Elephant specific information, if available, is in blue.

Chemistry – A synthetic pyrazolone derivative related chemically to aminopyrine, phenylbutazone occurs as a white to off-white, odorless crystalline powder that has a pKa of 4.5. It is very slightly soluble in water and 1 gram will dissolve in 28 ml of alcohol. It is tasteless at first, but has a slightly bitter after-taste.

 Storage/Stability/Compatibility – Oral products should be stored in tight, child-resistant containers if possible. The injectable product should be stored in a cool place (46 – 56° F) or kept refrigerated.

Pharmacology – Phenylbutazone has analgesic, anti-inflammatory, antipyrexic, and mild uricosuric properties. The proposed mechanism of action is by the inhibition of cyclooxy­genase, thereby reducing prostaglandin synthesis. Other pharmacologic actions phenylbu­tazone may induce include reduced renal blood flow and decreased glomerular filtration rate, decreased platelet aggregation, and gastric mucosal damage.

 Pharmacokinetics – Following oral administration, phenylbutazone is absorbed from both the stomach and small intestine. The drug is distributed throughout the body with highest levels attained in the liver, heart, lungs, kidneys, and blood. Plasma protein binding in horses exceeds 99%. Both phenylbutazone and oxyphenbutazone cross the placenta and are excreted into milk.

The serum half-life in the horse ranges from 3.5-6 hours, and like aspirin is dose-depen­dent. Therapeutic efficacy however, may last for more than 24 hours however, probably due to the irreversible binding of phenylbutazone to cyclooxygenase. In horses and other species, phenylbutazone is nearly completely metabolized, primarily to oxphenbutazone (active) and gamma-hydroxyphenylbutazone. Oxyphenbutazone has been detected in horse urine for up to 48 hours after a single dose. Phenylbutazone is more rapidly excreted into alkaline than into acidic urine .

Other serum half-lives reported for animals are: Cattle ≈ 40 – 55 hrs; Dogs ≈ 2.5 – 6 hrs; Swine ≈ 2 – 6 hrs.; Rabbits ≈ 3 hrs..

Uses/Indications – One manufacturer lists the following as the indications for phenylbuta­zone: “For the relief of inflammatory conditions associated with the musculoskeletal sys­tem in dogs and horses.” (Package Insert; Butazolidin® — Coopers). It has been used pri­marily for the treatment of lameness in horses and occasionally as an analgesic/anti-in­flammatory, antipyrexic in dogs, cattle, and swine.

 Contraindications/Precautions – Phenylbutazone is contraindicated in patients with a his­tory of, or preexisting hematologic or bone marrow abnormalities, preexisting GI ulcers, and in food producing animals or lactating dairy cattle. Cautious use in both foals and ponies is recommended because of increased incidences of hypoproteinemia and GI ulcer­ation. Foals with a heavy parasite burden or that are undernourished may be more suscep­tible to development of adverse effects.

 Phenylbutazone may cause decreased renal blood flow and sodium and water retention, and should be used cautiously in animals with preexisting renal disease or CHF.

 Because phenylbutazone may mask symptoms of lameness in horses for several days fol­lowing therapy, it can be used by unethical individuals to disguise lameness for “soundness” exams. States may have different standards regarding the use of phenylbuta­zone in track animals. Complete elimination of phenylbutazone in horses may take 2 months and it can be detected in the urine for at least 7 days following administration.

 Although phenylbutazone has shown no direct teratogenic effects, rodent studies have demonstrated reduced litter sizes, increased neonatal mortality, and increased stillbirth rates. Phenylbutazone should therefore be used in pregnancy only when the potential bene­fits of therapy outweigh the risks associated with it.

 Phenylbutazone is contraindicated in patients demonstrating previous hypersensitivity re­actions to it, and should be used very cautiously in patients that have a history of allergies to other drugs.

 Adverse Effects/Warnings – The primary concerns with phenylbutazone therapy in hu­mans include its bone marrow effects (agranulocytosis, aplastic anemia), renal and cardio­vascular effects (fluid retention to acute renal failure), and GI effects (dyspepsia to perfo­rated ulcers). Other serious concerns with phenylbutazone include, hypersensitivity reac­tions, neurologic, dermatologic, and hepatic toxicities.

 While phenylbutazone is apparently a safer drug to use in horses and dogs than in people, serious adverse reactions can still occur. Toxic effects that have been reported in horses include oral and GI erosions and ulcers, hypoalbuminemia, diarrhea, anorexia, and renal effects (azotemia, renal papillary necrosis). Unlike humans, it does not appear that phenylbutazone causes much sodium and water retention in horses at usual doses, but edema has been reported. In dogs however, phenylbutazone may cause sodium and water retention, and diminished renal blood flow. Phenylbutazone-induced blood dyscrasias have also been reported in dogs.

 Do not administer injectable preparation IM or SQ, as it is very irritating (swelling, to necrosis and sloughing). Intracarotid injections may cause CNS stimulation and seizures.

 Therapy should be halted at first signs of any toxic reactions (e.g., anorexia, oral lesions, depression, reduced plasma proteins, increased serum creatinine or BUN, leukopenia, or anemias). The use of sucralfate or the H2 blockers (cimetidine, ranitidine) have been sug­gested for use in treating the GI effects. Misoprostol, a prostaglandin E analog, may also be useful in reducing the gastrointestinal effects of phenylbutazone.

 Overdosage – Manifestations (human) of acute overdosage with phenylbutazone include, a prompt respiratory or metabolic acidosis with compensatory hyperventilation, seizures, coma, and acute hypotensive crisis. In an acute overdose, symptoms of renal failure (oliguric, with proteinuria and hematuria), liver injury (hepatomegaly and jaundice), bone marrow depression, and ulceration (and perforation) of the GI tract may develop. Other symptoms reported in humans include: nausea, vomiting, abdominal pain, diaphoresis, neurologic and psychiatric symptoms, edema, hypertension, respiratory depression, and cyanosis.

 Standard overdose procedures should be followed (empty gut following oral ingestion, etc.). Supportive treatment should be instituted as necessary and intravenous diazepam used to help control seizures. Monitor fluid therapy carefully, as phenylbutazone may cause fluid retention.

 Drug Interactions – Both phenylbutazone and the active metabolite oxyphenbutazone are highly bound to plasma proteins and may displace other highly bound drugs. This mecha­nism may affect serum levels and duration of actions of phentoin, valproic acid, oral anticoagulants, other antiinflammatory agents, sulfonamides, and the sulfonylurea antidiabetic agents. Phenylbutazone and oxyphenbutazone can induce hepatic microsomal enzymes and in­crease the metabolism of drugs affected by this system (e.g., digitoxin & phenytoin). Conversely, other microsomal enzyme inducers (e.g., barbiturates, promethazine, ri­fampin, corticosteroids, or chlorpheniramine, diphenhydramine) may decrease the plasma half-life of phenylbutazone. Phenylbutazone may increase the plasma half-life of penicillin G or lithium. Phenylbutazone administered concurrently with hepatotoxic drugs may increase the chances of hepatotoxicity developing. Phenylbutazone may antagonize the increased renal blood flow effects caused by furosemide. Concurrent use with other NSAIDs may increase the potential for adverse reactions de­veloping, however many clinicians routinely use phenylbutazone concomitantly with flu­nixin in horses.

 Laboratory Test Interference – Phenylbutazone and oxyphenbutazone may interfere with thyroid function testsby competing with thyroxine at protein binding sites or by inhibit­ing thyroid iodine uptake.

 Doses –

Horses:

a)   4.4 – 8.8 mg/kg q24hrs PO or 3-6 mg/kg q12h IV (Do not exceed 8.8 mg/kg/day (Jenkins 1987)

b)   1 – 2 grams IV per 454 kg (1000 lb.) horse. Injection should be made slowly and with care. Limit IV administration to no more than 5 successive days of therapy. Follow with oral forms if necessary; or 2 – 4 grams PO per 454kg (1000 lb.) horse. Do not exceed 4 grams/day. Use high end of dosage range initially, then titrate to lowest effective dose. (Package Insert; Butazolidin® – Coopers)

c)   4.4 mg/kg PO twice on the first day, then 2.2 mg/kg PO bid for 4 days, then 2.2 mg/kg PO once daily or every other day. (Taylor et al. 1983)

 Elephants:

As of June 2003, there are no published pharmacokinetic studies however, one such study is in progress.

a) Anecdotal doses of 1-2 mg/kg every 24 hours (route of administration not specified) have been reported.  This is based on a survey of 20 zoo veterinarians in the U.S.  The author cautions that phenylbutazone has potential for adverse effects and that the treatment interval reported by survey participants is much shorter than that predicted by metabolic scaling (2.5 mg every 40 hours). (Mortenson, 1998, 1998, 2001).

b) Two cases of segmental gangrene and sloughing of elephants’ ears after intravenous injection of phenylbutazone have been reported (dose not specified).  The author  recommends that phenylbutazone be administered orally whenever possible.  (Miller, 1977).

Elephant References:

a )Mortenson,J. and Sierra S.  1998. Determining dosages for antibiotic and anti-inflammatory agents in elephants. Proceedings of the First North American Conference on Elephant Foot care and Pathology. Pages: 50-55  Abstract: Clinical application of drug use in elephants for safe, reliable, and effective results necessitates the establishment of a treatment response curve or blood concentration profile for each drug and species (African vs. Asian).  Because of the difficulty in obtaining accurate pharmacokinetic information, it is more common to select a drug dosage and frequency interval used in other species, specifically the cow and the horse.  Where treatment monitoring with serum concentrations of the drug are difficult to obtain, extrapolation of treatment regimens between species of extraordinary size difference may be done by metabolic scaling to establish drug dosage rates and frequency intervals.  The principle of metabolic scaling of pharmacokinetic parameters is based on the well established scaling of physiological processes across animals of various sizes.  The goals of this paper are to cover what antibiotics are currently used now with Asian and African elephants by surveying North American zoos, reviewing standard equine doses, discussing metabolic scaling attempts, and reviewing pharmacokinetic studies done. Based on the survey, zoo veterinarians generally are not utilizing metabolic scaling formulas to determine antibiotic and anti-inflammatory drug dosages for elephants.  It appears that several drugs are being dosed too frequently (amikacin, amoxicillin), and not frequent enough (trimethoprim-sulfamethoxazole) based on pharmacokinetic study results.  Metabolic scaling dosages and treatment intervals do not correspond well with antibiotic pharmacokinetic studies done in both African and Asian elephants.

a) Mortenson,J.  1998. Determining dosages for anti-inflammatory agents in elephants. Proceedings AAZV and AAWV Joint Conference. Pages: 477-479

     a) Mortenson,J., 2001. Determining dosages for antibiotics and anti-inflammatory agents. In: Csuti,B., Sargent,E.L., and Bechert,U.S. (Editors), The Elephant’s Foot. Iowa State University Press, Ames, Iowa, USA pp. 141-144

     b) Miller,R.M. 1977. Segmental gangrene and sloughing of elephants’ ears after intravenous injection of phenylbutazone. Veterinary Medicine Small Animal Clinician 72 (4): 633-637

Monitoring Parameters – 1) Analgesic/anti-inflammatory/antipyrexic effect 2) Regular complete blood counts with chronic therapy (especially in dogs). The manufacturer rec­ommends weekly CBC’s early in therapy, and biweekly with chronic therapy 3) Urinalysis &/or renal function parameters (serum creatinine/BUN) with chronic therapy 4) Plasma protein determinations, especially in ponies, foals, and debilitated animals.

 Client Information/FDA Approval Status – Do not administer injectable preparation IM or SQ.

Approved for use in dogs and horses not intended for food. While phenylbutazone is not approved for use in cattle, it is used. A general guideline for meat withdrawal times are: one dose=30 days, 2 doses=35 days, and 3 doses=40 days. Phenylbutazone is a veterinary prescription drug.

 Dosage Forms/Preparations (Veterinary) –

Phenylbutazone Tablets 100 mg, 400 mg, 1 gram tablets; 2 gram boluses, 4 gram bo­luses ; Butazolidin® (Schering); also available generically

Phenylbutazone Paste Oral syringes containing 6 grams or 12 grams/syringe; Butazolidin® Paste ( Schering); Phenylzone® Paste (Luitpold)

Phenylbutazone Oral Gel: Each 30 grams of gel contains 4 grams phenylbutazone, 30 grams (of gel) per syringe; Butatron®   (Rhone Merieux)

Phenylbutazone Micro-encapsulated powder; Equipalazone®  (Steri-Vet); 1 gm packets, 60’s

Phenylbutazone Injection 200 mg/ml; 100 ml vials; Butazolidin® (Schering); generic