The drug should be considered contrain-dicated in dogs known to be hypersensitive to diﬂoxacin or other drugs in its class (quinolones). The manufacturer states that diﬂoxacin should be used with cau-tion in animals with known or suspected CNS disorders (e. g., seizure disorders) as rarely drugs in this class have been associated with CNS stimulation and seizures. While diﬂoxacin may ﬁnd use in other species, early anecdotal reports state that it can cause nausea and vomiting in cats. Its oph-thalmic safety has not been determined in cats. Adverse Effects While the manufacturer reports that only self-limited gastrointes-tinal effects (anorexia, vomiting, diarrhea) were reported during clinical studies (at 5 mg/kg dosing) in adult animals, higher doses or additional experience with use of the drug may demonstrate ad-ditional adverse effects. Reproductive/Nursing Safety Safety in breeding or pregnant dogs has not been established. It is not known whether diﬂoxacin is excreted into milk. Overdosage/Acute Toxicity Dogs receiving up to 2. 5X (25 mg/kg) for 30 days did not demon-strate overly signiﬁcant adverse effects. Facial erythema/edema, di-arrhea, decreased appetite and weight loss were noted. Drug Interactions The manufacturer reports that diﬂoxacin was used concurrently in ﬁeld trials with a variety of drugs including heartworm preventative, thyroid hormones, ectoparasiticides, antiseizure drugs, anesthetics, antihistamines, and topical antibiotic/antiinﬂammatory preps with-out untoward effects. However, the following drug interactions have either been re-ported or are theoretical in humans or animals receiving other oral ﬂuoroquinolones and may be of signiﬁcance in veterinary patients receiving diﬂoxacin: !TANTACIDS/DAIRY PRODUCTS containing cations (Mg++, Al+++, Ca++): May bind to ciproﬂoxacin and prevent its absorption; separate doses of these products by at least 2 hours from diﬂoxacin !TANTIBIOTICS, OTHER (aminoglycosides, 3rd-generation cephalosporins, penicillins—extended-spectrum : Synergism may occur, but is not predictable, against some bacteria (particularly Pseudomonas aeruginosa) with these compounds. Although diﬂoxacin has min-imal activity against anaerobes, in vitro synergy has been reported when ﬁrst generation ﬂuoroquinolones have been used with clin-damycin against strains of Peptostreptococcus, Lactobacillus and Bacteroides fragilis. !TCYCLOSPORINE : Fluoroquinolones may exacerbate the nephro-toxicity and reduce the metabolism of cyclosporine (used systemically) !TGLYBURIDE : Severe hypoglycemia possible !TIRON, ZINC (oral): Decreased diﬂoxacin absorption; separate doses by at least two hours !TMETHOTREXATE : Increased MTX levels possible with resultant toxicity !TNITROFURANTOIN may antagonize the antimicrobial activity of the ﬂuoroquinolones and their concomitant use is not recommended !TPHENYTOIN : Diﬂoxacin may alter phenytoin levels !TPROBENECID : Blocks tubular secretion of ciproﬂoxacin and may also increase the blood level and half-life of diﬂoxacin !TSUCRALFATE : May inhibit absorption of diﬂoxacin; separate doses of these drugs by at least 2 hours !TTHEOPHYLLINE : Diﬂoxacin may increase theophylline blood levels !TWARFARIN : Potential for increased warfarin effects Laboratory Considerations !TIn some human patients, the ﬂuoroquinolones have caused in-creases in liver enzymes, BUN, and creatinine and decreases in hema-tocrit. The clinical relevance of these mild changes is not known at this time. Doses !TDOGS: a) For susceptible infections: 5-10 mg/kg once daily PO for 2-3 days beyond the cessation of clinical signs to a maximum of 30 days therapy (Package Insert; Dicural®) !THORSES: a) For susceptible infections (MIC ≤ 0. 25 mcg/m L): 7. 5 mg/kg PO (non-fasted) once daily (q24h). Appears to be safe, ad-equately absorbed and well distributed. Further investigation is warranted to substantiate. Unknown whether administra-tion of diﬂoxacin to young, growing horses should be avoid-ed. (Adams, Haines et al. 2005) Monitoring/Client Information !TEfﬁcacy is the most important monitoring parame ter. !TClients should be instructed on the importance of giving the medication as instructed and not to discontinue it on their own. Chemistry/Synonyms A 4-ﬂuoroquinolone antibiotic, diﬂoxacin HCl is poorly water solu-ble at neutral p H. At a p H of 5 solubility is increased and it is highly water soluble at a p H of 9. Diﬂoxacin HCl may also be known as: A-56619, Abbott-56619, or Dicural®. Storage/Stability Com mercially available tablets should be stored between 15-30°C (59-86°F) and protected from excessive heat. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: Diﬂoxacin Oral Scored Tablets: 11. 4 mg (single scored), 45. 4 mg (single scored), & 136 mg (double scored); Dicural® (Fort Dodge); (Rx). Approved for use in dogs. Federal law prohibits the extra-label use of the drug in food-producing animals. HUMAN-LABELED PRODUCTS: None	pppbs.pdf
DIGOXIN 291 DIGOXIN (di-jox-in) Lanoxin®, Cardoxin® CARDIAC GLYC OSIDE Prescriber Highlights TT Oral & parenteral cardiac glycoside used for CHF & SVT's in many species; usually with other agents TT Contraindications: V-ﬁb, digitalis intoxication; many vet-erinarians feel that digoxin is relatively contraindicated in cats with hypertrophic cardiomyopathy TT Extreme Caution: Patients with glomerulonephritis & heart failure or with idiopathic hypertrophic subaortic stenosis (IHSS) TT Caution: Severe pulmonary disease, hypoxia, acute myo-carditis, myxedema, or acute MI, frequent VPC's V-tach, chronic constrictive pericarditis or incomplete AV block TT Adverse Effects usually associated with high or toxic blood levels: Cardiac effects may include almost every type of cardiac arrhythmia described with a resultant worsening of heart failure clinical signs. Extracardiac: mild GI upset, anorexia, weight loss & diarrhea TT Drug Interactions TT Monitoring of blood levels highly suggested Uses/Indications The veterinary indications for digoxin include treatment of conges-tive heart failure, atrial ﬁbrillation or ﬂutter, and supraventricular tachycardias. Digoxin therapy is controversial for treating heart failure. T oday, many cardiologists no longer feel that digoxin is ﬁrst line therapy for heart failure in dogs and cats and with the availability of pimoben-dan this trend is expected to continue. Many state that digoxin can have beneﬁcial effects in certain patients when used with diuretics and, possibly, ACE inhibitors, but digoxin alone is rarely, if ever, used for heart failure. Pharmacology/Actions The pharmacology of the digitalis glycosides have been extensively studied, but a thorough discussion is beyond the scope of this refer-ence. Digitalis glycosides cause the following effects in patients with a failing heart: increased myocardial contractility (inotropism) with increased cardiac output; increased diuresis with reduction of ede-ma secondary to a decrease in sympathetic tone; reduction in heart size, heart rate, blood volume, and pulmonary and venous pres-sures; and (usually) no net change in myocardial oxygen demand. The digitalis glycosides have several electrocardiac effects, in-cluding: decreased conduction velocity through the A V node, and prolonged effective refractory period (ERP). They may increase the PR interval, decrease the QT interval and cause ST segment depression. The exact mechanism of action of these agents has not been fully described, but their ability to increase the availability of Ca++ to myocardial ﬁbers and to inhibit Na+-K+-ATPase with resultant increased intracellular Na+ and reduced K+ probably explains their actions. For additional information, it is suggested to refer to a pharma-cology text. Pharmacokinetics Absorption following oral administration occurs in the small intes-tine and is variable dependent upon the oral dosage form used (see Dosage Forms below). Food may delay, but not alter, the extent of absorption in most species studied. Food reportedly decreases the amount absorbed by 50% in cats after tablet administration. Peak serum levels generally occur within 45-60 minutes after oral elixir and about 90 minutes after oral tablet administration. In patients receiving an initial oral dose of digoxin, peak effects may occur in 6-8 hours after the dose. The drug is distributed widely throughout the body with highest levels found in kidneys, heart, intestine, stomach, liver and skeletal muscle. Lowest concentrations are found in the brain and plasma. Digoxin does not signiﬁcantly enter ascitic ﬂuid, so dosage adjust-ments may be required in animals with ascites. At therapeutic lev-els, approximately 20-30% of the drug is bound to plasma pro-teins. Because only small amounts are found in fat, obese patients may receive dosages too high if dosing is based on total body weight versus lean body weight. Digoxin is metabolized slightly, but the primary method of elimination is renal excretion both by glomerular ﬁltration and tu-bular secretion. As a result, dosage adjustments must be made in patients with signiﬁcant renal disease. Values reported for the elimi-nation half-life of digoxin in dogs and cats have been highly vari-able, with values reported from 14. 4-56 hours for dogs; 30-173 hours for cats. Elimination half-lives reported in other species in-clude: Sheep≈7. 15 hours; Horses ≈16. 9-23. 2 hours; and Cattle≈7. 8 hours. Contraindications/Precautions/Warnings Many cardiologists feel that digoxin is relatively contraindicated in cats with hypertrophic cardiomyopathy as it may increase myocar-dial oxygen demand and lead to dynamic outﬂow obstruction. Digoxin is actively transported by the p-glycoprotein pump and certain breeds susceptible to MDR1-allele mutation (Collies, Australian Shepherds, Shelties, Long-haired Whippet) are at higher risk for toxicity, particularly CNS effects. Digitalis cardioglycosides are contraindicated in patients with ventricular ﬁbrillation or in digitalis intoxication. They should be used with extreme caution in patients with glomerulonephritis and heart failure or with idiopathic hypertrophic subaortic steno-sis (IHSS). They should be used with caution in patients with se-vere pulmonary disease, hypoxia, acute myocarditis, myxedema, or acute myocardial infarction, frequent ventricular premature con-tractions, ventricular tachycardias, chronic constrictive pericarditis or incomplete A V block. They may be used in patients with stable, complete A V block or severe bradycardia with heart failure if the block was not caused by the cardiac glycoside. When used to treat atrial ﬁbrillation or ﬂutter prior to admin-istration with an antiarrhythmic agent that has anticholinergic ac-tivity (e. g., quinidine, procainamide, disopyramide), digitalis glyco-sides will reduce, but not eliminate, the increased ventricular rates that may be produced by those agents. Since digitalis glycosides may cause increased vagal tone, they should be used with caution in patients with increased carotid sinus sensitivity. Elective cardioversion of patients with atrial ﬁbrillation should be postponed until digitalis glycosides have been withheld for 1-2 days, and should not be attempted in patients with signs of digitalis toxicity. Principally eliminated by the kidneys, digoxin should be used with caution and serum levels monitored in patients with renal dis-ease. Animals that are hypernatremic, hypokalemic, hypercalcemic, hyper-or hypothyroid may require smaller dosages; monitor carefully.	pppbs.pdf
292 DIGOXIN Adverse Effects Adverse effects of digoxin are usually associated with high or toxic serum levels and are categorized into cardiac and extracardiac clini-cal signs. There are species differences with regard to the sensitivity to digoxin's toxic effects also. Cats are relatively sensitive to digoxin while dogs tend to be more tolerant of high serum levels. Cardiac effects may be seen before other extra-cardiac clini-cal signs and may include almost every type of cardiac arrhythmia described with a resultant worsening of heart failure clinical signs. More common arrhythmias or ECG changes observed include: com-plete or incomplete heart block, bigeminy, ST segment changes, par-oxysmal ventricular or atrial tachycardias with block, and multifocal premature ventricular contractions. Because these effects can also be caused by worsening heart disease, it may be difﬁcult to determine if they are a result of the disease process or digitalis intoxication. If in doubt, monitor serum levels or stop digoxin therapy temporarily. Extracardiac clinical signs most commonly seen in veterinary medicine include mild GI upset, anorexia, weight loss, and diar-rhea. Vomiting has been associated with IV injections and should not cause anxiety or alarm. Ocular and neurologic effects are rou-tinely seen in humans, but are not prevalent in animals or are not detected. 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 fe-line pregnancy (Papich 1989), this drug is categorized as in class: A (Probably safe. Although speciﬁc studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women. ) Studies have shown that digoxin concentrations in mother's se-rum and milk are similar; however, it is unlikely to have any phar-macological effect in nursing offspring. Overdosage/Acute Toxicity Clinical signs of chronic toxicity are discussed above. In dogs the acute toxic dose after IV administration has been reported to be 0. 177 mg/kg. Treatment of chronic digoxin toxicity is dictated by the severity of the clinical signs associated with it. Many patients will do well after temporarily stopping the drug and reevaluating the dosage regimen. If an acute ingestion has recently occurred and no present car-diotoxic or neurologic signs (coma, seizures, etc. ) have manifested, emptying the stomach may be indicated followed with activated charcoal administration. Because digoxin can be slowly absorbed and there is some enterohepatic recirculation of the drug, repeated charcoal administration may be beneﬁcial even if the ingestion oc-curred well before treatment. Anion-exchange resins such as colesti-pol or cholestyramine have been suggested to reduce the absorption and enterohepatic circulation of digoxin, but are not readily avail-able in most veterinary practices. Dependent on the type of cardiotoxicity, supportive and symp-tomatic therapy should be implemented. Serum electrolyte concen-trations, drug level if available on a “stat” basis, arterial blood gases if available, and continuous ECG monitoring should be instituted. Acid-base, hypoxia, and ﬂuid and electrolyte imbalances should be corrected. The use of potassium in normokalemic patients is very controversial and should only be attempted with constant monitor-ing and clinical expertise. The use of speciﬁc antiarrhythmic agents in treating life-threat-ening digitalis-induced arrhythmias may be necessary. Lidocaine and phenytoin are most commonly employed for these arrhythmias. Atropine may be used to treat sinus bradycardia, SA arrest, or 2nd or 3rd degree A V block. Digoxin immune Fab is a promising treatment for digoxin or dig-itoxin life-threatening toxicity. It is produced from speciﬁc digoxin antibodies from sheep and will bind directly to the drug, inactivat-ing it. It is very expensive however and veterinary ex perience with it is extremely limited. Drug Interactions There are many potential drug interactions associated with digoxin and the following list is not necessarily all inclusive. Because of the narrow therapeutic index associated with the drug, consider en-hanced monitoring when these drugs (are those in the same class) are added to patients stabilized on digoxin. The following drug interactions have either been reported or are theoretical in humans or animals receiving digoxin and may be of signiﬁcance in veterinary patients: The following drugs may reduce digoxin serum levels : !!AMINOSALICYLIC ACID !!ANTACIDS !!CHOLESTYRAMINE !!CIMETIDINE !!METOCLOPRAMIDE !!NEOMYCIN (oral) !!St JOHN'S WORT !!SULFASALAZINE The following agents may increase serum levels, decrease the elimina-tion rate, or enhance the toxic effects of digoxin: !!AMIODARONE !!ANTICHOLINERGICS !!CAPTOPRIL (or other ACEIs ) !!DIAZEPAM !!DILTIAZEM (data conﬂicts) !!ERYTHROMYCIN !!FUROSEMIDE !!KETOCONAZOLE/ITRACONAZOLE !!OMEPRAZOLE (or other PPIs ) !!QUINIDINE !!RESERPINE !!SUCCINYLCHOLINE !!TETRACYCLINE !!VERA PAMIL !TBETA-BLOCKERS : Can have additive negative effects on A V conduc-tion, complete heart block possible !TCALCIUM-CHANNEL BLOCKERS (diltiazem, etc. ): Can have additive negative effects on A V conduction !TPENICILLAMINE : May decrease serum levels of digoxin independent of route of digoxin dosing. !TPOTASSIUM/ELECTROLY TE BALANCE, DRUGS A FFECTING (e. g., diuret-ics, amphotericin B, glucocorticoids, laxatives, sodium polystyrene sulfonate, glucagon, high dose IV dextrose, dextrose/insulin infu-sions, furosemide, thiazides ): May predispose the patient to digitalis toxicity !TSPIRONOLACTONE : May enhance or decrease the toxic effects of digoxin !TTHYROID S UPPLEMENTS : Patients on digoxin that receive thyroid re-placement therapy may need their digoxin dosage adjusted	pppbs.pdf
DIGOXIN 293 Laboratory Considerations !TNo speciﬁc laboratory test concerns !TDigoxin can cause prolonged PR interval and ST segment depres-sion, and false-positive changes on EKG ST-T in human patients during exercise testing Doses !TDOGS: a) Because of the variability in pharmacokinetics in individual animals, administration to any animal should be considered a pharmacological “experiment”: Initially, in dogs weighing less than 18 kg (40 lbs. ) give 0. 0044-0. 011 mg/kg PO q12h. In dogs weighing more than 18 kg (40 lbs), initial dose is 0. 25 mg/M2 PO q12h. Moni-tor for signs of toxicity and efﬁcacy and measure serum con-centration 3-5 days later (draw sample 6-8 hours after last dose) to see if therapeutic (0. 5-2 ng/m L). Readjust dosage accordingly. (Kittleson 2000) b) Initial dose: 0. 005-0. 01 mg/kg q12h (up to a maximum of 0. 375 mg, or rarely, 0. 5 mg/day). Use lean body weight to determine dosage. Measure serum digoxin level 5-10 days later. Draw level 8-10 hours after dosing. Therapeutic level: 1-2 ng/m L. If level is less than 0. 8 ng/m L, increase dose up to 30% and repeat serum level monitoring as above. If toxic-ity is suspected, stop therapy for at least 1-2 days and then resume at a reduced dose (by 50%). (Ware and Keene 2000) c) For adjunctive treatment of atrial ﬁbrillation: 0. 003-0. 005 mg/kg PO q12h (Hogan 2004) d) If pimobendan is not available or too expensive, especially if refractory heart failure exists or atrial ﬁbrillation is ob-served: Start with a low dose (0. 005 mg/kg PO twice a day) and round down if needed. (Meurs 2006b) !TCATS: For dilated cardiomyopathy or advanced atrioventricular valve insufﬁciency ( Note : digoxin is generally contraindicated for fe-line hypertrophic cardiomyopathy): a) Initial dose: 0. 007 mg/kg PO every other day. Use lean body weight to determine dosage. Measure serum digoxin level 10+ days later. Draw level 8-10 hours after dosing. Thera-peutic level: 1-2 ng/m L. If level is less than 0. 8 ng/m L, in-crease dose up to 30% and repeat serum level monitoring as above. If toxicity is suspected, stop therapy for at least 1-2 days and then resume at a reduced dose (by 50%). (Ware and Keene 2000) b) Tablets: 0. 005-0. 008 mg/kg/day PO divided twice daily Alternatively: For cats weighing: 2-3 kg = G of a 0. 125 mg tablet every other day; 4-5 kg = G of a 0. 125 mg tablet every day; 6 kg or > or = G of a 0. 125 mg tablet twice daily (Kittle-son 1985a) c) Oral maintenance 0. 007-0. 015 mg/kg once daily to every other day. Rapid IV: 0. 005 mg/kg lean body weight divided between three doses (1/2 the dose initially, then 60 minutes later another G of the dose, 60 minutes later the remainder (if necessary) or to effect. Stop if marked bradycardia, di-minished A V conduction, other digoxin related arrhythmias or clinical signs of toxicity are present. Begin oral therapy as soon as the last IV dose is completed. (Miller 1985) !TFERRETS: For adjunctive therapy for heart failure: a) For dilated cardiomyopathy: 0. 01 mg/kg PO once daily ini-tially (use oral liquid). May increase to twice daily if neces-sary. Monitor as per dogs and cats. (Hoeffer 2000) b) 0. 005-0. 01 mg/kg PO once to twice daily using the elixir; for maintenance; monitor blood levels if possible (Williams 2000) c) Treatment follows the same principles of other small animal medicine: Dilated cardiomyopathy long-term maintenance with furosemide (2 mg/kg q12h), enalapril (0. 5 mg/kg q48h) and digoxin (0. 01 mg/kg q24h). Monitor potassium if using diuretics longer than a few days. (Johnson-Delaney 2005c) !TRABBITS/RODENTS/SMALL MAMMALS: a) Hamsters: For dilated cardiomyopathy: 0. 05-0. 1 mg/kg PO q12h (Adamcak and Otten 2000) !TCATTLE : a) 0. 25 mg/100 lbs body weight (not destroyed in rumen), titrate dose to normalize atrial rate; not excreted in milk (Mc Con-nell and Hughey 1987) !THORSES: (Note : ARCI UCGFS Class 4 Drug) a) Loading dose: 11 mcg/kg IV given slowly or in divided doses, or 44 mcg/kg PO; Maintenance Dose: 2. 2 mcg/kg IV every 12h or 11 mcg/kg PO every 12 hours. Maintain plasma concentrations between 0. 5-2 ng/m L. (Mogg 1999) !TBIRDS: a) Because of its very small therapeutic margin, it may be best to use digoxin to stabilize patients in an emergency rather than for long-term therapy; initial doses are 0. 02-0. 5 mg/kg q12h for 2-3 days, then decreased to 0. 01 mg/kg q12-24h. Consider switching to an ACE inhibitor. (Johnson-Delaney 2005a) Monitoring !TSerum levels: Because of the signiﬁcant interpatient pharmacoki-netic variation seen with this drug, and its narrow therapeutic index, it is strongly recommended to monitor serum levels to help guide therapy. Unless the patient received an initial load-ing dose, at least 6 days should pass after beginning therapy to monitor serum levels to allow levels to approach steady-state. Suggested therapeutic serum levels in the dog are 0. 9-3 ng/m L (some believe that levels above 2. 5 ng/m L are “poisonous”) and 0. 9-2 ng/m L in cat (Neff-Davis 1985). For other species, values from 0. 5-2 ng/m L can be used as guidelines. Levels at the higher end of the suggested range may be necessary to treat some atrial arrhythmias, but may also result in higher incidences of adverse effects. Usually a trough level (just before next dose or at least 8 hours after last dose) is recommended, but drawing a sample anytime is acceptable !TAppetite/weight !TCardiac rate, ECG changes !TSerum electrolytes !TClinical efﬁcacy for CHF (improved perfusion, decreased edema, increased venous (or ar terial) O2 levels). Client Information !TContact veterinarian if animal demonstrates changes in behavior, vomits, has diarrhea, shows lack of appetite, clinical signs of colic (horses), or becomes lethargic or depressed. Chemistry/Synonyms A cardiac glycoside, digoxin occurs as bitter tasting, clear to white crystals or as white, crystalline powder. It is practically insoluble in water, slightly soluble in diluted alcohol, and very slightly soluble in 40% propylene glycol solution. Above 235°C, it melts with de-composition.	pppbs.pdf
294 DIHYDROTACHYSTEROL Digoxin may also be known as: digoxinum or digoxosidum; many trade names are available. Occasionally, digoxin is described DIHYDROTACHYSTEROL as digitalis. DHT Storage/Stability/Compatibility (dye-hye-droe-tak-ee-ster-ole) DHT®, Hytakerol® The commercial injection consists of a 40% propylene glycol, 10% alcohol solution having a p H of 6. 6-7. 4. VITAMIN D ANALOG Digoxin tablets, capsules, elixir and injection should be stored at room temperature (15-30°C) and protected from light. Prescriber Highlights At p H's from 5-8, digoxin is stable, but in solutions with a p H of less than 3, it is hydrolyzed. TT Commercial dosage forms reportedly discontinued; may be available from compounding pharmacies The injectable product is compatible with most commercially available IV solutions, including lactated Ringer's, D 5W, and nor-TT Vitamin D analog for hypocalcemia secondary to mal saline. T o prevent the possibility of precipitation occurring, one hypoparathyroidism or renal disease manufacturer (Glaxo Wellcome) recommends that the injection be TT Raises calcium faster than ergocalciferol & effects dis-diluted by a volume at least 4 times; with either sterile water, D 5W, sipate more rapidly after the drug is stopped or normal saline. Digoxin injection has been demonstrated to be TT Contraindications: Hypercalcemia, vitamin D toxicity, compatible with bretylium tosylate, cimetidine HCl, lidocaine HCl, malabsorption syndrome, or abnormal sensitivity to and verapamil HCl. the effects of vitamin D. Extreme caution: hyperphos-Digoxin is incompatible with dobutamine HCl, acids, and alkalies. phatemia, renal dysfunction (when receiving the drug The manufacturer does not recommend mixing digoxin injection for non-renal indications) with other medications. Compatibility is dependent upon factors such as p H, concentration, temperature and diluent used; consult TT Adverse Effects: Hypercalcemia (may present as polydipsia, polyuria & anorexia), nephrocalcinosis, & specialized references or a hospital pharmacist for more speciﬁc in-hyperphosphatemia TT Some animals are resistant to therapy formation. Dosage Forms/Regulatory Status TT Monitoring serum calcium mandatory There are bioavailability differences between dosage forms and in tablets produced by different manufacturers. It is recommended that tablets be used from a manufacturer that the clinician has conﬁdence in and that brands not be routinely interchanged. Should a change Uses/Indications in dosage forms be desired, the following bioavailability differences DHT is used in small animals to treat hypocalcemia secondary to can be used as guidelines in altering the dose: Intravenous = 100%, hypoparathyroidism or severe renal disease. IM ≈ 80%, Oral tablets ≈ 60%, Oral elixir ≈ 75%, Oral capsules ≈ Pharmacology/Actions 90-100%. The bioavailability of digoxin in veterinary species has DHT is hydroxylated in the liver to 25-hydroxy-dihydrotachysterol only been studied in a limited manner. One study in dogs yielded that is the active form of the drug and is an analog of 1,25-dihy-similar values as those above for oral tablets and elixir, but in horses droxyvitamin D. Vitamin D is considered a hormone and, in con-only about 20% of an intragastric dose was bioavailable. junction with parathormone (PTH) and calcitonin, regulates cal-VETERINARY-LABELED PRODUCTS: cium homeostasis in the body. Active analogues (or metabolites) of The veterinary-labeled products are no longer available commer-vitamin D enhance calcium absorption from the GI tract, promote cially in the USA. reabsorption of calcium by the renal tubules, and increase the rate of The ARCI (Racing Commissioners International) has designated this accretion and resorption of minerals in bone. drug as a class 4 substance. See the appendix for more information. Pharmacokinetics HUMAN-LABELED PRODUCTS: If fat absorption is normal, vitamin D analogs are readily absorbed Digoxin for Injection: 0. 1 mg/ m L in 1 m L amps (pediatric) and 0. 25 from the GI tract (small intestine). There are anecdotal reports of mg/m L in 2 m L amps, and 1 and 2 m L Tubex or Carpuject; Lanoxin® dogs and cats not responding to the oral tablets or capsule forms (Glaxo Wellcome); (Rx); generic; (Rx) of the drug, but responding to the oral liquid dosage forms. Bile is required for adequate absorption and patients with steatorrhea, liver Digoxin Tablets: 0. 125 mg, and 0. 25 mg; Lanoxin® (Glaxo Well-or biliary disease will have diminished absorption. DHT is hydroxy-come); Digitek® (Bertek Pharm); generic; (Rx) lated in the liver to 25-hydroxy-di hydrotachysterol that is the active Digoxin Capsules: 0. 05 mg, 0. 1 mg & 0. 2 mg; Lanoxicaps® (Cardinal form of the drug. Unlike some other forms of vitamin D, DHT does Health); (Rx) not require parathormone activation in the kidneys. The time re-Digoxin Elixir Pediatric: 0. 05 mg/m L in 60 m L dropper bottle, and quired for maximal therapeutic effect is usually seen within the ﬁrst UD 2. 5 and 5 m L; generic; (Rx) week of treatment. Unlike some other forms of vitamin D, DHT of-ﬂoads relatively rapidly (1-3 weeks). Contraindications/Precautions/Warnings DHT is contraindicated in patients with hypercalcemia, vitamin D toxicity, malabsorption syndrome, or abnormal sensitivity to the ef-fects of vitamin D. It should be used with extreme caution in pa-tients with hyperphosphatemia (many clinicians believe hyperphos-phatemia or a combined calcium/phosphorous product of >70 mg/ dl is a contraindication to its use), or in patients with renal dysfunc-tion (when receiving the drug for non-renal indications).	pppbs.pdf
DIHYDROTACHYSTEROL 295 Adverse Effects Hypercalcemia, nephrocalcinosis, and hyperphosphatemia are potential complications of DHT therapy. Clinical signs of hyper-calcemia include polydipsia, polyuria, and anorexia. Monitoring of serum calcium levels is mandatory while using this drug. Reproductive/Nursing Safety Hypervitaminosis D has caused fetal abnormalities in a variety of species. 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. ) Weigh the risks versus beneﬁts of treating animal patients with this drug during pregnancy. Vitamin D is excreted in breast milk in limited amounts; use with caution. Overdosage/Acute Toxicity Acute ingestions should be managed using established protocols for removal or prevention of the drug being absorbed from the GI. Orally administered mineral oil may reduce absorption and en-hance fecal elimination. Hypercalcemia secondary to chronic dosing of the drug should be treated by ﬁrst temporarily dis continuing DHT and exogenous calcium therapy. If the hypercalcemia is severe, furosemide, cal-cium-free IV ﬂuids (e. g., normal saline), urine acidiﬁcation, and corticosteroids may be employed. Because of the long duration of action of DHT (usually one week and potentially up to 3 weeks), hypercalcemia may persist. Restart DHT/calcium therapy at a re-duced dosage with diligent monitoring when calcium serum levels return to the normal range. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving DHT and may be of signiﬁcance in veterinary patients: !TCALCIUM-CONTAINING PHOSPHORUS BINDING AGENTS (e. g., calcium car-bonate ): Use with vitamin D analogs may induce hypercalcemia !TCORTICOSTEROIDS : Can nullify the effects of vitamin D analogs !TDIGOXIN or VERAPAMIL : Patients on verapamil or digoxin are sen-sitive to the effects of hypercalcemia; intensiﬁed monitoring is required !TMINERAL OIL, SUCRALFATE, CHOLESTYRAMINE : May reduce the amount of drug absorbed !TPHENYTOIN, BARBITURATES or PRIMIDONE : May induce hepatic en-zyme systems and increase the metabolism of Vitamin D analogs thus decreasing their activity !TTHIAZIDE D IURETICS : May cause hypercalcemia when given in con-junction with Vitamin D analogs Laboratory Considerations !TSerum cholesterol levels may be falsely elevated by vitamin D ana-logs when using the Zlatkis-Zak reaction for determination. Doses Vitamin D therapy for hypocalcemic conditions is often used with exogenously administered calcium products. Refer to the calcium monograph or the references cited below for further information. !TDOGS: For hypocalcemia secondary to hypoparathyroidism: a) Initially give 0. 03 mg/kg PO for several days or until effect is demonstrated, then give 0. 02 mg/kg for 2 days, then 0. 01 mg/kg per day. Pet should remain hospitalized until serum calcium concentration remains stable between 8-9. 5 mg/ d L. Recheck serum calcium on a weekly basis during early stages of treatment; recheck every 2-3 months long-term. Some dogs and cats that appear to be resistant to treatment on tablets or capsules may respond to the liquid form. (Feld-man 2005a) b) Once life-threatening signs of hypocalcemia have been controlled with intravenous calcium, give DHT initially at 0. 03-0. 06 mg/kg/day PO for 2-3 days, then 0. 02-0. 03 mg/ kg/day for 2-3 days, and ﬁnally 0. 01 mg/kg/day until further dosage adjustments are required. Stable serum calcium levels (8. 5-9. 5 mg/dl) are usually achieved in a week. Determine serum calcium levels twice daily during initial treatment period until levels have stabilized in the low-normal range. (Peterson 1986) c) For secondary hypoparathyroidism : During initial loading peri-od with calcium and DHT, monitor serum calcium 1-2 times daily for 5-10 days. Give loading dose of DHT at 0. 02-0. 05 mg/kg PO once daily for 2-3 days, then 0. 01-0. 03 mg/kg PO once daily for 1 week. After a low, normal serum calcium is achieved, give 0. 01 mg/kg PO once every other day and then every third day, etc., until it can be ﬁnally stopped. Dose should be individualized for each animal. During loading period, calcium should be given at 25-50 mg (elemental cal-cium)/kg/day divided 2-4 times a day. After 1 week, decrease dose to 15-25 mg (elemental calcium)/kg/day divided and gradually reduce. The goal is to keep serum calcium levels in the low-normal range (7. 5-9. 5 mg/dl) so that the remaining parathyroid tissue will respond via feedback mechanisms. For primary hypoparathyroidism (animals will require therapy for life): Loading regimen is the same as for secondary hy-poparathyroidism. Then DHT may be given at 0. 01 mg/kg PO once daily and eventually every other day if serum cal-cium levels permit. Reduce oral calcium supplementation to as low a dose as possible; may consider replacing pharma-ceuticals with a high calcium diet. Monitoring of calcium levels may be reduced to 1-2 times per month after loading regimen is completed and animal is relatively stable. Dosage adjustments of either DHT or calcium should be made in in-crements of about 25%. Eventually, animal may only need to be monitored (serum calcium) several times a year. (Meuten and Armstrong 1989) For hypocalcemia secondary to severe renal failure: Note : Because of dihydrotachysterol's relatively long off-load-ing time in comparison to calcitriol, many endocrinologists/ nephrologists prefer using calcitriol. a) After hyperphosphatemia is controlled (do not use calcium and vitamin D if calcium/phosphate product is in excess of 70 mg/dl), use oral calcium carbonate therapy. If calcium alone does not resolve hypocalcemia add DHT at 0. 125 mg per dog PO 3 times per week. Adjust dose based on serial calcium determinations. Maximum effect may require 2-4 weeks and duration may persist up to 1 week after treatment is discontinued. (Allen 1989) b) In combination with calcium therapy, give DHT initially at 0. 03 mg/kg/day for 2 days, then 0. 02 mg/kg/day for 2 days, then 0. 01 mg/kg/day maintenance dose. (Kay and Richter 1988) !TCATS: For hypocalcemia secondary to hypoparathyroidism: a) Initially give 0. 03 mg/kg PO for several days or until effect is demonstrated, then give 0. 02 mg/kg for 2 days, then 0. 01 mg/ kg per day. Pet should remain hospitalized until serum calci-um concentration remains stable between 8-9. 5 mg/d L. Re-	pppbs.pdf
296 DILTIAZEM HCL check serum calcium on a weekly basis during early stages of treatment; recheck every 2-3 months long-term. Some dogs DILTIAZEM HCL and cats that appear to be resistant to treatment on tablets or (dil-tye-a-zem) Cardizem®, Dilacor XR® capsules may respond to the liquid form. (Feldman 2005a) b) In combination with calcium therapy (initially at 50-100 CALCIUM CHANNEL BLOCKER mg/kg/day divided 3-4 times daily of elemental calcium), give DHT initially at 0. 125-0. 25 mg PO per day for 2-3 days, Prescriber Highlights then 0. 08-0. 125 mg per day for 2-3 days and ﬁnally 0. 05 TT Calcium channel blocker used in dogs, cats, & ferrets mg PO per day until further dosage adjustments are neces-for SVT's, hypertension, or hypertrophic cardiomyopa-sary. Stable serum calcium levels (8. 5-9. 5 mg/dl) are usually thy; may prove useful in horses (after more research achieved in about a week. Continue to monitor and adjust accomplished)dosages of DHT and calcium to lowest levels to maintain nor-mocalcemia. (Peterson and Randolph 1989) ( Note : refer to the TT Contraindications: Severe hypotension, sick sinus syndrome or 2nd or 3rd degree AV block, acute MI, radiographically documented pulmonary congestion, calcium monograph for further information. ) Monitoring hypersensitivity T ! Serum calcium levels should be monitored closely (some clini-TT Caution: Geriatric patients or those with heart failure cians recommend twice daily) during the initial treatment period. (particularly if also receiving beta blockers), or hepatic When the animal is stabilized, frequency may be reduced but nev-or renal impairment er discontinued. All animals receiving DHT therapy should have calcium levels determined at least 2-4 times yearly TT Potential teratogen (high doses) T ! Serum phosphorous (particularly in renal failure patients) Client Information Uses/Indications T ! Clients should be briefed on the clinical signs of hypercalce-Diltiazem may be useful in the treatment of hypertension, atrial ﬁ-mia (polydipsia, polyuria, anorexia) and hypocalcemia (muscle brillation, and supraventricular tachycardias. tremors, twitching, tetany, weakness, stiff gait, ataxia, behavioral Diltiazem was a drug of choice by many clinicians for the treat-changes, and seizures) and instructed to report these symptoms ment of feline hy pertrophic cardiomyopathy, but enthusiasm for its to the veterinarian. use for this indication has cooled considerably in recent years as its efﬁcacy appears questionable. Chemistry/Synonyms A vitamin D analog, dihydrotachysterol (DHT) occurs as odorless, Pharmacology/Actions colorless or white crystals, or crystalline white powder. It is prac-Diltiazem is a calcium-channel blocker similar in action to drugs tically insoluble in water, sparingly soluble in vegetable oils, and such as verapamil or nifedipine. While the exact mechanism remains soluble in alcohol. unknown, diltiazem inhibits the transmembrane inﬂux of extracel-Dihydrotachysterol may also be known as: DHT, dichysterol, or lular calcium ions in myocardial cells and vascular smooth muscle, dihydrotachysterol 2, AT 10, Atiten, DHT®, Dihydral®, Dygratyl®, but does not alter serum calcium concentrations. The net effect of Tachyrol®, or Tachystin®. this action is to inhibit the cardiac and vascular smooth muscle con-tractility, thereby dilating main systemic and coronary arteries. T otal Storage/Stability peripheral resistance, blood pressure, and cardiac afterload are all All DHT products should be stored at room temperature (15-30°C). reduced. Capsules or tablets should be stored in well-closed, light-resistant Diltiazem has effects on cardiac conduction. It slows A V node containers and the oral concentrate should be stored in tight, light-conduction and prolongs refractory times. Diltiazem rarely affects resistant containers. SA node conduction, but in patients with Sick Sinus Syndrome, rest-ing heart rates may be reduced. Dosage Forms/Regulatory Status Although diltiazem can cause negative inotropic effects, it is rare-VETERINARY-LABELED PRODUCTS: None ly of clinical importance (unlike verapamil or nifedipine). Diltiazem HUMAN-LABELED PRODUCTS: apparently does not affect plasma renin, aldosterone, glucose, or in-Note: Although the following dosage forms are still listed in some sulin concentrations. updated human drug references, they have reportedly been discon-Pharmacokinetics tinued by the manufacturer. Dosage forms may be available from In humans after an oral dose, about 80% of the dose is absorbed compounding pharmacies. rapidly from the gut, but because of a high ﬁrst pass effect, only Dihydrotachysterol Oral Tablets: 0. 125 mg, 0. 2 mg & 0. 4 mg; DHT® about half of the absorbed drug reaches the systemic circulation. (Roxane); (Rx) Bioavailability in cats is reported to range from 50-80% with peak Dihydrotachysterol Intensol Solution: 0. 2 mg/m L in 30 m L dropper levels occurring about 45 minutes after oral dosing. In dogs, bio-bottles; DHT® (Roxane); (Rx) availability may only be around 30%. Pharmacokinetics of a long acting product (Cardizem® CD) given at 10 mg/kg once daily to healthy cats were: bioavailability 22-59%; half-life 411 +/-59 min-utes; peak levels achieved in 340 +/-140 minutes. Approximately 75% of the drug is bound to serum proteins in humans. Diltiazem enters milk in concentrations approximating those found in plasma. Diltiazem is rapidly and almost completely metabolized in the liver to several metabolites, including two that are active. Serum half-life in cats is about 2 hours, about 3 hours in dogs, and about 90 minutes	pppbs.pdf
DILTIAZEM HCL 297 in horses. In humans, elimination half-life ranges from 3. 5 to 10 hours. Renal impairment may only slightly increase half-lives. Contraindications/Precautions/Warnings Diltiazem is contraindicated in patients with severe hypotension (<90 mm Hg systolic), sick sinus syndrome or 2nd or 3rd degree A V block (unless a functioning pacemaker is in place), acute MI, radiographically documented pulmonary congestion, or when the patient is hypersensitive to it. Diltiazem should be used with caution in geriatric patients or those with heart failure (particularly if also receiving beta blockers), or hepatic or renal impairment. If giving direct IV administration (push), give over at least two minutes. Adverse Effects At usual doses, bradycardia is the most prominent side effect re-ported in dogs. In cats, vomiting is reported as the most common side effect. Potentially, lethargy, GI distress (anorexia), hypotension, heart block or other rhythm disturbances, CNS effects, rashes, or elevations in liver function tests could occur in either species. Cats receiving the 60 mg sustained-release pellet (found in 240 mg sustained-release capsules) are prone to developing signiﬁcant adverse effects. Reproductive/Nursing Safety High doses in rodents have resulted in increased fetal deaths and skeletal abnormalities. Use during pregnancy only when the ben-eﬁts outweigh the potential risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans. ) Diltiazem is excreted in milk and concentrations may approxi-mate those found in the serum; use during nursing with caution. Overdosage/Acute Toxicity The oral LD 50 in dogs has been reported as >50 mg/kg. Clinical signs noted after overdosage may include heart block, bradycardia, hypotension, and heart failure. Treatment should consist of gut emptying protocols when warranted, and supportive and symp-tomatic treatment. Atropine may be used to treat bradycardias or 2nd or 3rd degree A V block. If these do not respond to vagal block-ade, isoproterenol may be tried (with caution). Fixed block may re-quire cardiac pacing. Inotropics (e. g., dobutamine, dopamine, iso-proterenol) and pressors (e. g., dopamine, norepinephrine) may be required to treat heart failure and hypotension. A slow intravenous calcium infusion (1 m L/10 kg body weight of 10% calcium glucon-ate) may also be useful for severe acute toxicity. Drug Interactions The following drug interactions have either been reported or are theoretical in humans or animals receiving diltiazem and may be of signiﬁcance in veterinary patients: !TANESTHETICS, GENERAL : May increase cardiac depressant effects of diltiazem !TBENZODIAZEPINES : Diltiazem may increase benzodiazepine levels !TBETA-BLOCKERS : Diltiazem may increase the likelihood of brady-cardia, A V block or CHF developing in patients also receiving beta-blockers (including ophthalmic beta-blockers ); additionally, diltiazem may substantially increase the bioavailability of pro-pranolol !TBUSPIRONE : Diltiazem may increase buspirone levels !TDIGOXIN : While data conﬂicts regarding whether diltiazem affects digoxin pharmacokinetics, diligent monitoring of digoxin serum concentrations should be performed !TCIMETIDINE/RANITIDINE : Cimetidine may increase plasma diltiaz-em concentrations; increased monitoring of diltiazem's effects is warranted. Ranitidine may also affect diltiazem concentrations, but to a lesser extent. !TCYCLOSPORINE : Diltiazem may increase cyclosporine serum concentrations; increased monitoring and dosage adjustments may be required !TRIFAMPIN : May decrease diltiazem levels !TQUINIDINE : Diltiazem may increase quinidine serum concentra-tions; increased monitoring and dosage adjustments may be required Doses !TDOGS: For treatment of supraventricular tachyarrhthymias: a) For acute management: 0. 125-0. 35 mg/kg IV; for chronic management: 0. 5-1. 5 mg/kg PO q8h (used in combination with digoxin for patients. with CHF) (Wright 2000) b) For acute treatment of atrial tachycardia: 0. 05-0. 15 mg/kg slowly IV, repeat every 5 minutes to effect or until a total dose of 0. 1-0. 3 mg/kg; or give 0. 5 mg/kg PO followed by 0. 25 mg/ kg PO every hour until conversion or a total oral dose of 1. 5-2 mg/kg has been given. Chronically: May give an initial dose of 0. 5 mg/kg PO q8h up to 2 mg/kg. (Ware 2000) c) For emergency treatment: Initially, 0. 25 mg/kg IV bolus giv-en over 2 minutes; subsequent 0. 25 mg/kg boluses may be repeated at 15 minute intervals until conversion occurs or to a maximum (total) dose of 0. 75 mg/kg. (Rush 2005b) For supraventricular arrhythmias, hypertrophic cardiomyopa-thy, hypertension: a) 0. 5-1. 5 mg/kg PO q8h; titrate upwards to effect (Miller, Tilley et al. 1994) For emergency management of hypertension when the capabili-ties for using nitroprusside are unavailable: a) 0. 5 mg/kg PO q6h (if blood pressure not controlled, may add a beta-blocker (e. g., atenolol) (Brown and Henik 2000) !TCATS: For treatment of supraventricular tachyarrhythmias: a) 0. 5-1 (up to 1. 5) mg/kg PO q8h (Pion 1992) b) For acute management: 0. 125-0. 35 mg/kg IV; for chronic management: 7. 5 mg (per cat) PO q8h (used in combination with digoxin for patients. with CHF unless cat has hyper-trophic cardiomyopathy and atrial ﬁb, then digoxin not used) (Wright 2000) c) For emergency treatment: Initially, 0. 25 mg/kg IV bolus giv-en over 2 minutes; subsequent 0. 25 mg/kg boluses may be repeated at 15 minute intervals until conversion occurs or to a maximum (total) dose of 0. 75 mg/kg. (Rush 2005b) For treatment of hypertrophic cardiomyopathy: a) 7. 5 mg PO q8-12h; Long-acting forms: Cardizem® CD Cap-sules: 10 mg/kg once daily. Dilacor® XR Capsules: 15-30 mg total dose q12-24h. Some cats tolerate 60 mg daily, but vom-iting may be a problem. (Fox 2000) b) 1. 75-2. 5 mg/kg PO q8h or sustained release (Dilacor®) dosed at 30 mg (total dose) PO q12h (Ware and Keene 2000) For supraventricular arrhythmias, hypertrophic cardiomyopa-thy, hypertension: a) 0. 5-2. 5 mg/kg PO q8h (Miller, Tilley et al. 1994)	pppbs.pdf
298 DIMINAZENE ACETURATE For emergency management of hypertension when the capabili-ties for using nitroprusside are unavailable: DIMINAZENE ACETURATE a) 0. 5 mg/kg PO q6h (if blood pressure not controlled, may add (dye-min-ah-zeen ass-ah-toor-ate) Berenil®a beta-blocker (e. g., atenolol) (Brown and Henik 2000) T ! FERRETS: ANTIPROTOZOAL For hypertrophic cardiomyopathy: a) 2-7. 5 mg/kg PO twice daily; adjust as necessary. May result in Prescriber Highlights heart block. (Williams 2000) TT Antiprotozoal agent used in several species for trypano-somiasis, babesiosis, or cytauxzoonosis Monitoring T ! ECG/Heart rate TT Available in several countries, but not in USA T ! Blood pressure T ! Adverse effects Uses/Indications Client Information Diminazene is used to treat trypanosomiasis in dogs and livestock T ! Inform clients of potential adverse effects. Stress adherence to (sheep, goats, cattle), Babesia infections in dogs and horses, and cy-dosing regimen. tauxzoonosis in cats. The drug is not commercially available in the USA, but is available and used in many countries. Chemistry/Synonyms A calcium channel blocker, diltiazem HCl occurs as a white to off-Pharmacology/Actions white crystalline powder having a bitter taste. It is soluble in water Diminazene's exact mechanism of action is not well understood. and alcohol. Potencies may be expressed in terms of base (active With Babesia, it is thought to interfere with aerobic glycolysis and moiety) and the salt. Dosages are generally expressed in terms of DNA synthesis. the salt. Diminazene may not completely eradicate the organism but be-Diltiazem may also be known as: CRD-401, diltiazemi hydro-cause it is slowly metabolized, suppression of recurrence of clinical chloridum, latiazem hydrochloride, and MK-793; many trade names signs or prophylaxis can be attained for several weeks after a single are available. dose. Storage/Stability/Compatibility Pharmacokinetics Diltiazem oral products should be stored at room temperature in Diminazene's pharmacokinetics have been investigated in several tight, light resistant containers. species. The drug is rapidly absorbed after IM administration in tar-The powder for injection should be stored between 15-30°C. get species studied and distributed rapidly. High levels can be found After reconstituting, discard after 24 hours. Diltiazem is compatible in the liver and kidney. The drug appears to enter the CSF, but at lev-with D5W and sodium chloride 0. 9% digoxin, bumetanide, dobu-els signiﬁcantly lower than that found in plasma in healthy animals. tamine, dopamine, epinephrine, lidocaine, morphine, nitroglycerin, CSF levels are higher in infected dogs with African trypanosomiasis, potassium chloride, sodium nitroprusside, and vasopressin. It is in-probably due to meningeal inﬂammation. Diminazene apparently is compatible with diazepam, furosemide, phenytoin and thiopental. metabolized somewhat in the liver, but identiﬁcation and whether metabolites possess anti-protozoal activity is not known. Dosage Forms/Regulatory Status Elimination half-lives are reportedly widely variable. Reported VETERINARY-LABELED PRODUCTS: None values range from 10-30 hours in dogs, goats, and sheep, to over The ARCI (Racing Commissioners International) has designated this 200 hours in one study for cattle. Differences in assay methodology drug as a class 4 substance. See the appendix for more information. and study design may account for some of this variation, but even within an individual study in dogs using a modern assay (HPLC), HUMAN-LABELED PRODUCTS: wide inter-patient variability was noted. Diltiazem Tablets: 30 mg, 60 mg, 90 mg, and 120 mg; Cardizem® (Biovail); generic; (Rx) Contraindications/Precautions/Warnings Camels appear highly susceptible to the toxic effects of dimina-mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg and 420 mg; Cardizem Diltiazem Tablet & Capsules Extended/Sustained Release: 60 mg, 90 zene, and product labels may state the drug is contraindicated in camelids. CD® & LA ® (Biovail); Cartia XT® (Andrx); Dilacor XR® (Watson); Tiazac® (Forest), Diltia XT® & Taztia XT® (Andrx); Dilt-CD® & Adverse Effects XR® (Apotex); generic; (Rx) At usual dosages in domestic livestock, diminazene is reportedly Diltiazem Injection: 5 mg/m L in 5, 10 and 25 m L vials; 25 mg in relatively free of adverse effects. Adverse effects associated with single-use containers (carton of 6 Lyo-Ject syringes with diluent); therapeutic dosages of diminazene in dogs may include vomiting Cardizem® (Biovail); generic; (Rx) and diarrhea, pain and swelling at the injection site, and transient decreases in blood pressure. Very rarely (<0. 1%) ataxia, seizures, or death have been reported. Reproductive/Nursing Safety Little information is available. Rats given up to 1 g/kg PO on days 8-15 demonstrated no teratogenic effects, but decreased body weights and increased resorptions were noted at the highest dose. Diminazene is distributed into milk; safety for nursing offspring has not been established.	pppbs.pdf
DIMENHYDRINATE 299 Overdosage/Acute Toxicity Little information is available. Diminazene appears most toxic in dogs and camels. Dosages greater than 7 mg/kg can be very toxic to camels; dosages above 10 mg/kg IM in dogs can cause severe gastro-intestinal, respiratory, nervous system, or musculoskeletal effects. Drug Interactions No signiﬁcant drug interactions were identiﬁed. Laboratory Considerations No issues were noted. Doses Note : There is a multitude of protozoal diseases worldwide that may respond to diminazene. Depending on the species/strain (proto-zoan) and species of the patient treated, there may be local speciﬁc recommendations for chemotherapy treatment or prevention. The following should be used as general guidelines only. T ! DOGS: For treatment of Babesia: a) 3. 5-5 mg/kg IM, once for B. canis, repeat in 24 hours for B. gibsoni. Risk for neurotoxicity higher when total dosages are 7 mg/kg or higher. (T oboada and Lobetti 2006) b) For small Babesia (Okinawa): 3. 5 mg/kg IM; repeat once in 24 hours. (Brosey 2003) c) For treatment of Babesia (South Africa): 4. 2 mg/kg IM. Do not repeat within a 21-day period. (Miller, Swan et al. 2005) For treatment of African trypanosomiasis: a) 3. 6-7 mg/kg IM every 2 weeks as needed to control relapse or reinfection. (Barr 2006b) T ! CATS: For treatment of cytauxzoonosis: a) 3-5 mg/kg IM one time, tick control remains the best means of preventing disease as treatment attempts meet with little success. (Blagburn 2005a) b) 2 mg/kg IM, repeat in one week. (Greene, Meinkoth et al. 2006) T ! HORSES, CATTLE, SHEEP, GOATS: For treatment of susceptible protozoal (Trypanosomes, Babesia) infections (West Africa): a) In general, 3. 5 mg/kg IM one time. Depending on susceptibil-ity, dose can be increased to 8 mg/kg. Do not exceed 4 grams total dose per animal. (Label directions; Berenil®—Intervet West Africa) Monitoring T ! For Babesia infections in dogs monitoring would include surveil-lance for potential adverse effects of diminazene and signs for clinical efﬁcacy, including monitoring serial CBCs. Severe cases may have elevated BUN or liver enzymes and hypokalemia. T ! Current recommendation for determining “clearing” of the or-ganism (Babesia gibsoni) is to perform a PCR test at 60 and 90 days post-therapy Client Information T ! Clients should understand that depending on the species treated, parasites may not be completely eradicated and that retreatment may be required Chemistry/Synonyms Diminazene aceturate is an aromatic diamidine derivative chemi-cally related to pentamidine. One gram of diminazene is soluble in approximately 14 m L of water and it is slightly soluble in alcohol. Diminazene aceturate may also be known as: diminazene di-aceturate, or diminazeno; many international trade names are available. Storage/Stability Read and follow label directions for storage and preparation of each product used; diminazene powder, granules, or packets for recon-stitution for injection should generally be stored in a dry, cool place out of direct sunlight. Once reconstituted, the solution's stability is temperature dependent; up to 14 days when refrigerated, up to 5 days at 20°C and only for 24 hours at temperatures above 50°C. Dosage Forms/Regulatory Status VETERINARY-LABELED PRODUCTS: None in the USA. Diminazene aceturate is available in many countries either alone, or in combination products (e. g., with antipyrine), with the following trade names: Azidine®, Azidin®, Babezeen®, Crede-Bab-Minazene®, Berenil®, Dimisol®, Dizine®, Ganaseng®, Ganasegur®, Pirocide®, or Veriben®. The FDA may allow legal importation of this medication for com-passionate use in animals; for more information, see the Instruc-tions for Legally Importing Drugs for Compassionate Use in the USA found in the appendix. Withdrawal times may vary depending on the product, dosage, and the country where it is used. In South Africa, Berenil® (Intervet), has an animal slaughter withdrawal period of 21 days. The JECFA of FAO/WHO has established the following maximum residue limit recommendations for diminazene in cattle: muscle (500 mcg/kg), liver (12000 mcg/kg), kidney (6000 mcg/kg), and milk (150 mcg/L). HUMAN-LABELED PRODUCTS: None DIMENHYDRINATE (dye-men-hye-dri-nate) Dramamine® ANTIHISTAMINE Prescriber Highlights TT Antihistamine used primarily for prevention of motion sickness in dogs & cats; may be useful as an adjunctive treatment for feline pancreatitis TT Contraindications: Hypersensitivity to it or others in class. TT Caution: Angle closure glaucoma, GI or urinary obstruc-tion, COPD, hyperthyroidism, seizure disorders, cardiovas-cular disease or hypertension; may mask clinical signs of ototoxicity TT Adverse Effects: CNS depression & anticholinergic ef-fects. GI effects (diarrhea, vomiting, anorexia) are less common Uses/Indications In veterinary medicine, dimenhydrinate is used primarily for its an-tiemetic effects for vomiting and in the prophylactic treatment of motion sickness in dogs and cats. Dimenhydrinate may be useful as an adjunctive treatment for feline pancreatitis. As dimenhydrinate is often thought of as “half-strength diphenhydramine” it can be employed whenever a histmine-1 blocker is desired.	pppbs.pdf
300 DIMENHYDRINATE Pharmacology/Actions Dimenhydrinate has antihistaminic (H1), antiemetic, anticholin-ergic, CNS depressant and local anesthetic effects. These principle pharmacologic actions are thought to be a result of only the diphen-hydramine moiety. Used most commonly for its antiemetic/motion sickness effects, dimenhydrinate's exact mechanism of action for this indication is unknown, but the drug does inhibit vestibular stimula-tion. The anticholinergic actions of dimenhydrinate may play a role in blocking acetylcholine stimulation of the vestibular and reticular systems. T olerance to the CNS depressant effects can ensue after a few days of therapy and antiemetic effectiveness may also diminish with prolonged use. Theoretically, histamine-1 (diphenhydramine, dimenhydrinate, etc. ) and histamine-2 (ranitidine, famotidine, etc. ) blockers may re-duce histamine-mediated increases in microvasculature permeabil-ity that is associated with the development of hemorrhagic necrosis in feline pancreatitis. Pharmacokinetics The pharmacokinetics of this agent have apparently not been studied in veterinary species. In humans, the drug is well absorbed after oral administration with antiemetic effects occurring within 30 minutes of administration. Antiemetic effects occur almost immediately af-ter IV injection. The duration of effect is usually 3-6 hours. Diphenhydramine is metabolized in the liver, and the majority of the drug is excreted as metabolites into the urine. The terminal elimination half-life in adult humans ranges from 2. 4-9. 3 hours. Contraindications/Precautions/Warnings Dimenhydrinate is contraindicated in patients who are hyper-sensitive to it or to other antihistamines in its class. Because of their anticholinergic activity, antihistamines should be used with caution in patients with angle closure glaucoma, prostatic hypertrophy, py-loroduodenal or bladder neck obstruction, and COPD if mucosal secretions are a problem. Additionally, they should be used with caution in patients with hyperthyroidism, seizure disorders, cardio-vascular disease or hypertension. It may mask the clinical signs of ototoxicity and should therefore be used with this knowledge when concomitantly administering with ototoxic drugs. The sedative effects of antihistamines, may adversely affect the performance of working dogs. Adverse Effects Most common adverse reactions seen are CNS depression (lethargy, somnolence) and anticholinergic effects (dry mouth, urinary reten-tion). GI effects (diarrhea, vomiting, anorexia) are less common, but have been noted. The sedative effects of antihistamines may dimin-ish with time. Reproductive/Nursing Safety In humans, the FDA categorizes this drug as category B for use dur-ing pregnancy (Animal studies have not yet demonstrated risk to the fetus, but there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, but adequate studies in pregnant women have not demonstrated a risk to the fetus in the ﬁrst trimester of pregnancy, and there is no evidence of risk in later trimesters. ) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: B (Safe for use if used cautiously. Studies in laboratory animals may have un-covered some risk, but these drugs appear to be safe in dogs and cats or these drugs are safe if they are not administered when the animal is near term. ) Small amounts of dimenhydrinate are excreted in milk; this is unlikely to pose much risk to nursing offspring. Overdosage/Acute Toxicity Overdosage may cause CNS stimulation (excitement to seizures) or depression (lethargy to coma), anticholinergic effects, respiratory depression and death. Treatment consists of emptying the gut if the ingestion was oral. Induce emesis if the patient is alert and CNS sta-tus is stable. Administration of a saline cathartic and/or activated charcoal may be given after emesis or gastric lavage. Treatment of other clinical signs should be performed using symptomatic and supportive therapies. Phenytoin (IV) is recommended in the treat-ment of seizures caused by antihistamine overdose in humans; use of barbiturates and diazepam are avoided. Drug Interactions Dimenhydrinate has been demonstrated to induce hepatic mi-crosomal enzymes in animals (species not speciﬁed); the clinical implications of this effect are unclear. The following drug interactions have either been reported or are theoretical in humans or animals receiving dimenhydrinate and may be of signiﬁcance in veterinary patients: !TANTICHOLINERGIC D RUGS (including tricyclic antidepressants ): Di-menhydrinate may potentiate the anticholinergic effects of other anticholinergic drugs !TCNS DEPRESSANT D RUGS : Increased sedation can occur if dimenhy-drinate (diphenhydramine) is combined with other CNS depres-sant drugs Laboratory Considerations !TAntihistamines can decrease the wheal and ﬂare response to anti-gen skin testing. In humans, it is suggested that antihistamines be discontinued at least 4 days before testing. Doses !TDOGS: For prevention and treatment of motion sickness: a) 25-50 mg PO once to 3 times a day (Morgan 1988) b) 4-8 mg/kg PO q8h (Washabau and Elie 1995), (Dowling 2003a) As an antihistamine: a) 4-8 mg/kg q8-12h (Papich 2000) !TCATS: For prevention and treatment of motion sickness/vomiting: a) 12. 5 mg (total dose) PO q8h (Davis 1985b) b) 12. 5 mg PO once to 3 times a day (Morgan 1988) c) 8 mg/kg PO q8h (De Novo 1986), (Scherk 2003c) d) 4-8 mg/kg PO q8h (Washabau and Elie 1995), (Dowling 2003a) As an antihistamine: a) 4 mg per cat PO q8h (Scherk 2006) For adjunctive treatment of pancreatitis: a) 8 mg/kg PO q8h (Scherk 2005a) Monitoring !TClinical efﬁcacy !TAdverse effects (sedation, anticholinergic signs, etc. ) Chemistry/Synonyms An ethanolamine derivative antihistamine, dimenhydrinate contains approximately 54% diphenhydramine and 46% 8-chlorotheophyl-line. It occurs as an odorless, bitter-tasting and numbing, white crys-talline powder with a melting range of 102°-107°C. Dimenhydrinate is slightly soluble in water and is freely soluble in propylene glycol or alcohol. The p H of the commercially available injection ranges from 6. 4 to 7. 2.	pppbs.pdf