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Introduction

Although many drugs may be used legally in both human and animal patients, certain drugs have unique human toxicities and are approved for use only in non-human species. In some cases, these drugs were approved initially for use in humans but withdrawn after serious adverse effects emerged. In other cases, these drugs were identified as toxic to humans early in development and never approved for human use.

Given that pharmacists are the only health care professionals expected by society to provide pharmaceutical care for all species, it is highly likely that pharmacists will encounter prescriptions for veterinary-only medications. Accordingly, it is critically important that pharmacists possess a working knowledge of the names, mechanisms of action, indications, dosing, adverse effects, safety profiles, and counseling points for drugs that may belong to similar therapeutic classes as those used in humans but may cause serious adverse effects if dispensed to a human accidentally. Even more important, because medication administration to animals by necessity involves a human, pharmacists must be able to advise human caregivers about possible risks from veterinary drugs.

More than 1,400 drugs are approved by the Food and Drug Administration (FDA) Center for Veterinary Medicine. Modules 5 and 6 focus on the 25 veterinary drugs most likely to be encountered by community pharmacists. (Because of the sheer number of parasiticides available, the modules do not address flea and tick products, heartworm preventatives, or anthelmintics.)

This module covers antimicrobial agents and nonsteroidal anti-inflammatory drugs (NSAIDs). Module 6 covers hormonal drugs and selected individual agents.

Antimicrobial Agents

The veterinary antimicrobial agents most likely to be encountered by community pharmacists are cefovecin, enrofloxacin, marbofloxacin, pradofloxacin, florfenicol, tilmicosin, and tylosin tartrate.

Cefovecin (Convenia)

Cefovecin (sef-oh-VEH-sin) is a third-generation cephalosporin antibiotic. Its bactericidal action comes through binding bacterial transpeptidase and carboxypeptidase and interfering with cell wall synthesis. Minimum inhibitory concentrations (MICs) <2 mcg/mL are recommended as the breakpoint.

Cefovecin is not as active against gram-negative organisms as cefotaxime or ceftazidime. It is not effective against Pseudomonas species, methicillin-resistant Staphylococcus, or enterococcus.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Cefovecin Summary.

Indications. Cefovecin is indicated for the treatment of skin and wound infections in dogs and cats. It has been used off-label to treat urinary tract infections in dogs and cats. It also was reported to be effective for septic peritonitis in a captive lion.¹

Dosage. Cefovecin is administered via subcutaneous injection, typically at the veterinarian’s office. The usual dosage for dogs and cats is 8 mg/kg as a single injection. In dogs, a second dose of cefovecin may be administered in 7 to 14 days, not to exceed two injections total.

Pharmacokinetics. Cefovecin is highly protein bound after injection (98.5% in dogs and 99.8% in cats) and dissociates slowly, providing a long elimination half-life. Cefovecin can be detected for 65 days after administration in dogs and cats. In other species, cefovecin apparently binds selectively to proteins and may or may not have a long elimination half-life. It has a favorable pharmacokinetic profile in marine mammals but not sharks.^2,3 Cefovecin is not suitable for use in birds, reptiles, or non-human primates because of a poor pharmacokinetic profile (low plasma protein binding).^4,5

Cefovecin undergoes primarily renal elimination, with the majority of a dose excreted unchanged in the urine. A small portion of drug may be secreted in bile.

Adverse Reactions. The adverse reactions reported most commonly in dogs and cats treated with cefovecin are lethargy, anorexia, and vomiting. Because of the long elimination half-life of cefovecin, adverse reactions may take up to 2 months to resolve. Anaphylaxis is possible, especially in animals with β-lactam hypersensitivity.

Some animals treated with cefovecin have moderate to mild increases in hepatic enzymes and blood urea nitrogen (BUN)/creatinine. Anemia has been reported in cats.

Monitoring. Patients should be monitored for efficacy (resolution of infection) at 1 to 2 weeks following injection. Serum chemistries should be performed to check hepatic enzymes and BUN/creatinine if adverse reactions occur.

Safety Considerations for Humans. Humans could be exposed to cefovecin via the dermal, ocular, or subcutaneous routes. Irritation studies with the active substance indicate that cefovecin is unlikely to be irritating to the skin or eye. Accidental self- injection during drug administration likely would involve a very small amount of active drug. The dose of cefovecin is 1 mL of reconstituted product per 10 kg of body weight; in a worst-case scenario, the maximum self-injection volume would be 4 mL (320 mg cefovecin for a 40-kg dog), which translates to 5.3 mg/kg for a 60-kg person.

Cephalosporins may cause hypersensitivity reactions following injection, inhalation, ingestion, or skin contact. Symptoms (e.g., skin rash; swelling of the face, lips, or eyes; difficulty breathing) can be serious and may require urgent medical attention. Animal caregivers should handle cefovecin with great care to avoid exposure, taking all recommended precautions.

Hypersensitivity to penicillins may lead to cross-sensitivity to cephalosporins and vice versa. Animal caregivers allergic to penicillins or cephalosporins should avoid contact with contaminated pet waste and litter. In the event of contact, caregivers should wash the affected skin with soap and water.

Pharmacist Scenario Example: Cefovecin A dog owner presents to the pharmacy with a prescription for firocoxib, a nonsteroidal anti-inflammatory drug (NSAID) for veterinary use. Her dog is recovering from wounds suffered in a fight with another dog. A discussion of recent medical history reveals that the dog had an injection of cefovecin 4 days ago at the veterinary clinic. Firocoxib is >96% protein bound and may displace circulating cefovecin, reducing antibiotic effect. You contact the veterinarian to inform him of this risk.

Enrofloxacin (Baytril)

Enrofloxacin (en-roe-FLOX-a-sin) is a fluoroquinolone antibiotic. It is a concentration-dependent bactericidal agent that works by inhibiting bacterial DNA-gyrase (a type-II topoisomerase), thereby preventing DNA supercoiling and DNA synthesis.

Fluoroquinolone antibiotics generally have weak activity against Streptococcus speciesand anaerobic organisms and may confer rapid resistance in Pseudomonas species.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Enrofloxacin Summary.

Indications. Enrofloxacin is indicated for the treatment of infections caused by susceptible bacteria in dogs and cats.

Dosage. Enrofloxacin is administered orally in dogs and cats. In dogs, the weight-based dosage of enrofloxacin is 5–20 mg/kg (2.27–9.07 mg/lb) daily, based on disease severity and pathogen susceptibility. The total daily amount may be administered as a single dose or two equally divided doses administered at 12-hour intervals. Enrofloxacin should be administered for at least 2–3 days after cessation of clinical signs, to a maximum of 30 days.

Although enrofloxacin is approved for use in cats, most veterinary clinicians consider it to be relatively contraindicated because of the risk of retinal toxicity (see Adverse Effects section). The prescribing information states the oral dosage as 5 mg/kg (2.27 mg/lb) administered as a single daily dose or two divided doses administered at 12-hour intervals.

Enrofloxacin has an extremely bitter taste. Film-coated tablets should be administered intact (i.e., not crushed) if possible. Fractionated tablets should be placed in a food ball for administration.

Enrofloxacin is not approved for use in horses. When it is used off-label, the oral dosage of enrofloxacin is 5–7.5 mg/kg every 24 hours; the intravenous dosage is 5 mg/kg every 24 hours.⁶

When enrofloxacin is administered to food-producing animals, it must be used exactly as directed in approved labeling. Extra-label use of enrofloxacin in food-producing animals is prohibited by law.

Various dosing regimens for administration to exotic animals have been published, all within the range of 5–20 mg/kg every 12–24 hours orally or as a subcutaneous or intramuscular injection. Species-specific drug references should be consulted prior to dispensing.

Pharmacokinetics. Enrofloxacin is absorbed well following oral administration in most species. Food delays the rate but not the extent of absorption. Foods with increased divalent or trivalent cation concentrations (e.g., dairy and iron products) chelate fluoroquinolones and reduce bioavailability.

Enrofloxacin is widely distributed, with high concentrations in the bile, kidney, liver, lungs, reproductive system (including prostatic fluid and tissue), and macrophages. Concentrations are not as high in bone, synovial fluid, skin, muscle, aqueous humor, or pleural fluid. Enrofloxacin does not distribute well into the central nervous system (CNS).

Enrofloxacin is converted to a number of metabolites, many of which are less active than the parent drug. Approximately 10%–40% of the parent drug is metabolized to ciprofloxacin in most species. Metabolites are eliminated in both the urine (30%–50%) and feces.

Adverse Reactions. The adverse reactions reported most commonly during treatment with enrofloxacin are vomiting, nausea, and diarrhea. Enrofloxacin is best administered on an empty stomach; however, doses may be administered with food or a small treat to animals that vomit or act sick after dosing. To avoid possible chelation, enrofloxacin should not be administered concurrently with dairy products or any food or supplement (e.g., vitamins) containing calcium, iron, zinc, or aluminum (see Drug Interactions section in Enrofloxacin Summary).

Enrofloxacin has the potential to cause severe photosensitization in animals if applied topically. (See Safety Considerations for Humans section.) If dermal contact occurs, the affected area should be washed thoroughly with soap and water and the animal should be kept out of direct sunlight.

Enrofloxacin can causeretinal toxicity and blindness in cats at doses greater than 5 mg/kg/day.Feline-specific amino acid changes in the ABCG2 transporter at the blood–aqueous barrier cause a functional defect of the transport protein, allowing enrofloxacin to enter the inner eye. When light enters the inner eye through the pupil, enrofloxacin is photoactivated to reactive oxygen species that are toxic to the retina.⁷ A safer alternative (e.g., marbofloxacin) should be considered.

Injectable formulations of enrofloxacin are highly alkaline and cause tissue damage and pain when administered by the subcutaneous or intramuscular route. Intrauterine infusion of enrofloxacin also can cause serious tissue damage, including endometrial ulceration, necrosis, fibrosis, inflammation and hemorrhage.

Injectable enrofloxacin solution should not be administered orally. According to one report, three of six horses treated with an oral enrofloxacin gel compounded using the injectable solution became inappetent because of mucosal lesions; a fourth horse also developed mucosal ulcerations but did not become inappetant.⁸ If the injectable solution must be administered orally, the animal’s oral cavity should be rinsed thoroughly following administration.

Rapid intravenous administration of enrofloxacin to horses causes ataxia and other neurologic effects and should be avoided.

Based on reports involving administration to rodents, enrofloxacin may lower the seizure threshold and should be used carefully in patients with a history of seizures.

Enrofloxacin may cause cartilage erosion and stunt bone growth or cause joint abnormalities in developing animals. Consequently, enrofloxacin is relatively contraindicated in small and medium dog breeds up to 8 months of age, large breeds up to 12 months, and giant breeds up to 18 months. It also is labeled as contraindicated in cats younger than 12 months of age.

Monitoring. Culture and sensitivity testing should be performed to assess the efficacy of enrofloxacin therapy. Cats should be monitored for mydriasis (an early sign of retinal damage), squinting, or any sign of vision loss.

Safety Considerations for Humans. The addition of an ester group to the piperazinyl ring of ciprofloxacin confers additional lipophilicity to enrofloxacin over ciprofloxacin. In humans, this functional group also leads to hallucinations, severe headache, sleep disturbances, vivid dreams, and seizures. Many anecdotal stories of CNS stimulation in humans exist, but no controlled studies have been published.

In humans, there is a risk of photosensitization within a few hours after dermal exposure to quinolones (including enrofloxacin). If dermal contact occurs, the affected area should be washed with soap and water and protected from direct sunlight. In cases of ocular exposure, the eyes should be flushed immediately with copious amounts of water for 15 minutes. A physician should be consulted if irritation persists following ocular or dermal exposure.

Individuals with a history of hypersensitivity to fluoroquinolones should avoid contact with enrofloxacin.

Pharmacist Scenario Example: Enrofloxacin A dog owner presents a prescription for enrofloxacin 68-mg chewable treat tablets by mouth every 12 hours for her 10-kg dog. The dog’s patient profile indicates a food allergy and states that chewable treats are to be avoided. You contact the prescribing veterinarian to confirm whether flavored or film-coated tablets should be dispensed to this patient.

Marbofloxacin (Zeniquin)

Marbofloxacin (mar-boe-FLOX-a-sin) is a fluoroquinolone antibiotic. Like enrofloxacin, it is a concentration-dependent bactericidal agent that works by inhibiting bacterial DNA-gyrase (a type-II topoisomerase), thereby preventing DNA supercoiling and DNA synthesis.

Fluoroquinolone antibiotics generally have weak activity against Streptococcus speciesand anaerobic organisms and may confer rapid resistance in Pseudomonas species.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Marbofloxacin Summary.

Indications. Marbofloxacin is indicated for the treatment of skin and soft tissue infections in dogs and cats and urinary tract infections in dogs caused by bacteria susceptible to marbofloxacin.

Dosage. In dogs and cats, marbofloxacin is administered orally at dosages of 2.75–5.5 mg/kg once daily. Treatment for skin and soft tissue infections should continue for 2–3 days after cessation of clinical signs. Treatment for urinary tract infections in dogs should continue for at least 10 days.

Marbofloxacin has an extremely bitter taste. Film-coated tablets should be administered intact (i.e., not crushed) if possible. Fractionated tablets should be placed in a food ball for administration.

Marbofloxacin is not approved for use in other species. When it is used off-label in horses, the dosage is 2 mg/kg by mouth every 24 hours.⁹ Marbofloxacin also has been used to treat ball pythons (Python regius) at a dosage of 10 mg/kg orally at least every 48 hours.¹⁰

Pharmacokinetics. Marbofloxacin is absorbed rapidly and almost completely following oral administration, with 94% bioavailability in dogs and 99% bioavailability in cats. Bioavailability is lower in horses (60%). Foods with increased divalent or trivalent cation concentrations (e.g., dairy and iron products) chelate fluoroquinolones and reduce bioavailability.

Approximately 15% of a dose of marbofloxacin is metabolized in the liver. Marbofloxacin is eliminated primarily as unchanged drug in the urine, feces, or (to a lesser extent) bile, with approximately 40% of a dose excreted in the urine.

Adverse Reactions. The adverse reactions reported most commonly in dogs and cats treated with marbofloxacin are vomiting, nausea, and diarrhea. Animals also may experience inappetence or anorexia. Although marbofloxacin is best administered on an empty stomach, doses may be administered with food or a small treat to animals that vomit or act sick after dosing. To avoid possible chelation, marbofloxacin should not be administered concurrently with dairy products or any food or supplement (e.g., vitamins) containing calcium, iron, zinc, or aluminum (see Drug Interactions section in Marbofloxacin Summary).

Marbofloxacin has the potential to cause severe photosensitization in animals if applied topically (see Safety Considerations for Humans section). If dermal contact occurs, the affected area should be washed thoroughly with soap and water and the animal should be kept out of direct sunlight.

In contrast to enrofloxacin, marbofloxacin did not produce ocular lesions in cats at doses up to 10 times greater than the upper end of the labeled dosing range.¹¹

Although no cases have been documented, marbofloxacin could lower the seizure threshold and should be used carefully in patients with a history of seizures.

Like enrofloxacin, marbofloxacin may cause cartilage erosion and stunt bone growth or cause joint abnormalities in developing animals. Consequently, marbofloxacin is relatively contraindicated in small and medium dog breeds up to 8 months of age, large breeds up to 12 months, and giant breeds up to 18 months. It also is labeled as contraindicated in cats younger than 12 months of age.

Monitoring. Culture and sensitivity testing should be performed to assess the efficacy of marbofloxacin therapy.

Safety Considerations for Humans. In humans, there is a risk of photosensitization within a few hours after dermal exposure to quinolones (including marbofloxacin). If dermal contact occurs, the affected person should wash the area with soap and water and avoid direct sunlight. In cases of ocular exposure, the eyes should be flushed immediately with copious amounts of water for 15 minutes. A physician should be consulted if irritation persists following ocular or dermal exposure.

Individuals with a history of hypersensitivity to fluoroquinolones should avoid contact with marbofloxacin.

Pharmacist Scenario Example: Marbofloxacin A cat owner presents a prescription for marbofloxacin 25 mg by mouth every 24 hours for her 5-kg cat. When the owner sees the film-coated tablets, she expresses doubt about her ability to administer them to her cat and asks whether a liquid formulation of marbofloxacin is available. You consult the USP Compounding Compendium and find a verified formula for Marbofloxacin Compounded Oral Suspension 25 mg/mL. You contact the veterinarian to convey the cat owner’s request and ask if it is okay to dispense the compounded marbofloxacin suspension. You remind the veterinarian that another option is to switch to a commercially available veterinary liquid fluoroquinolone (pradofloxacin oral suspension).

Pradofloxacin (Veraflox)

Pradofloxacin (pra-doe-FLOX-a-sin) is a unique, third-generation fluoroquinolone antibiotic with enhanced activity against aerobic gram-positive organisms and activity against anaerobic organisms. Like enrofloxacin and marbofloxacin, it is a concentration-dependent bactericidal agent that works by inhibiting bacterial DNA-gyrase (a type-II topoisomerase), thereby preventing DNA supercoiling and DNA synthesis.

Pradofloxacin is the only antibiotic that has been proven to eliminate Mycoplasma haemofelis from the blood of experimentally inoculated cats.¹²

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Pradofloxacin Summary.

Indications. Pradofloxacin is approved for the treatment of skin infections (wounds and abscesses) in cats caused by susceptible strains of Pasteurella multocida, Streptococcus canis, Streptococcus aureus, Staphylococcus felis, and Staphylococcus pseudointermedius. Pradofloxacin has been used off-label in cats to treat urinary tract infections, Mycoplasma haemofelis respiratory infections, and other Mycobacterial infections (e.g., feline leprosy).

Pradofloxacin is not approved for use in dogs in the United States because of reports of bone marrow suppression, potentially resulting in severe thrombocytopenia and neutropenia. Myelosuppression was observed during a toxicity study using doses six times greater than the recommended dose; myelosuppression is not seen at usual doses in dogs (3–4.5 mg/kg every 24 hours). Pradofloxacin is approved for use in dogs in the United Kingdom, for the following indications:

• Wound infections caused by susceptible strains of the Staphylococcus pseudointermedius group (including S. pseudointermedius).
• Superficial and deep pyoderma caused by susceptible strains of the Staphylococcus pseudointermedius group (including S. pseudointermedius).
• Acute urinary tract infections caused by susceptible strains of Eschericia coli and the Staphylococcus pseudointermedius group (including S. pseudointermedius).
• Adjunctive treatment to mechanical or surgical periodontal therapy in the treatment of severe infections of the gingiva and periodontal tissues caused by susceptible strains of anaerobic organisms (e.g., Porphyromonas species and Prevotella species).

Many U.S. veterinarians prescribe pradofloxacin suspension for use in dogs if benefit outweighs risk, and they monitor closely for bone marrow suppression. However, orbifloxacin (Orbax Oral Suspension)—a liquid fluoroquinolone formulation approved for use in dogs in the United States—is a better and safer choice than pradofloxacin.

Dosage. Pradofloxacin is administered orally to cats at a dosage of 7.5 mg/kg every 24 hours. However, this is the equivalent of 0.3 mL/kg of the commercially available oral suspension (25 mg/mL), which translates into a relatively large administration volume for cats that weigh more than 5 kg (11 pounds).

Pharmacokinetics. Pradofloxacin is absorbed rapidly following oral administration. The bioavailability of an oral dose is 60%–70%. Pradofloxacin is widely distributed, with high concentrations in cartilage, liver, kidneys, and interstitial fluid.

Pradofloxacin is metabolized primarily via glucuronidation and sulfation. In cats,approximately 40% of an administered dose is excreted in the urine, with 85% eliminated within 24 hours. Approximately 40% of a dose is excreted unchanged, with the remainder excreted primarily as glucuronide metabolites.

Adverse Reactions. Vomiting, nausea, and diarrhea are the most common adverse effects of treatment with pradofloxacin. Animals also may experience inappetence or anorexia. Although pradofloxacin is best administered on an empty stomach, doses may be administered with food or a small treat to animals that vomit or act sick after dosing. To avoid possible chelation, pradofloxacin should not be administered concurrently with dairy products or any food or supplement (e.g., vitamins) containing calcium, iron, zinc, or aluminum (see Drug Interactions section in Pradofloxacin Summary).

Pradofloxacin may cause cartilage erosion and stunt bone growth or cause joint abnormalities in developing animals. Pradofloxacin use is contraindicated in cats younger than 12 months of age. It also should not be used in small and medium dog breeds up to 8 months of age, large breeds up to 12 months, and giant breeds up to 18 months.

Although no cases have been documented, pradofloxacin could lower the seizure threshold and should be used carefully in patients with a history of seizures.

Pradofloxacin may prolong the QT interval in dogs.¹³

Monitoring. Culture and sensitivity testing should be performed to assess the efficacy of pradofloxacin therapy. If pradofloxacin is administered to dogs, follow-up examination is very important to monitor for adverse effects on bone marrow and heart function. Follow-up should include a complete blood count (CBC) and electrocardiogram (ECG) to detect myelosuppression or prolonged QT interval.

Safety Considerations for Humans. In humans, there is a risk of photosensitization within a few hours after dermal exposure to quinolones. However, pradofloxacin was shown to have a moderate photoreactive potential in guinea pigs and a low photoreactive potency in mice, as well as a relatively lower risk of photosensitization compared to other quinolones. Pradofloxacin also is considered to be nonirritating to eyes and skin.¹⁴

Individuals with a history of hypersensitivity to fluoroquinolones should avoid contact with marbofloxacin.

Pharmacist Scenario Example: Pradofloxacin The owner of a 5-kg dog suffering from deep Staphylococcal pyoderma presents with a prescription for pradofloxacin 20 mg by mouth every 24 hours for 21 days. You dispense a 30 mL bottle of Veraflox and mark the provided dosing syringe at the level of the correct dosing amount (the 0.8 mL mark). You counsel the pet owner to shake the suspension well before using and show her how to draw up the correct amount. You also remind the owner to watch her dog for unusual bleeding, bruising, or fever (all signs of possible bone marrow suppression) and to contact the veterinarian immediately if she notices any of these.

Florfenicol (NuFlor, Osurnia Otic Gel)

Florfenicol (flor-FEN-i-kol) is a chloramphenicol derivative substituted with fluorine at the 3-carbon position. This substitution reduces the sites available for bacterial inactivation by acetylation. Florfenicol is more potent than chloramphenicol; it also lacks the para-nitro group that is responsible for chloramphenicol-induced aplastic anemia.

Chloramphenicol derivatives inhibit bacterial protein synthesis at the 50S ribosomal subunit.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Florfenicol Summary.

Indications. In the United States, florfenicol injectable solution is approved for use in cattle only, for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, or Mycoplasma bovis. Veterinarians may occasionally prescribe oral use of the injectable product for dogs and exotic animals. Florfenicol injectable solution should not be used systemically in cats because of the high concentration of propylene glycol, which may cause Heinz body anemia in cats.

An otic gel combination product contains florfenicol 10 mg, terbinafine 10 mg, and betamethasone acetate 1 mg in each 1-mL, single-dose tube. The otic gel is approved for use in dogs for the treatment of otitis externa associated with susceptible strains of bacteria (Staphylococcus pseudointermedius) and yeast (Malassezia pachydermatis). Many veterinarians use florfenicol injectable solution topically for otitis if steroids are contraindicated or if there is no evidence of fungal otitis.

Florfenicol is not recommended for use in horses because of the possibility of elevated bilirubin and loose stools. ¹⁵

Dosage. Florfenicol is administered to cattle by intramuscular or subcutaneous injection. For intramuscular injection, a dose of 20 mg/kg is administered in neck muscle only, with a second dose administered in 48 hours. For subcutaneous injection, a single dose of 40 mg/kg is administered in the neck. No more than 10 mL of injectable solution should be administered per injection site.

When florfenicol injectable solution is prescribed for oral use in dogs or exotic animals, the usual dosage is 20 mg/kg.

The florfenicol otic gel combination product usually is administered in the veterinary clinic. The dosage is one tube per affected ear, with administration repeated in 7 days. The external ear canal should be cleaned and dried before the first dose is administered; the ear canal should not be cleaned again for 45 days to facilitate contact of the gel with the ear canal.

When florfenicol injectable solution is used topically for otitis, the usual dosage is 0.3 mL in the affected ear(s) once daily for at least 3 weeks.

Pharmacokinetics. Florfenicol is well absorbed by most routes in all species. The drug is widely distributed in most tissues, withhigh concentrations in kidney, bile, urine, and small intestine.

Approximately 64% of a dose of florfenicol is excreted unchanged in the urine.

Adverse Reactions. Common adverse reactions following florfenicol administration include inappetance, decreased water consumption, and diarrhea. Use of the otic gel in dogs may cause elevations in ALT enzymes.

Bone marrow suppression was reported following use in a gazelle.¹⁶

Because florfenicol injectable solution contains a high concentration of propylene glycol that could cause Heinz body anemia in cats, cats should be prevented from grooming the affected area if florfenicol injectable solution is applied topically.

Monitoring. Animals should be monitored for antimicrobial efficacy following florfenicol administration. If the drug is administered intramuscularly or subcutaneously, the injection site should be examined for signs of irritation or other reactions. Serum chemistries should be performed in dogs treated with the otic gel to monitor for ALT elevation.

Safety Considerations for Humans. Florfenicol injectable solutioncontains materials that can be irritating to skin and eyes. In case of accidental ocular exposure, the eyes should be flushed with water for 15 minutes. In case of accidental dermal exposure, any contaminated clothing should be removed, and the affected skin area should be washed with soap and water. Accidental injection of florfenicol may cause local irritation; if accidental injection occurs, a physician should be consulted immediately.

Pharmacist Scenario Example: Florfenicol Pharmacists occasionally may encounter prescriptions for florfenicol injectable solution to be applied topically for the treatment of otitis. Pharmacists may be asked to repackage the injection into a container suitable for withdrawing doses into syringes for topical application in the ear canal—for example, an amber bottle with syringe adapter. In these instances, pharmacists also should dispense marked dosing syringes, usually 1 dedicated syringe per affected ear.

Tilmicosin (Micotil, Pulmotil)

Tilmicosin (til-MYE-coe-sin) is a macrolide antibiotic closely related to erythromycin. It inhibits bacterial protein synthesis at the 50S ribosomal subunit.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Tilmicosin Summary.¹⁷

Indications. Tilmicosin is used to treat a variety of bovine and swine respiratory infections. It should not be used in dairy animals or veal calves.

Tilmicosin also has been used to treat Pasteurellosis in rabbits.¹⁸

Dosage. Tilmicosin usually is administered by subcutaneous injection. Tilmicosin is fatal in many species (including humans) if administered intravenously. It is advisable to aspirate when injecting subcutaneously to ensure that the needle is not in a vessel.

The dosage of tilmicosin in cattle and sheep is 10–20 mg/kg as a single subcutaneous injection. In rabbits, tilmicosin may be administered as a single 25 mg/kg injection, with the dose repeated in 3 days in necessary. An alternative approach calls for an initial 5 mg/kg injection; if that dose is tolerated, it should be followed by 10 mg/kg injections on days 7 and 14.

To treat infections in swine, tilmicosin is added to the drinking water at a concentration of 200 mg per liter.

Pharmacokinetics. Tilmicosin is absorbed rapidly following oral administration. It is widely distributed and achieves high concentrations in the lungs.

Tilmicosin is metabolized primarily by demethylation via hepatic microsomal enzymes. Approximately 2%–5% of a dose is excreted unchanged in the urine.

Adverse Reactions. The most common adverse effects of subcutaneous administration of tilmicosin are swelling and edema at the injection site. Intramuscular injection can result in severe tissue necrosis.

Rabbits treated with tilmicosin may experience weakness, pallor, or tachypnea.

Tilmicosin can cause sudden death in many species—including humans, non-human primates, horses, camelids (alpacas and llamas), goats, and swine—following intravenous administration. Death occurs subsequent to chelation and rapid depletion of intracellular cardiac calcium, resulting in negative inotropic effects. Dobutamine partially offset the negative inotropic effects when administered to dogs. Epinephrine potentiated the lethality of tilmicosin in pigs.

Horses should not be permitted to drink water treated with tilmicosin intended for oral use in swine. Macrolides cause potentially fatal dysbiosis when administered orally to horses and other hindgut fermenting species.

Monitoring. Animals treated with tilmicosin should be monitored for antimicrobial efficacy. If tilmicosin is administered by subcutaneous injection, the injection site should be monitored for signs of irritation, swelling, or necrosis.

Safety Considerations for Humans. At least 12 human deaths have been reported from accidental injection of tilmicosin.¹⁹ Pharmacists must exercise caution when repackaging this drug or preparing doses for administration. In particular, extreme caution is required to avoid accidental self-injection—for example, use of automatic injectors should be avoided. Pharmacists also should avoid splashing tilmicosin into the eyes.

Humans (or pets) exposed to tilmicosin unintentionally should seek immediate emergency medical care. Ice or a cold pack should be applied to the injection site to minimize absorption. The cardiovascular system is the target of toxicity and should be monitored closely. Tilmicosin persists in tissues for several days.

If resuscitation attempts are necessary following accidental self-injection of tilmicosin, emergency personnel should be warned not to administer epinephrine.

Pharmacist Scenario Example: Tilmicosin Pharmacists who serve food animal populations are most likely to encounter tilmicosin. Other pharmacists may see an occasional prescription for tilmicosin use in rabbits—for example, tilmicosin 0.08 mL for subcutaneous administration to a 1-kg rabbit with pasteurellosis. Given the danger associated with inadvertent self-injection, it would not be unusual for the rabbit owner to be instructed to bring the drug and animal back to the veterinary clinic for actual administration of tilmicosin.

Tylosin Tartrate (Tylan)

Tylosin tartrate (TYE-loe-sin) is a macrolide antibiotic that inhibits bacterial protein synthesis at the 50S ribosomal subunit.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Tylosin Tartrate Summary.

Indications. Tylosin is indicated for the treatment of various respiratory infections in chickens and turkeys. It also is approved for treatment of dysentery in swine and American Foulbrood (Paenibacillus larvae) in honey bees.

Tylosin often is used off-label for the treatment of diarrhea associated with inflammatory bowel disease in small animals (e.g., dogs, cats, ferrets, rabbits).

Dosage. When used to treat dogs and cats, tylosin is administered orally at a dosage of 25 mg/kg every 24 hours. The usual oral dosage in ferrets is 10 mg/kg every 12–24 hours. Because solutions prepared from the soluble powder must be prepared fresh every 72 hours, tylosin often is prescribed to be compounded as patient-specific gelatin capsules for oral administration. Tylosin powder has an extremely bitter taste; if not administered in capsules, the powder should be hidden in a food ball to avoid rejection by the pet.

Tylosin is not recommended for oral administration to rabbits, gerbils, hamsters, or other hindgut fermenters. When indicated, tylosin should be administered by subcutaneous injection at a dose of 10 mg/kg.

Pharmacokinetics. Tylosin is absorbed well following oral administration. It is widely distributed in tissues but does not penetrate cerebrospinal fluid easily.

Nearly all (99%) of a dose of tylosin is eliminated unchanged in urine and bile. Metabolism is neglible.

Adverse Reactions. Tylosin may cause gastrointestinal upset following oral administration. Administering doses with food may decrease gastrointestinal upset.

Dysbiosis and severe (sometimes fatal) enterocolitis are possible if tylosin is administered orally in hindgut fermenters.

Irritation and swelling may occur at the injection site may occur following subcutaneous administration of tylosin.

Tylosin should not be administered to horses by any route. Severe dysbiosis and enterocolitis are possible following oral administration, and deaths have occurred following injection in horses.

Monitoring. Animals treated with tylosin should be monitored for antimicrobial efficacy. Rabbits that receive tylosin by subcutaneous injection should be observed for signs of dysbiosis, and the injection site should be monitored for signs of irritation or swelling.

Safety Considerations for Humans. Tylosin poses no known risks to humans. Individuals with known hypersensitivity to tylosin or other macrolides should avoid contact.

Pharmacist Scenario Example: Tylosin The owner of a dog that weighs 10 kg presents a prescription for tylosin 250 mg by mouth every 24 hours for 3 months for treatment of inflammatory bowel disease. You check the dosage and prepare 90 capsules from Tylan soluble powder, each containing tylosin 250 mg.

Nonsteroidal Anti-Inflammatory Drugs

The veterinary NSAIDs most likely to be encountered by community pharmacists are carprofen, deracoxib, firocoxib, robenacoxib, flunixin, and phenylbutazone.

Carprofen (Rimadyl)

Carprofen (car-PROE-fin) is an NSAID that prevents prostaglandin formation through inhibition of cyclooxygenase (COX). It is selective for COX-2 in dogs but less COX-2 selective in cats and horses.

Carprofen was approved for human use in Europe in 1985 and in the United States in 1987. It was used widely in humans from 1987 to 1995. The manufacturer (Roche Laboratories) voluntarily withdrew carprofen from the human market in 1995 for “commercial reasons.”

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Carprofen Summary.²⁰

Indications. Carprofen is indicated for the relief of pain and inflammation in dogs. In Europe, carprofen is approved for use as a single injection in cats and horses, as well as for short-term oral use in horses. (Veterinarians in the United States typically do not prescribe carprofen for cats or horses because safer NSAIDs are available for use in these species.)

Carprofen is used off-label in multiple species as an anti-inflammatory analgesic therapy.

Dosage. Carprofen is administered orally, by subcutaneous injection, or by intravenous injection. The dosage varies by species (see Carprofen Summary).

Pharmacokinetics. Carprofen is rapidly and completely absorbed following oral administration. Absorption is slower when carprofen is administered by subcutaneous injection.

Carprofen is highly bound to plasma proteins and has a low volume of distribution. It is metabolized extensively through glucuronidation and oxidation.

The majority (70%–80%) of a dose of carprofen is eliminated in feces. Approximately 10%–20% is eliminated in the urine.

Adverse Reactions. Carprofen can cause gastrointestinal irritation when administered by mouth. Administering doses with food may decrease gastrointestinal upset.

As a class, NSAIDs may be associated with gastrointestinal, renal, and hepatic toxicity. All NSAIDs have the potential to produce gastrointestinal ulceration or perforation (or both). Possible signs of NSAID toxicity include:

• Anorexia.
• Vomiting.
• Diarrhea.
• Black, tarry, or bloody stools.
• Lethargy.
• Ataxia.
• Seizures.
• Increased aggression.

Rare cases of fatal hepatocellular necrosis have been reported in dogs. Hepatocellular necrosis is thought to be immune-mediated following formation of reactive glucuronide metabolites. Carprofen should be used with caution (if at all) in dogs that have pre-existing hepatic or renal insufficiency or are at increased risk of those problems. If the benefits of therapy are deemed to outweigh risks, the dosage of carprofen should be adjusted to account for altered hepatic or renal metabolism. There is a perception that Labrador Retrievers are more susceptible to hepatocellular necrosis; however, the increased risk is not statistically significant and may be attributable to overrepresentation of Labradors as pets (i.e., increased exposure to medical therapy) rather than breed predisposition.

Carprofen may accumulate or form toxic metabolites in cats subsequent to inefficient glucuronide conjugation. Acute renal failure, gastric ulceration, and gastric perforation are possible consequences.

Monitoring. Animals treated with carprofen should have repeat laboratory tests—CBC, serum chemistries, and urinalysis—performed at 1, 2, and 4 weeks of therapy to monitor hepatic and renal values. Testing should continue every 3 to 6 months if tolerated. The importance of honoring “recheck bloodwork” appointments should be emphasized to pet owners as the primary way to avoid serious toxicity.

Animals treated with carprofen also should be monitored for signs of possible NSAID toxicity.

Safety Considerations for Humans. Carprofen was approved for human use. It poses no specific risks other than adverse effects usually seen during NSAID therapy.

Pharmacist Scenario Example: Carprofen The owner of a 32-kg Labrador Retriever presents a prescription for carprofen 75 mg by mouth every 12 hours. The dosage form was not specified on the prescription; you maintain an inventory of both the caplets and chewable tablets. You ask the owner which she prefers and inquire whether the dog has any known food allergies. The owner is unaware of any allergies and opts for the chewable tablets; you consult the veterinarian for confirmation before dispensing.

Deracoxib (Deramaxx)

Deracoxib (dare-a-COX-ib) is an NSAID that prevents prostaglandin formation through inhibition of COX. It is selective for COX-2 in dogs but less COX-2 selective in cats and horses.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Deracoxib Summary.

Indications. Deracoxib is indicated for the treatment of pain and inflammation in dogs. There is some evidence that it may be useful for antiangiogenic therapy for transitional cell carcinoma of the bladder in dogs.²¹

Deracoxib is not approved or recommended for use in cats.

Although deracoxib sometimes is used off-label in horses, such use is not common because the tablets are beef-flavored (and thus not appealing to horses) and the tablets are relatively expensive at the dosage required in horses.²²

Dosage. Deracoxib is administered by mouth. When used to treat postoperative pain in dogs, the usual dosage is 3–4 mg/kg every 24 hours for a maximum of 7 days. Deracoxib also is used for the chronic treatment of osteoarthritis in dogs at a usual dosage of 1–2 mg/kg every 24 hours as needed.

Pharmacokinetics. Deracoxib is well absorbed following oral administration. The volume of distribution is relatively low because of high protein binding.

Deracoxib is metabolized in the liver to four major metabolites that are excreted in urine and feces. At doses greater than 8 mg/kg, dermacoxib exhibits nonlinear elimination and accumulates. Postoperative dosing (3–4 mg/kg) should not continue for more than 7 days to avoid possible toxicity.

Adverse Reactions. Deracoxib can cause gastrointestinal irritation when administered by mouth. Administering doses with food may decrease gastrointestinal upset.

As a class, NSAIDs may be associated with gastrointestinal, renal, and hepatic toxicity. All NSAIDs have the potential to produce gastrointestinal ulceration or perforation (or both). Possible signs of NSAID toxicity include:

• Anorexia.
• Vomiting.
• Diarrhea.
• Black, tarry, or bloody stools.
• Lethargy.
• Ataxia.
• Seizures.
• Increased aggression.

Monitoring. Animals treated with deracoxib should have repeat laboratory tests—CBC, serum chemistries, and urinalysis—performed at 1, 2, and 4 weeks of therapy to monitor hepatic and renal values. Testing should continue every 3 to 6 months if tolerated. The importance of honoring “recheck bloodwork” appointments should be emphasized to pet owners as the primary way to avoid serious toxicity.

Animals treated with deracoxib also should be monitored for signs of possible NSAID toxicity.

Safety Considerations for Humans. Unlike carprofen, deracoxib never was approved for use in humans, and no safety studies have been conducted in humans. It is structurally similar to celecoxib, which has been associated with serious cardiovascular injury in humans. Although myocardial issues have not been observed in dogs exposed to deracoxib, humans may react in a manner more similar to celecoxib.

Pharmacist Scenario Example: Deracoxib The owner of a 32-kg dog with osteoarthritis presents a prescription for deracoxib 100 mg by mouth every 24 hours for 30 days. The prescription authorizes three refills. You notice that based on this dog’s weight, the dosage prescribed is for short-term postoperative use, not chronic administration. You contact the veterinarian and inquire as to whether the prescription was intended for 1 week only, or if perhaps the daily dose was meant to be in the range of 32–64 mg. The veterinarian confirms that the dose as written is incorrect and changes the prescription to 50 mg by mouth every 24 hours.

Firocoxib (Previcox, Equioxx)

Firocoxib (fear-oh-COX-ib) is an NSAID that prevents prostaglandin formation through inhibition of COX.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Firocoxib Summary.

Indications. Firocoxib is indicated for the treatment of postoperative and chronic pain and inflammation in dogs and horses.

Firocoxib is not approved or recommended for use in cats.

Dosage. Firocoxib is administered by mouth to dogs at a dosage of 5 mg/kg every 24 hours. The product labeling states that firocoxib cannot be dosed accurately in dogs weighing less than 12.5 lb (5.7 kg); however, the chewable tablets can be used to compound patient-specific capsules with the appropriate dose.

In horses, firocoxib is administered by mouth (as equine paste) at a dosage of 0.1 mg/kg every 24 hours, not to exceed 14 days of therapy. It also may be administered by intravenous injection at a dosage of 0.09 mg/kg every 24 hours for up to 9 days.

Although one tube of equine paste contains the same amount of firocoxib as a 57-mg canine tablet, the manufacturer warns against using the canine tablets in horses. The dose of firocoxib is 50 times greater in dogs than in horses.

Pharmacokinetics. The oral availability of firocoxib is low in dogs (38%) but high in horses (79%). Food delays the rate but not the extent of absorption.

Firocoxib is widely distributed to all tissues.

In dogs, firocoxib is metabolized by dealkylation and glucuronidation. In horses, firocoxib is metabolized by decyclopropylmethylation and glucuronidation. The metabolites are excreted primarily in bile and feces in dogs and in urine in horses.

Adverse Reactions. Firocoxib can cause gastrointestinal irritation when administered by mouth. Administering doses with food may decrease gastrointestinal upset. Horses treated with firocoxib may develop ulcers or sores on the tongue or in the mouth, as well as sores or lesions on facial skin or lips.

As a class, NSAIDs may be associated with gastrointestinal, renal, and hepatic toxicity. All NSAIDs have the potential to produce gastrointestinal ulceration or perforation (or both). Possible signs of NSAID toxicity include:

• Anorexia.
• Vomiting (in dogs).
• Diarrhea.
• Black, tarry, or bloody stools.
• Lethargy.
• Ataxia.
• Seizures.
• Increased aggression (in dogs).

Horses may have yellowing of the whites of eyes or mucous membranes. They also may exhibit changes in usual behavior or activity, or consumption of feed or water.

Monitoring. Animals treated with firocoxib should have repeat laboratory tests—CBC, serum chemistries, and urinalysis—performed at 1, 2, and 4 weeks of therapy to monitor hepatic and renal values. Testing should continue every 3 to 6 months if tolerated. The importance of honoring “recheck bloodwork” appointments should be emphasized to pet owners as the primary way to avoid serious toxicity.

Animals treated with firocoxib also should be monitored for signs of possible NSAID toxicity.

Safety Considerations for Humans. Firocoxib has never been approved for use in humans, and no safety studies have been conducted in humans. It is structurally similar to celecoxib, which has been associated with serious cardiovascular injury in humans. Although myocardial issues have not been observed in dogs or horses exposed to firocoxib, humans may react in a manner more similar to celecoxib.

Pharmacist Scenario Example: Firocoxib A pet owner who has a dog being treated with firocoxib asks you if she can give firocoxib to her cat with arthritis. You explain to the pet owner that firocoxib is not approved for use in cats and could be very dangerous for the cat. You further warn the pet owner that all NSAIDs approved for human use are extremely toxic to cats. You encourage the pet owner to consult a veterinarian about the best treatment options for the arthritic cat.

Robenacoxib (Onsior)

Robenacoxib (roe-ben-a-COX-ib) is an NSAID that prevents prostaglandin formation through inhibition of COX. It is approximately 140 times more selective for COX-2 than COX-1 in dogs, 500 times more selective in cats, and 61.1 times more selective in horses (all data are in vitro).^23-25

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Robenacoxib Summary.

Indications. Robenacoxib is indicated for the treatment of pain and inflammation in cats. Ongoing clinical trials are evaluating chronic use for osteoarthritis in cats.

Robenacoxib is approved for use in dogs in the United Kingdom.

Dosage. Robenacoxib is administered by mouth or subcutaneous injection. The oral dosage in cats is 1 mg/kg every 2 hours, rounded up to the nearest whole table. The subcutaneous dosage is 2 mg/kg once daily for up to 3 days.

Pharmacokinetics. Food affects the absorption of robenacoxib. Distribution is low because of high plasma protein binding.

Robenacoxib is metabolized extensively, with metabolites excreted in bile (70%) and urine (30%).

Adverse Reactions. Robenacoxib can cause gastrointestinal irritation when administered by mouth. Although robenacoxib ideally is administered on an empty stomach, it may be necessary to administer a dose with a small amount of food to prevent gastrointestinal upset.

As a class, NSAIDs may be associated with gastrointestinal, renal, and hepatic toxicity. All NSAIDs have the potential to produce gastrointestinal ulceration or perforation (or both). Possible signs of NSAID toxicity include:

• Anorexia.
• Vomiting.
• Diarrhea.
• Black, tarry, or bloody stools.
• Lethargy.
• Ataxia.
• Seizures.

Monitoring. Animals treated with robenacoxib should have repeat laboratory tests—CBC, serum chemistries, and urinalysis—performed at 1, 2, and 4 weeks of therapy to monitor hepatic and renal values. Testing should continue every 3 to 6 months if tolerated. The importance of honoring “recheck bloodwork” appointments should be emphasized to pet owners as the primary way to avoid serious toxicity.

Animals treated with robenacoxib also should be monitored for signs of possible NSAID toxicity.

Safety Considerations for Humans. Robenacoxib has never been approved for use in humans, and no safety studies have been conducted in humans. It is structurally similar to celecoxib, which has been associated with serious cardiovascular injury in humans. Although myocardial issues have not been observed in animals exposed to robenacoxib, humans may react in a manner more similar to celecoxib.

Pharmacist Scenario Example: Robenacoxib It is possible that a cat owner could present to the pharmacy with prescriptions for the cat, just after the cat has received 3 days of injectable robenacoxib in the veterinary clinic. Robenacoxib is highly protein bound. As was the case for cefovecin, a thorough medical history and subsequent drug interaction checking by the pharmacist can help to prevent adverse events related to displacement of highly protein-bound drugs.

Flunixin Meglumine (Banamine)

Flunixin meglumine (flew-NIX-in MEH-gloo-mean) is an NSAID that prevents prostaglandin formation through inhibition of COX. It is more selective for COX-2 at higher concentrations.²⁶

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Flunixin Meglumine Summary.²⁷

Indications. Flunixin is indicated for (1) alleviation of inflammation and pain associated with musculoskeletal disorders and (2) alleviation of visceral pain in horses. Veterinary ophthalmologists prefer systemic flunixin over other systemic NSAIDs for equine ocular pain.

Flunixin also is approved for use as an analgesic in cattle and swine.

Flunixin is approved for use in dogs in the United Kingdom. It is considered to be superior to meloxicam and carprofen when administered before ocular surgery.²⁸

Flunixin is not approved or recommended for use in cats.

Dosage. Flunixin is administered by mouth or intravenous injection. Although flunixin is labeled for intramuscular injection in horses, this route of administration can result in severe clostridial myonecrosis (gangrene).

The dosage of flunixin in horses is 0.5–1.1 mg/kg every 8–12 hours by either route. In cattle, the dosage is 1.1–2.2 mg/kg every 24 hours by intravenous injection for up to 3 days.

Pharmacokinetics. Flunixin is absorbed rapidly and completely when administered by the oral route. Although it is highly protein bound, the free fraction distributes widely and persists in inflammatory tissues.

Flunixin is metabolized by hydroxylation. Both the parent drug and metabolites are excreted in urine and bile.

Adverse Reactions. Flunixin can cause gastrointestinal irritation when administered by mouth. Administering doses with food may decrease gastrointestinal upset. In horses, signs of gastric irritation include bruxism (grinding teeth), off feed, diarrhea, dark stools, and tiredness.

The pH of the injectable solution is highly alkaline (˜9.0). If the injectable solution is given orally, the dosage volume should be diluted and the animal’s oral cavity should be rinsed well after administration. Intramuscular administration of flunixin to horses has resulted in pain, swelling, and induration at the injection site, frequently leading to clostridial myonecrosis (gangrene). Intra-arterial administration can cause ataxia, incoordination, hyperventilation, agitation, and muscle weakness.

Rare cases of hypoproteinura and myelosuppression have been reported during flunixin therapy.

As a class, NSAIDs may be associated with gastrointestinal, renal, and hepatic toxicity. All NSAIDs have the potential to produce gastrointestinal ulceration or perforation (or both). Concurrent gastroprotection is recommended during flunixin therapy in horses and ponies, because these have a higher risk for gastric ulceration. Flunixin is most likely to cause nephrotoxicity when administered in higher doses, especially in birds and dogs.

Possible signs of NSAID toxicity include:

• Anorexia.
• Diarrhea.
• Black, tarry, or bloody stools.
• Lethargy.
• Ataxia.
• Seizures.

Monitoring. Animals treated with flunixin on a chronic or long-term basis should have periodic laboratory tests—CBC, serum chemistries, and urinalysis—to monitor hepatic and renal values. All animals should be monitored for signs of possible NSAID toxicity. Injection sites should be inspected for signs of infection.

Safety Considerations for Humans. Flunixin has never been approved for use in humans. Human exposure has resulted in acute encephalopathy, severe gastrointestinal bleeding, and respiratory and metabolic imbalance.²⁹ Care should be taken to avoid self-injection. Flunixin injectable solution is highly alkaline (pH ˜9.0) and can cause corneal burns and ulceration if splashed in the eyes.

Pharmacist Scenario Example: Flunixin The owner of a horse being treated for a fungal eye ulcer presents a prescription for flunixin meglumine injection 550 mg to be administered by mouth every 12 hours for 5 days. You confirm that the horse’s weight is 500 kg, and you repackage 120 mL of flunixin 50 mg/mL injection into an amber oral dispensing bottle with an adapter cap and a 20 mL oral dosing syringe marked to indicate the correct dosing volume (11 mL). You explain to the owner how to prepare each dose: withdraw 11 mL of flunixin from the bottle, then dilute it by drawing water or syrup into the syringe until the total volume is 20 mL (i.e., syringe capacity). That total volume should be administered into the oral cavity. You counsel the owner to rinse the horse’s oral cavity thoroughly with water following administration and watch for signs of oral ulcers or blisters.

Phenylbutazone (Butazolidin)

Phenylbutazone (feen-il-BYOOT-a-zone)—also known as “bute”—is an NSAID that prevents prostaglandin formation through inhibition of COX. It is relatively nonselective; lack of selectivity for COX-2 is responsible for adverse effects involving the gastrointestinal mucosa, kidneys, platelets, and liver.

Phenylbutazone was approved initially with the trade name Butazolidin. However—unlike human drugs—the same approved animal drug can be legally marketed under several labels, and each distributor can use a different trade name for the drug. As of February 2016, there were 23 actively-marketed phenylbutazone products approved by the FDA for use in horses.³⁰

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Phenylbutazone Summary.

Indications. Phenylbutazone is indicated for the treatment of musculoskeletal inflammation and pain in horses. Although phenylbutazone also was approved for use in dogs and cattle, safer NSAIDs with better COX-2 specificity have become available and are preferred for use in those species.

Phenylbutazone is not approved or recommended for use in cats.

Dosage. Phenylbutazone is administered to horses by mouth or intravenous injection. The usual dosage is 2.2–4.4 mg/kg every 12 hours by either route. If phenylbutazone will be administered to horses for more than 4 days, the dosage should be reduced to the lowest effective amount. Intravenous administration should not exceed 5 days.

Pharmacists occasionally may be asked to compound phenylbutazone oral paste, because this dosage form frequently is in short supply.

Pharmacokinetics. Phenylbutazone is rapidly and completely absorbed following oral administration. It is widely distributed with high concentrations in liver, heart, lungs, kidneys, and blood.

Phenylbutazone undergoes hepatic metabolism by oxidation and glucuronidation, primarily to oxyphenbutazone (active) and gamma-hydroxyphenylbutazone. Both the parent drug and metabolites are excreted in the urine. Metabolites are detectable in urine for 48 hours after dosing.

Adverse Reactions. As a class, NSAIDs may be associated with gastrointestinal, renal, and hepatic toxicity. Phenylbutazone can cause gastrointestinal irritation as well as erosions and ulcers of the nose, oral cavity, and gastrointestinal tract. Signs of toxicity in horses treated with phenylbutazone include inappetance and anorexia, diarrhea, jaundice, changes in water consumption or urination, tiredness, and unusual bruising or bleeding.

Other possible adverse effects of phenylbutazone therapy include hypoalbuminemia, right dorsal colitis, azotemia, and renal papillary necrosis.

Phenylbutazone injectable solution is highly alkaline (pH 10.0). It should not be administered by subcutaneous or intramuscular injection because of the possibility of severe tissue necrosis. Intra-arterial administration can cause severe CNS stimulation and seizures.

Monitoring. Animals treated with phenylbutazone should be monitored for signs of possible

NSAID toxicity. If toxicity is suspected, CBC and serum chemistries should be performed.

Safety Considerations for Humans. Phenylbutazone had been approved for use in humans, but it was withdrawn from marketing in 1985 because of serious toxicities. Among the adverse events reported were nausea, vomiting, epigastric pain, excessive perspiration, euphoria, psychosis, headaches, giddiness, vertigo, nystagmus, insomnia, tinnitus, difficulty in hearing, edema (sodium retention), hypertension, cyanosis, respiratory depression, agitation, hallucinations, drowsiness, and stupor. More serious reactions include respiratory or metabolic acidosis with hyperventilation progressing to coma, trismus, tonic clonic seizures, and shock syndrome (with hypotension and oliguria). Renal failure (with proteinuria, oliguria, and hematuria), liver damage (with hepatomegaly and toxic jaundice), acute bone marrow depression, abnormalities of formed blood elements, ulceration of the buccal or GI mucosa, and acute perforation of peptic ulcer also have been reported.

Given these toxicities, humans should take great care to avoid contact with phenylbutazone, especially accidental self-injection.

Pharmacist Scenario Example: Phenylbutazone The owner of a 200-kg pony with a foot abscess presents a prescription for phenylbutazone 2.2 mg/kg by mouth every 12 hours for 4 days, then every 24 hours for 4 more days. The veterinarian did not specify a dosage form. You calculate that each dose for this pony should be 440 mg; you ask the owner if she thinks she can administer half of a 1000 mg tablet to the pony. The owner says yes. You contact the veterinarian and confirm that a 500 mg dose using half of a 1000 mg tablet would be acceptable. You counsel the owner to watch the pony for signs that phenylbutazone is not being tolerated and advise her and to contact the veterinarian immediately if she observes any of these signs.

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