volume 27 supplement 1 june 2004
USP Veterinary Pharmaceutical Information Monographs – Anti-inflammatories
USP VETERINARY PHARMACEUTICAL INFORMATION
MONOGRAPHS – ANTI-INFLAMMATORIES
CONTENTS
1
Introduction
4
Aspirin (Veterinary—Systemic)
15
Carprofen (Veterinary—Systemic)
24
Corticosteroids—Glucocorticoid Effects (Veterinary—Systemic)
61
Deracoxib (Veterinary—Systemic)
64
Etodolac (Veterinary—Systemic)
70
Flunixin (Veterinary—Systemic)
75
Ketoprofen (Veterinary—Systemic)
87
Meloxicam (Veterinary—Systemic)
92
Phenylbutazone (Veterinary—Systemic)
100
Tepoxalin (Veterinary—Systemic)
104
Indications Index
106
Dosing Index
108
Veterinary Brand and Generic Name Index
110
Human Brand and Generic Name Index
Introduction 1
Introduction
WHAT’S DIFFERENT ABOUT A USP DRUG INFORMATION
MONOGRAPH
The Veterinary Medicine Expert Committee on Drug Information
gratefully acknowledges the financial support of its parent organization, the United States Pharmacopeia (USP), to publish these
monographs. It also is appreciative to the Food Animal Residue
Avoidance Databank (FARAD) for supplying slaughter and milk
withdrawal information where extra-label drug use in food animals
is noted.
USP history, organizational structure, and publications
In pursuit of its mission to promote public health, the USP
develops authoritative information about the appropriate use of
medicines, including those used in animals. This non-government,
not-for-profit organization draws on a long-standing dedication to
public involvement in the establishment of scientific standards.
USP achieves its goals through the contributions of volunteer
health care scientists representing academia, the U.S. and other
governments, the pharmaceutical industry, and consumer organizations.
USP was established in 1820 with the primary goal of setting
standards for the identity, strength, and quality of medicinal
compounds and preparations and this remains at the core of the
organization. Currently, USP provides standards for more than
3,800 prescription and non-prescription ingredients and drug
products, nutritional and dietary supplements, veterinary drugs,
and health care products. These standards are published in the
United States Pharmacopeia (USP) and the National Formulary (NF),
which are officially recognized in the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. § 321 et seq.). USP also produces
Reference Standards, which are an integral part of USP’s standards
program.
The development of USP information on the best use of medications was
begun in 1970, growing out of the public process of developing quality
standards. USP information advisory panels were created to assure
that the information under development was evidence-based, consensus-established, practical, and clinically relevant. This work was
expanded into a separate public health program and in 1980 the first
USP DI was published.
The veterinary drug information monograph creation process
Very soon after the USP DI was first published, an advisory panel on
veterinary medicine was created. Since 1982, veterinary pharmacologists, pharmacists, and other specialists have contributed their
time and expertise in creating and revising drug information
through USP’s unique process. This drug information is developed
by exhaustive compilation of approved product label information
and also collection and analysis of publicly available data on each
drug from research studies and clinical reports. Careful attention is
paid to differentiating species-specific information. Each draft chapter
2004 The United States Pharmacopeial Convention, Inc.
or monograph is then put through a review process that includes
USP Veterinary Medicine Expert Committee members, regulatory
representatives, pharmaceutical manufacturers, ad hoc specialists,
and the public. At present, USP monographs are the only drug
information source in veterinary medicine undergoing such extensive expert review, a process through which the credibility of the
information is maintained.
USP drug information is a work-in-progress. The information is in
constant revision and is a continuous collection of the current
judgments of experts in the use of medications. The following chapters
have been developed over 7 years, with information added and revised,
as necessary.
Unique features
This special issue of the Journal of Veterinary Pharmacology and Therapeutics contains a series of drug information monographs on antiinflammatories used in veterinary medicine. What makes this information different from other sources of veterinary drug information? A
succinct listing would include:
• The incorporation of extra-label and label indications and dosages
for all domestic species. See the section below, ‘‘Finding the specific
drug information you need; Label and extra-label uses,’’ for details
on how this information is differentiated.
• The inclusion of slaughter and milk withdrawals when extra-label
drug use in food animals is considered an acceptable option for
therapy. Withdrawal times have been provided by FARAD for the
specified conditions noted.
• The inclusion of information about both U.S. and Canadian
veterinary drug products.
• The grouping of indications into three categories. The ‘‘Accepted’’
category indicates that clear evidence exists to support use of the
drug for a particular purpose. ‘‘Acceptance not established’’
(potentially useful) indicates that use of the drug for an indication
may be worthy of consideration if superior therapies do not exist,
but the evidence is either scant or subject to concern based on
experimental design. If a use is viewed as ineffective or has been
replaced by clearly superior therapies, the indication is deemed
‘‘Unaccepted.’’ These categorizations are applied to label and extralabel uses.
• The use of tables of scientific evidence to address controversial issues
during the review process, particularly relative to extra-label drug
use.
• Review of the information by a Food and Drug Administration
(FDA) liaison to the Expert Committee. Although comments made
by the FDA are taken quite seriously, those opinions are nonbinding
on the USP. The information contained in these monographs should
not be considered an endorsement or ‘‘acceptance’’ by the FDA as to
a given use or dosage.
• The review of each monograph by the USP Veterinary Medicine
Expert Committee. This committee consists of 10 to 15 volunteers
recognized as experts in pharmacology, internal medicine, or species
discipline(s).
All rights reserved
2 Introduction
FINDING THE SPECIFIC DRUG INFORMATION YOU NEED
ACKNOWLEDGEMENTS
Label and extra-label uses
The following individuals are recognized for their contributions and
support towards the production of this body of work:
The Indications section of each drug monograph is designed to provide
information about indications in drug product labeling in the U.S. and
Canada. Extra-label indications for which clinical and research data
have been evaluated are also included. Indications found in product
labeling are listed first. Brackets around an indication signify that it
was not found in any product labeling in the U.S. at the time of last
major revision. Some indications are followed by a superscript 1,
meaning they are not included in Canadian product labeling.
Examples of bracket and superscript 1 placement in the monographs:
[Pneumonia, bacterial (treatment)] An extra-label use in the U.S. An
indication is included in Canadian product labeling.
Pneumonia, bacterial (treatment)1 An indication found in U.S. product labeling but not in Canadian
product labeling.
[Pneumonia, bacterial (treatment)]1 An extra-label use in both the
U.S. and Canada.
Species and dosage forms
Within each category of the Indications section the information is arranged
in a hierarchy as follows: indication, followed by the species to which
that indication applies, and finally the dosage forms used in that species
for that indication. You will see that some species and dosage forms are
also given bracket and superscript 1 designations; these have the same
meaning for species and dosage forms as described above for indications.
To decrease clutter and confusion, only the highest level of the hierarchy
is given a bracket or superscript 1 (indication > species > dosage form).
That is, if the indication is not found on any label in the U.S. (a bracketed,
extra-label use) then the species under it will not be bracketed because it
is obvious that no species are on the label of any product in the United
States for this indication.
Dosing
In the USP veterinary drug information monographs, dosage forms are
always listed separately to provide an opportunity to list specific
information for each type of product. In the Dosage Forms section,
indications and species are bracketed or given a superscript 1 following
the same rules applied in the Indications section, except that they reflect
the labeling of the specific dosage form. Dosages listed are not always
label dosages even if the species is in the product labeling.
Label and extra-label withdrawal times
Established withdrawal times from product labeling are listed in the
Withdrawal times tables for each dosage form labeled for use in foodproducing animals. But be sure to consult the approved labeling on the
product you are using for the specific government established dose and
withdrawal time.
Extra-label withdrawal times are listed in the Withdrawal times section for
each extra-label use and/or dose recommended for food-producing
animals. As always, veterinarians should use their own clinical
judgment, following the guidelines of the Animal Medicinal Drug Use
Clarification Act, to determine a safe extra-label withdrawal time.
Cory Langston, DVM, PhD, DACVCP
Chair, USP Veterinary Medicine Expert Committee on Drug Information
2004 The United States Pharmacopeial Convention, Inc.
USP Staff
Roger Williams, MD (CEO and Executive Vice President, USP)
Ian DeVeau, PhD (Senior Scientist, Veterinary Drugs, Information and
Standards Development, USP)
Amy S. Neal, DVM (USP consultant, writer and editor)
Jerome A. Halperin, BS, MPH, MS (former CEO and Executive Vice
President, USP)
Keith Johnson (former Director, Drug Information Division, USP)
David Nash, DVM (former Director, Veterinary Medicine, Information
and Standards Development, USP)
E. Kathryn Meyer, VMD (former Drug Information Specialist and
Coordinator, Veterinary Practitioners’ Reporting Program, USP)
2000 to 2005 Veterinary Medicine Committee
Cory Langston, DVM, PhD, DACVCP, Chair
Michael D. Apley, DVM, PhD, BS, DACVCP
Dawn M. Boothe, BS, MS, DVM, PhD, DACVCP, DACVIM
Terrence P. Clark, DVM, PhD, DACVCP
Gigi F. Davidson, BS, RPh, DICVP
Patricia Dowling, DVM, MS, DACVIM, DACVCP
Douglas T. Kemp, PharmD, DICVP
Mark G. Papich, DVM, MS, BS, DACVCP
M. Gatz Riddell, DVM, MS
Jim E. Riviere, DVM, PhD, MS, BS
Roderick C. Tubbs, DVM, PhD
Jeff R. Wilcke, DVM, MS, DACVCP
1995 to 2000 Veterinary Medicine Advisory Panel
Cory Langston, DVM, PhD, DACVCP, Chair
Michael D. Apley, DVM, PhD, BS, DACVCP
Gordon Brumbaugh, DVM, PhD, DACVCP
Thomas Burkgren, DVM, MBA
Cynthia T. Culmo, RPh
Lloyd E. Davis, PhD, DVM
Patricia Dowling, DVM, MS, DACVIM, DACVCP
Stuart Forney, RPh, MS
Antoinette D. Jernigan, DVM, PhD, DACVCP
Mark G. Papich, DVM, MS, DACVCP
Thomas E. Powers, DVM, PhD
Jim E. Riviere, DVM, PhD
Charles R. Short, DVM, PhD, DACVCP
Hector Sumano Lopez, DVM, Ph2D
Jeff R. Wilcke, DVM, MS, DACVCP
1990 to 1995 Veterinary Medicine Advisory Panel
Lloyd E. Davis, DVM, PhD, Chair
Arthur L. Aronson, DVM, PhD
Gordon Brumbaugh, DVM, PhD, DACVCP
Gordon L Coppoc, DVM, PhD
Sidney A. Ewing, DVM, PhD
Stuart D. Forney, RPh, MS
William G. Huber, DVM, PhD
All rights reserved
Introduction 3
William L. Jenkins, DVM, PhD, DACVCP
Cory Langston, DVM, PhD, DACVCP
Mark G. Papich, DVM, MS, DACVCP
John W. Paul, DVM, PhD
Thomas E. Powers, DVM, PhD, DACVCP
Charles R. Short, DVM, PhD, DACVCP
Richard H. Teske, DVM, PhD
Jeff R. Wilcke, DVM, MS, DACVCP
1985 to 1990 Panel on Veterinary Medicine
Lloyd E. Davis, PhD, DVM, Chair
Arthur L. Aronson, DVM, PhD
Nicholas H. Booth, DVM, PhD
Gordon L Coppoc, DVM, PhD
Sidney A. Ewing, DVM, PhD
Stuart D. Forney, RPh, MS
Diane K. Gerken, DVM, PhD
William G. Huber, DVM, PhD
William L. Jenkins, DVM, PhD
Robert W. Phillips, DVM, PhD
Thomas E. Powers, DVM, PhD
Charles R. Short, DVM, PhD
Richard H. Teske, DVM, PhD
Jeff R. Wilcke, DVM, MS
Arthur L. Aronson, DVM, PhD
Nicholas H. Booth, DVM, PhD
Gordon L Coppoc, DVM, PhD
George T. Edds, DVM, PhD
Sidney A. Ewing, DVM, PhD
Peter A. Eyre, BVMS, PhD
Stuart D. Forney, RPh, MS
William G. Huber, DVM, PhD
Robert W. Phillips, DVM, PhD
Thomas E. Powers, DVM, PhD
I.A. Schipper, DVM, PhD
Richard H. Teske, DVM, PhD
For more information about USP Veterinary Pharmaceutical Information
monographs you may visit USP website, www.usp.org, or contact:
Ian F. DeVeau, Ph.D.
United States Pharmacopeia
12601 Twinbrook Parkway
Rockville, Maryland 20852
United States
Telephone: 301-816-8178
Fax: 301-816-8178
E-mail: veterinary@usp.org
1983 to 1985 Panel on Veterinary Medicine
Lloyd E. Davis, PhD, DVM, Chair
H. Richard Adams, DVM, PhD
2004 The United States Pharmacopeial Convention, Inc.
All rights reserved
4 ASPIRIN Veterinary—Systemic
ASPIRIN Veterinary—Systemic
Some commonly used brand names are:
For veterinary-labeled products—AniPrin F; AniPrin P; Arthricare;
Asen; Asen 240 Bolus; Asp-Rin; Centra ASA 240à; Durasol; Equiphar
ArthriBan; Equi-Prin; Equi-Spirin; Health Measures; Palaprin 65;
Palaprin 325; and Vetrin.
For human-labeled products—Apo-ASA; Aspirin Caplets; Aspirin Children’s Tablets; Aspirin Tablets; Aspir-Low; Aspirtab; Aspirtab-Max;
Bayer Children’s Aspirin; Empirin; Extra Strength Bayer Aspirin Caplets;
Extra Strength Bayer Aspirin Tablets; Genuine Bayer Aspirin Caplets;
Genuine Bayer Aspirin Tablets; Headache Tablet; Healthprin Adult Low
Strength; Healthprin Full Strength; Healthprin Half-Dose; Norwich
Aspirin; PMS-ASA; and St. Joseph Adult Chewable Aspirin.
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
à
Aspirin is a brand name in Canada; acetylsalicylic acid is the generic
name. ASA, a commonly used designation for aspirin (or acetylsalicylic acid) in both the U.S. and Canada, is the term used in Canadian
product labeling.
CATEGORY:
Analgesic, anti-inflammatory (nonsteroidal); antidiarrheal (Escherichia
coli–induced diarrhea); antipyretic; antirheumatic (nonsteroidal antiinflammatory); platelet aggregation inhibitor.
[Cardiomyopathy (treatment adjunct)]1—Cats: Thromboembolism is a
common sequelae to hypertrophic cardiomyopathy. Although aspirin
is often employed to minimize the recurrence of this complication,
there is no convincing evidence of its efficacy.{R-1; 2}
[Escherichia coli diarrhea (treatment)]1—Piglets: Aspirin has been shown
to reduce diarrhea and mortality in piglets infected with pathogenic
E. coli.
[Heartworm disease (treatment adjunct)]1—Cats and dogs: Aspirin has
failed to produce a demonstrable benefit when administered during
treatment of heartworm disease.{R-3-6}
[Laminitis (treatment)]1—Horses: Although aspirin is sometimes employed to decrease thromboembolism in horses with laminitis, there
are no studies that have investigated the safety or efficacy of this use.
[Thromboembolism (prophylaxis)]1—Aspirin, through inhibition of
platelet thromboxane, has been shown to inhibit platelet aggregation
in man, cats, dogs, and horses.{R-2; 6; 7-11} The actual efficacy of
aspirin to prevent thromboembolism has been controversial and varies
with the disease. Aspirin is ineffective in preventing the aggregation of
bovine platelets.{R-12} Studies in man have indicated that concurrent
use of other nonsteroidal anti-inflammatory drugs (NSAIDs) may
decrease the antithrombotic activity of aspirin.
1
Not included in Canadian product labeling or product not commercially
available in Canada.
INDICATIONS
Note: Bracketed information in the Indications section refers to uses that
either are not included in U.S. product labeling or are for products not
commercially available in the U.S.
ACCEPTED
Note: Although veterinary forms of aspirin are marketed with label
indications for pain, fever, and inflammation, the drug has never been
approved by the United States Food and Drug Administration Center
for Veterinary Medicine (FDA CVM) for these purposes.
Inflammation (treatment)1—Dogs and [cats]: Aspirin is used for the relief
of inflammation associated with arthritis and joint problems.
Pain (treatment)—Cattle, dogs1, pigs1, and [cats]1: Aspirin is used for relief
from mild to moderate somatic pain, such as incisional pain following
surgery, pain following dental procedures, and discomfort associated
with cystitis.
Fever (treatment)1—Cattle, dogs, pigs, and [cats]: Aspirin is used to reduce
fever; however, the treatment of fever with antipyretic medications is
controversial and specific therapy for the underlying disease should be
sought.
ACCEPTANCE NOT ESTABLISHED
Inflammation (treatment);
Pain (treatment); or
Fever (treatment)1—Horses: Due to the rapid elimination of salicylate by
horses, it is questionable whether therapeutic yet nontoxic concentrations can be maintained in the horse using conventional dosage
intervals.
Ó 2004 The United States Pharmacopeial Convention, Inc.
REGULATORY CONSIDERATIONS
U.S.—
Aspirin does not have specific approval by the Food and Drug
Administration for use in animals; therefore, there are no established
withdrawal times for use of this medication in food-producing
animals.{R-13} See recommendations on withdrawals for extra-label
administration in the Dosage Forms section of this monograph.
CHEMISTRY
Source: Manufactured from salicylic acid and acetic anhydride.{R-14}
Chemical name: Benzoic acid, 2-(acetyloxy)-.{R-15}
Molecular formula: C9H8O4.{R-15}
Molecular weight: 180.16.{R-15}
Description: Aspirin USP—White crystals, commonly tabular or needlelike, or white, crystalline powder. Is odorless or has a faint odor. Is
stable in dry air; in moist air it gradually hydrolyzes to salicylic and
acetic acids.{R-16}
pKa: 3.5.{R-14; 17}
Solubility: Aspirin USP—Slightly soluble in water; freely soluble in
alcohol; soluble in chloroform and in ether; sparingly soluble in
absolute ether.{R-16}
All rights reserved
ASPIRIN Veterinary—Systemic 5
PHARMACOLOGY/PHARMACOKINETICS
Note: See also Table 1. Pharmacology/Pharmacokinetics at the end of this
monograph.
Mechanism of action/Effect: The effectiveness of aspirin is largely due
to its ability to inhibit prostaglandin synthesis. This is done by irreversibly blocking cyclooxygenase (prostaglandin synthase), which
catalyzes the conversion of arachidonic acid to endoperoxide compounds; at appropriate doses, the drug decreases the formation of both
the prostaglandins and thromboxane A2 but not the leukotrienes.{R-18}
Other actions/effects: It has been proposed that the gastrointestinal
toxicity of salicylates, especially aspirin, may be caused primarily by
reduction of the activity of prostaglandins (which exert a protective
effect on the gastrointestinal mucosa) because upper gastrointestinal
toxicity has been reported following rectal or parenteral administration
of a nonsteroidal anti-inflammatory drug. However, when administered orally, these acidic medications (unless administered in an enteric-coated formulation) probably also exert a direct irritant or erosive
effect on the mucosa.{R-19}
Absorption: Salicylates are rapidly and completely absorbed following
oral administration to cats, dogs, and pigs. They are slowly and
incompletely absorbed by ruminants and horses.
Distribution: Free aspirin is widely distributed into various tissues of the
body.
Biotransformation: Aspirin is rapidly hydrolyzed to salicylic acid by
plasma esterases in all species.{R-20}
Time to peak plasma concentration: Human data—Generally 1 to 2
hours with single doses; may be more rapid with liquid dosage forms;
may be delayed with delayed-release tablet or capsule formulations.{R-19}
Peak plasma concentration: Therapeutic serum salicylate concentrations varied from 9.15 to 11.90 mg/dL in dogs given plain aspirin
orally at a dose of 25 mg per kg of body weight (mg/kg) every 8
hours.{R-21}
Milk concentrations: Human data—Peak salicylate concentrations of
173 to 483 mcg/mL were measured in breast milk 5 to 8 hours after
maternal ingestion of a single total aspirin dose of 650 mg.{R-19}
Elimination: Renal, primarily as free salicylic acid and as conjugated
metabolites. In the horse, salicylic acid is the primary salicyl compound found in urine while in other domesticated species varying
quantities of metabolites are excreted.
Cats: Aspirin has been shown to have dose-dependent elimination in cats,
with longer elimination half-lives seen with larger doses.
PRECAUTIONS TO CONSIDER
SPECIES SENSITIVITY
Cats—Cats may develop salicylism unless aspirin dosage is carefully
controlled. Cats are deficient in the enzyme glucuronyl transferase, an
important conjugation mechanism in other species.
Ó 2004 The United States Pharmacopeial Convention, Inc.
Dogs—Some individual dogs will not tolerate continuous therapy with
aspirin because they develop gastrointestinal irritation.
LACTATION
Salicylates are distributed into milk; however, problems have not been
observed in nursing offspring.
PEDIATRICS
Salicylates are more slowly eliminated in animals less than 30 days of
age. In addition, the extent of protein binding is less during this
period.
HUMAN PRECAUTIONS TO CONSIDER{R-19}
In addition to the above precautions for the use of this medication in
animals, the following precautions to consider have been reported in
humans and are included in the human monograph Salicylates
(Systemic) in USP DI Volume I; these precautions are intended for
informational purposes only and may or may not be applicable to the
use of aspirin in the treatment of animals.
Cross-sensitivity and/or related problems
Patients sensitive to one salicylate, including methyl salicylate (oil of
wintergreen), or to other nonsteroidal anti-inflammatory drugs
(NSAIDs) may be sensitive to salicylates also.
Patients sensitive to aspirin may not necessarily be sensitive to nonacetylated salicylates.
Patients sensitive to tartrazine dye may be sensitive to aspirin also, and
vice versa.
Cross-sensitivity between aspirin and other NSAIDS that result in
bronchospastic or cutaneous reactions may be eliminated if the
patient undergoes a desensitization procedure.
Pregnancy/reproduction
Fertility—Salicylates have caused increased numbers of fetal resorptions
in animal studies.
Pregnancy—
First trimester—Salicylates readily cross the placenta, but controlled
studies using aspirin in humans have not shown proof of teratogenicity. However, studies in animals have shown that salicylates
cause birth defects, including fissure of the spine and skull, facial
clefts, eye defects and malformation of the CNS, viscera and skeleton.
FDA pregnancy category D.
Third trimester—Chronic, high dose salicylate therapy may result in
prolonged gestation, increased risk of postmaturity syndrome (fetal
damage or death due to decreased placental function, if pregnancy is
greatly prolonged) and maternal antenatal hemorrhage. Overuse or
abuse of aspirin in late gestation has been reported to increase the
risk of stillbirth or neonatal death, possibly because of antenatal
hemorrhage or premature ductus arteriosis closure, leading to
persistent pulmonary hypertension and heart failure. Low birth
weight is also a consideration.
Labor and delivery—Chronic, high dose salicylate therapy late in
pregnancy may result in prolonged labor, complicated deliveries and
increased risk of maternal or fetal hemorrhage.
All rights reserved
6 ASPIRIN Veterinary—Systemic
Geriatrics
Geriatric patients may be more susceptible to the toxic effects of
salicytates, possibly because of decreased renal function. Lower doses
than those usually recommended for adults, especially for long-term
use or for use of long-acting salicylates, may be required.
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily inclusive; » ¼ major clinical significance:
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Corticosteroids or
Nonsteroidal anti-inflammatory analgesics
(concurrent use may increase the risk of hypernatremia and edema;
also, concurrent use will increase the risk of gastrointestinal
ulcers){R-22}
Digitalis glycosides
(aspirin given at a dosage of 50 mg per kg of body weight [mg/kg]
will increase digoxin serum concentrations up to 130% of normal)
HUMAN DRUG INTERACTIONS AND/OR RELATED
PROBLEMS:{R-19}
In addition to the above drug interactions reported in animals, the
following drug interactions have been reported in humans and are
included in the human monograph Salicylates (Systemic) in USP DI
Volume I; these drug interactions are intended for informational
purposes only and may or may not be applicable to the use of aspirin in
the treatment of animals.
Note: Combinations containing any of the following medications,
depending on the amount present, may also interact with this
medication.
In addition to the interactions listed below, the possibility should be
considered that additive or multiple effects leading to impaired blood
clotting and/or increased risk of bleeding may occur if a salicylate,
especially aspirin, is used concurrently with any medication having a
significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage.
For all salicylates
Acetaminophen
(prolonged concurrent use of acetaminophen with a salicylate is
not recommended because chronic, high dose administration of
the combined analgesics [1.35 grams daily, or cumulative
ingestion of 1 kg annually, for 3 years or longer] significantly
increases the risk of analgesic nephropathy, renal papillary
necrosis, end stage renal disease, and cancer of the kidney or
urinary bladder; also, it is recommended that for short-term use
the combined dose of acetaminophen plus a salicylate not exceed
that recommended for acetaminophen or a salicylate given
individually)
Acidifiers, urinary, such as:
Ammonium chloride
Ascorbic acid (Vitamin C)
Potassium or sodium phosphates
(acidification of the urine by these medications decreases salicylate excretion leading to increased salicylate plasma concentra-
Ó 2004 The United States Pharmacopeial Convention, Inc.
tions; initiation of therapy with these medications in patients
stabilized on a salicylate may lead to toxic salicylate concentrations)
(aspirin may increase urinary excretion of ascorbic acid; clinical
significance is unclear, but some clinicians recommend ascorbic
acid supplementation in patients receiving prolonged high-dose
aspirin therapy)
Alcohol or
Nonsteroidal anti-inflammatory drugs (NSAIDS), other
(concurrent use of these medications with a salicylate may increase
the risk of gastrointestinal side effects, including ulceration and blood
loss; also, concurrent use of a salicylate with an NSAID may increase
the risk of severe gastrointestinal side effects without providing
additional symptomatic relief and is therefore not recommended)
(aspirin may decrease the bioavailability of many NSAIDs, including
diflunisal, fenoprofen, indomethacin, meclofenamate, piroxicam [to
80% of the usual plasma concentration], and the active sulfide
metabolite of sulindac; aspirin has also been shown to decrease the
protein binding and increase the plasma clearance of ketoprofen, and
to decrease the formation and excretion of ketoprofen conjugates)
(concurrent use of other NSAIDs with aspirin may also increase the
risk of bleeding at sites other than the gastrointestinal tract because
of additive inhibition of platelet aggregation)
Alkalizers, urinary, such as:
Carbonic anhydrase inhibitors
Citrates
Sodium bicarbonate or
Antacids, chronic high-dose use, especially calcium- and/or magnesium containing
(alkalinization of the urine by these medications increases salicylate
excretion, leading to decreased salicylate plasma concentrations,
reduced effectiveness, and shortened duration of action; also,
withdrawal of a urinary alkalizer from a patient stabilized on a
salicylate may increase the plasma salicylate concentration to a toxic
level; however, the antacids present in buffered aspirin formulations
may not be present in sufficient quantities to alkalinize the
urine)
(metabolic acidosis induced by carbonic anhydrase inhibitors may
increase penetration of salicylate into the brain and increase the risk
of salicylate toxicity in patients taking large [antirheumatic] doses of
salicylate; if acetazolamide is used to produce forced alkaline diuresis
in the treatment of salicylate poisoning, the increased risk of severe
metabolic acidosis and increased salicylate toxicity must be considered and an alkaline intravenous solution given concurrently)
Anticoagulants, coumarin- or indandione-derivative or
Heparin or
Thrombolytic agents, such as:
Alteplase
Anistreplase
Streptokinase
Urokinase
(salicylates may displace a coumarin- or indandione-derivative
anticoagulant from its protein binding sites, and, in high doses,
may cause hypothrombinemia, leading to increased anticoagulation and risk of bleeding)
(the potential occurrence of gastrointestinal ulceration or hemorrhage during salicylate, especially aspirin, therapy may cause
increased risk to patients receiving anticoagulant or thrombolytic
therapy)
All rights reserved
ASPIRIN Veterinary—Systemic 7
(because aspirin-induced inhibition of platelet function may lead
to prolonged bleeding time and increased risk of hemorrhage,
concurrent use of aspirin with an anticoagulant or a thrombolytic agent is recommended only within a carefully monitored
antithrombotic regimen, although a recent study has shown
that initiation of therapy with 160 mg of aspirin a day
concurrently with short-term [1-hour] intravenous infusion
with streptokinase in patients with acute coronary arterial
occlusion significantly decreases the risk of reocclusion, reinfarction, stroke and death without increasing the risk of adverse
effects [as compared with streptokinase alone], other studies
using higher doses of aspirin and/or more prolonged administration of a thrombolytic agent have demonstrated an increased
risk of bleeding)
Anticonvulsants, hydantoin
(salicylates may decrease hydantoin metabolism, leading to
increases in hydantoin plasma concentrations, efficacy, and/or
toxicity; adjustment of hydantoin dosage may be required when
chronic salicylate therapy is initiated or discontinued)
Antidiabetic agents, oral or
Insulin
(effects of these medications may be increased by large doses of
salicylates; dosage adjustments may be necessary; potentiation of
oral antidiabetic agents may be caused partially by displacement
from serum proteins; glypizide and glyburide, because of their
nonionic binding characteristics, may not be affected as much as
the other oral agents; however, caution in concurrent use is
recommended)
Antiemetics, including antihistamines and phenothiazines
(antiemetics may mask the symptoms of salicylate-induced ototoxicity, such as dizziness, vertigo, and tinnitus)
Bismuth subsalicylate
(ingestion of large repeated doses as for traveler’s diarrhea may
produce substantial salicylate concentration; concurrent use with
large doses of analgesic salicylates may increase the risk of
salicylate toxicity)
Cefamandole or
Cefoperazone or
Cefotetan or
Plicamycin or
Valproic acid
(these medications may cause hypoprothrombinemia; in addition,
plicamycin or valproic acid may inhibit platelet aggregation;
concurrent use with aspirin may increase the risk of bleeding
because of additive interferences with blood clotting)
(hypoprothrombinemia induced by large doses of salicylates, and
the potential occurrence of gastrointestinal ulceration or hemorrhage during aspirin therapy may increase the risk of bleeding
complications in patients receiving these medications)
(concurrent use of aspirin with valproic acid has also been reported
to increase the plasma concentration of valproic acid and induce
valproic acid toxicity)
Corticosteroids or
Corticotropin (ACTH), chronic therapeutic use of
(glucocorticoids or corticotropin may increase salicylate excretion,
resulting in lower plasma concentrations and increased salicylate
dosage requirements; salicylism may result when glucocorticoids or
corticotropin dosage is subsequently decreased or discontinued,
Ó 2004 The United States Pharmacopeial Convention, Inc.
especially in patients receiving large [antirheumatic] doses of
salicylate; also, the risk of gastrointestinal side effects, including
ulceration and gastrointestinal blood loss, may be increased;
however, concurrent use in the treatment of arthritis may provide
additive therapeutic benefit and permit reduction of glucocorticoid
or corticotropin use)
(because adrenocorticoids and corticotropin may cause sodium
and fluid rentention, caution in concurrent use of large doses of
sodium salicylate is recommended)
Furosemide
(in addition to increasing the risk of ototoxicity, concurrent use of
furosemide with high doses of salicylate may lead to salicylate
toxicity because of competition for renal excretory sites)
Laxatives, cellulose-containing
(concurrent use may reduce the salicylate effect because of
physical binding or other absorptive hindrance; medications
should be administered 2 hours apart)
Methotrexate
(salicylates may displace methotrexate from its binding sites and
decrease its renal clearance, leading to toxic methotrexate plasma
concentrations; if they are used concurrently, methotrexate
dosages should be decreased, the patient observed for signs of
toxicity and/or methotrexate plasma concentration monitored;
also, it is recommended that salicylate therapy be discontinued 24
to 48 hours prior to administration of a high dose methotrexate
infusion, and not resumed until plasma methotrexate concentration has decreased to a nontoxic level [usually at least 12 hours
postinfusion])
Ototoxic medications, other, especially
Vancomycin
(concurrent or sequential administration of these medications
with a salicylate should be avoided because the potential for
ototoxicity may be increased; hearing loss may occur and may
progress to deafness even after discontinuation of the medication; these effects may be reversible, but usually are permanent)
Platelet aggregation inhibitors
(concurrent use with aspirin is not recommended, except in a
monitored antithrombotic regimen, because the risk of bleeding
may be increased)
(the potential of occurrence of gastrointestinal ulceration or
hemorrhage due to salicylate therapy, and the hypothrombinemic
effect of large doses of salicylate, may cause increased risk to
patients receiving a platelet aggregation inhibitor)
Probenecid or
Sulfinpyrazone
(concurrent use of a salicylate is not recommended when these
medications are used to treat hyperuricemia or gout, because the
uricosuric effect of these medications may be decreased by the
doses of salicylate that produce serum salicylate concentrations
above 5 mg per 100 mL; also, these medications may inhibit the
uricosuric effect achieved when serum salicylate concentrations
are above 10 to 15 mg per 100 mL)
(probenecid may decrease renal clearance and increase plasma
concentrations and toxicity of salicylates)
(sulfinpyrazone may decrease salicylate excretion and/or displace
salicylate from its protein binding sites, possibly leading to
increased salicylate concentrations and toxicity)
(although low doses of sulfinpyrazone and aspirin have been used
All rights reserved
8 ASPIRIN Veterinary—Systemic
concurrently to provide additive inhibition of platelet aggregation,
the efficacy of the combination has not been established and the
increased risk of bleeding must be considered; also, concurrent use
of sulfinpyrazone with aspirin may increase the risk of gastrointestinal ulceration or hemorrhage)
Salicylic acid or other salicylates, topical
(concurrent use with systemic salicylates may increase the risk of
salicylate toxicity if significant quantities are absorbed)
Vitamin K
(requirements for this vitamin may be increased in patients
receiving high doses of salicylate)
Zidovudine
(in theory, aspirin may completely inhibit the hepatic glucuronidation and decrease the clearance of zidovudine, leading to
potentiation of zidovudine toxicity; the possibility must be considered that aspirin toxicity may also be increased)
For buffered aspirin formulations, choline and magnesium salicylates or
magnesium salicylate (in addition to those interactions listed above as
applying to all salicylates)
Ciprofloxacin or
Enoxacin or
Itraconazole or
Ketoconazole or
Lomefloxacin or
Ofloxacin or
Tetracyclines, oral
(antacids present in buffered aspirin formulations, and the magnesium in choline and magnesium salicylate or magnesium salicylate,
interfere with absorption of these medications; if used concurrently,
the interacting salicylate should be taken at least 6 hours before or 2
hours after ciprofloxacin or lomefloxacin, 8 hours before or 2 hours
after enoxacin, 2 hours after itraconazole, 3 hours before or after
ketoconazole, 2 hours before or after norfloxacin or ofloxacin, and 3
to 4 hours before or after a tetracycline)
For enteric-coated formulations (in addition to those interactions listed above
as applying to all salicylates)
Antacids or
Histamine H2-receptor antagonists
(concurrent administration of these medications, which increase
intragastric pH, with an enteric-coated medication may cause
premature dissolution, and loss of the protective effect, of the enteric
coating)
For formulations containing caffeine (in addition to those interactions listed
above as applying to all salicylates)
CNS stimulation–producing medications, other
(concurrent use with caffeine may result in excessive CNS stimulation, which may cause unwanted effects such as nervousness,
irritability, insomnia, or possibly convulsions or cardiac arrhythmias; close observation is recommended)
Lithium
(caffeine increases urinary excretion of lithium, thereby possibly
reducing its therapeutic effect)
Monoamine oxidase (MAO) inhibitors, including furazolidone, pargyline, and procarbazine
(concurrent use of large amounts of caffeine with MAO inhibitors
may produce dangerous cardiac arrhythmias or severe hypertension
because of the sympathomimetic side effects of caffeine)
Ó 2004 The United States Pharmacopeial Convention, Inc.
HUMAN LABORATORY VALUE ALTERATIONS{R-19}
The following laboratory value alterations have been reported in
humans, and are included in the human monograph Salicylates
(Systemic) in USP DI Volume I; these laboratory value alterations are
intended for informational purposes only and may or may not be
applicable to the use of aspirin in the treatment of animals:
With diagnostic test results
For all salicylates
Copper sulfate urine sugar tests
(false-positive test results may occur with chronic use of salicylates
in doses equivalent in salicylate content to 2.4 grams or more of
aspirin a day, i.e., 3.2 grams of choline salicylate, 2.4 grams of
choline and magnesium salicylates, 2 grams of magnesium salicylate, 1.8 grams of salsalate, or 2.4 grams of sodium salicylate a day)
Gerhardt test for urine acetoacetic acid
(interference may occur because reaction with ferric chloride
produces a reddish color that persists after boiling)
Glucose enzymatic urine sugar tests
(false-negative test results may occur with chronic use of salicylates
in doses equivalent in salicylate content to 2.4 grams or more of
aspirin a day, i.e., 3.2 grams of choline salicylate, 2.4 grams of
choline and magnesium salicylates, 2 grams of magnesium salicylate, 1.8 grams of salsalate, or 2.4 grams of sodium salicylate a day)
Renal function test using phenolsulfonphthalein (PSP)
(salicylate may competitively inhibit renal tubular secretion of PSP,
thereby decreasing urinary PSP concentration and invalidating test
results)
Serum uric acid determinations
(falsely increased values may occur with colorimetric assay
methods when plasma salicylate concentrations exceed 13 mg
per 100 mL; the uricase assay method is not affected)
Thyroid imaging, radionucleotide
(chronic salicylate administration may depress thyroid function;
salicylate therapy should be discontinued at least 1 week prior to
administration of the radiopharmaceutical; however, a rebound
effect may occur following discontinuation of the salicylate
therapy, resulting in a period of 3 to 10 days of increased thyroidal
uptake)
Urine vanillylmandelic acid (VMA) determinations
(values may be falsely increased or decreased, depending on
method used)
For aspirin (in addition to those interferences listed above for all salicylates)
Protirelin-induced thyroid-stimulating hormone (TSH) release determinations
(TSH response to protirelin may be decreased by 2 to 3.6 grams of
aspirin daily; peak TSH concentrations occur at the same time after
administration, but are reduced)
Urine 5-hydroxyindoleacetic acid (5-HIAA) determinations
(aspirin may alter results when fluorescent method is used)
For caffeine-containing formulations (in addition to the diagnostic interferences listed above)
Myocardial perfusion imaging, radionuclide, when adenosine or
dipyridamole is used as an adjunct to the radiopharmaceutical
(caffeine may reverse the effects of adenosine or dipyridamole on
myocardial blood flow, thereby interfering with the test results;
patients should be advised to avoid caffeine for at least 8 to 12 hours
prior to the test)
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ASPIRIN Veterinary—Systemic 9
With physiology/laboratory test values
For all salicylates
Liver function tests, including;
Serum alanine aminotransferase (ALT [SGPT]) and
Serum alkaline phosphatase and
Serum aspartate aminotransferase (AST [SGOT])
(abnormalities may occur, especially in patients with juvenile
rheumatoid arthritis, systemic lupus erythematosus, or preexisting history of liver disease, or when plasma salicylate
concentrations exceed 25 mg per 100 mL; liver function test
values may return to normal despite continued use or when
dosage is decreased; however, if severe abnormalities occur, or if
there is evidence of active liver disease, the medication should be
discontinued and used with caution in the future)
Prothrombin time
(may be prolonged with large doses of salicylates, especially if
plasma concentrations exceed 30 mg per 100 mL)
Serum cholesterol concentrations
(may be decreased by chronic use of salicylates in doses equivalent
in salicylate content to 5 grams or more of aspirin per day, i.e., 6.7
grams of choline salicylate, 5 grams of choline and magnesium
salicylates, 4.1 grams of magnesium salicylate, 3.8 grams of
salsalate, or 5 grams of sodium salicylate a day)
Serum potassium concentrations
(may be decreased because of increased potassium excretion caused
by direct effect on renal tubules)
Serum thyroxine (T4) concentrations and
Serum triiodothyronine (T3) concentrations
(may be decreased when determined by radioimmunoassay—with
large doses of salicylates)
Serum uric acid concentrations
(may be increased or decreased, depending on salicylate dosage;
plasma salicylate concentrations below 10 to 15 mg per 100 mL
increase serum uric acid concentrations and higher plasma salicylate concentrations decrease uric acid concentrations)
T3 resin uptake
(may be increased with large doses of salicylate)
For aspirin only (in addition to the interferences listed above)
Bleeding time
(may be prolonged by aspirin for 4 to 7 days because of suppressed
platelet aggregation; as little as 40 mg of aspirin affects platelet
function for at least 96 hours following administration; however,
clinical bleeding problems have not been reported with small doses
[150 mg or less])
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
given in parentheses where appropriate)—not necessarily inclusive
(» = major clinical significance).
Except under special circumstances, this medication should not be
used when the following medical problems exist:
» Bleeding disorders
(increased risk of hemorrhage)
» Gastrointestinal bleeding or ulceration
(the presence of lesions before treatment can put an animal at risk of
exacerbation or perforation)
Ó 2004 The United States Pharmacopeial Convention, Inc.
Risk-benefit should be carefully considered when the following
medical problem exists:
Cats
Feline tracheobronchitis
PATIENT MONITORING
The following may be especially important in patient monitoring (other
tests may be warranted in some patients, depending on condition; » =
major clinical significance):
Cats and dogs
Blood chemistry
Complete blood count (CBC)
Test for occult blood in feces
(periodic laboratory tests during treatment have been suggested for
animals receiving high dose or long-term therapy)
SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their
potential clinical significance (possible signs and, for humans, symptoms in parentheses where appropriate—not necessarily inclusive):
THOSE INDICATING NEED FOR MEDICAL ATTENTION
Incidence more frequent
Cats and dogs
Gastric irritation (anorexia, nausea, or vomiting); ulceration of
gastrointestinal mucosa with bleeding—due to multiple effects,
including inhibition of prostaglandin synthesis in gut leading to
altered secretion of mucus and decreased cytoprotection
Incidence less frequent
Cats
Salicylism, acute
Incidence rare
All species
Allergic reactions
HUMAN SIDE/ADVERSE EFFECTS{R-19}
In addition to the above side/adverse effects reported in animals, the
following side/adverse effects have been reported in humans, and are
included in the human monograph Salicylates (Systemic) in USP DI
Volume I; these side/adverse effects are intended for informational
purposes only and may or may not be applicable to the use of aspirin in
the treatment of animals:
Incidence more frequent with aspirin; less frequent with enteric-coated or
buffered formulations of aspirin and with other salicylates
Gastrointestinal irritation
Incidence less frequent or rare
Anaphylactoid reaction; anemia—may occur secondary to gastrointestinal microbleeding; anemia, hemolytic—almost always
reported in patients with glucose-6-phosphate deficiency (G6PD);
bronchospastic allergic reaction; dermatitis, allergic; gastrointestinal ulceration, possibly with bleeding
Note: Salicylates may decrease renal function, especially when serum
salicylate concentrations reach 250 mcg per mL (25 mg per 100 mL).
However, the risk of complications due to this action appears minimal
in patients with normal renal function.
Aspirin-induced bronchospasm is most likely to occur in patients with
the triad of asthma, allergies, and nasal polyps induced by aspirin.
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10 ASPIRIN Veterinary—Systemic
Nonacetylated salicylates may rarely cause bronchospastic reactions in
susceptible people when very large doses are given.
Angioedema or urticaria may be more likely to occur in patients with a
history of recurrent idiopathic angioedema or urticaria.
Gastrointestinal side effects are more likely to occur with aspirin than
with other salicylates; also, they may be more likely to occur with
chronic, high-dose administration than with occasional use. Use of
enteric-coated formulations may reduce the potential for gastrointestinal side effects.
Adverse effects are more likely to occur at serum salicylate
concentrations of 300 mcg per mL (30 mg per 100 mL) or above;
however, they may also occur at lower serum concentrations,
especially in patients 60 years of age or older. Serum concentrations
at which adverse or toxic effects have been reported during chronic
therapy include:
Salicylate Concentration
(mcg per mL/
mg per 100 mL)
Effect
195–210/19.5–21
250/25
250/25
300/30
310/31
350/35
>400/40
Mild toxicity (tinnitus, decreased hearing)
Hepatotoxicity (abnormal liver function tests)
Decreased renal function
Decreased prothrombin time
Deafness
Hyperventilation
Metabolic acidosis, other signs of severe toxicity
increased susceptibility to salicylate toxicity in children, especially
with fever and dehydration
Use in the elderly—Increased susceptibility to salicylate toxicity
Other medications, especially anticoagulants, antidiabetic agents
(oral), those cephalosporins that may cause hypoprothrombinemia, plicamycin, valproic acid, methotrexate, NSAIDs, platelet
aggregation inhibitors, probenecid, sulfinpyrazone, urinary alkalizers, and vancomycin; also, for buffered aspirin, choline and
magnesium salicylates, and magnesium salicylate; fluoroquinolone antibiotics, itraconazole, ketoconazole, and oral tetracyclines
Other medical problems, especially coagulation or platelet function
disorders, gastrointestinal problems such as ulceration or erosive
gastritis (especially a bleeding ulcer), thyrotoxicosis, and (for
choline and magnesium salicylates and for magnesium salicylate)
chronic advanced renal insufficiency
OVERDOSE
HUMAN PATIENT CONSULTATION{R-19}
The following information has been recommended for human patient
consultation and is included in the human monograph, Salicylates
(Systemic), in USP DI Volume I; these recommendations are intended
for informational purposes only and may or may not be applicable to
the use of aspirin in the treatment of animals:
Before using this medication
Conditions affecting use, especially:
Sensitivity to any of the salicylates, including methyl salicylate, or
nonsteroidal anti-inflammatory drugs (NSAIDs), history of
Diet—Sodium content of sodium salicylate must be considered for
patients on a sodium restricted diet, especially with chronic use of
antirheumatic doses
Pregnancy—Salicylates and caffeine (present in some formulations)
cross the placenta; high dose chronic use or abuse of aspirin in
the third trimester may be hazardous to the mother as well as
the fetus and/or neonate, causing heart problems in fetus or
neonate and/or bleeding in mother, fetus, or neonate; high-dose
chronic use or abuse of any salicylate late in pregnancy may
also prolong and complicate labor and delivery; not taking
aspirin during the third trimester unless prescribed by a
physician
Breast-feeding—Salicylates and caffeine (present in some formula
tions) are excreted in breast milk
Use in children and teenagers—Checking with physician before
giving to children or teenagers with symptoms of acute febrile
illness, especially influenza or varicella, because of the risk of Reye’s
syndrome; determining ahead of time what physician wants done if
a child receiving chronic therapy develops fever or other symptoms
of acute illness that may predispose to Reye’s syndrome; also,
Ó 2004 The United States Pharmacopeial Convention, Inc.
For information in cases of overdose or unintentional ingestion, contact
the American Society for the Prevention of Cruelty to Animals
(ASPCA) National Animal Poison Control Center (888-426-4435
or 900-443-0000; a fee may be required for consultation) and/or the
drug manufacturer.
HUMAN CLINICAL EFFECTS OF OVERDOSE{R-19}
The following effects of overdose have been reported in human beings,
and are included in the human monograph, Salicylates (Systemic), in
USP DI Volume I; these effects are intended for informational purposes
only and may or may not be applicable to the use of aspirin in the
treatment of animals:
Note: See also the Human side/adverse effects section in this monograph
for serum salicylate concentrations associated with human toxicity.
Mild overdose
Salicylism (continuing ringing or buzzing in ears or hearing loss;
confusion; severe or continuing diarrhea, stomach pain, and/or
headache; dizziness or lightheadedness; severe drowsiness; fast or
deep breathing; continuing nausea and/or vomiting; uncontrollable
flapping movements of the hands, especially in elderly patients;
increased thirst; vision problems)—tinnitus and/or headache may be
the earliest symptoms of salicylism
Severe overdose
Bloody urine; convulsions; hallucinations; severe nervousness,
excitement, or confusion; shortness of breath or troubled
breathing; unexplained fever
Note: In young children, the only signs of an overdose may be changes
in behavior, severe drowsiness or tiredness, and/or fast or deep
breathing.
Laboratory findings in overdose may indicate encephalographic
abnormalities, alterations in acid-base balance (especially respiratory
alkalosis and metabolic acidosis), hyperglycemia or hypoglycemia
(especially in children), ketonuria, hyponatremia, hypokalemia, and
proteinuria.
FOR TREATMENT OF OVERDOSE
Acute salicylism in animals is best treated by procedures that facilitate
the removal of salicylate from the body, as there is no specific antidote
available.
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ASPIRIN Veterinary—Systemic 11
Gastric lavage will remove unabsorbed drug from the stomach. Alkalization of the urine with intravenously administered sodium bicarbonate will enhance renal excretion of salicylate by decreasing tubular
reabsorption of the drug. This effect may be enhanced by instituting an
osmotic diuresis with mannitol solution. Peritoneal dialysis is effective
in removing salicylate from the plasma. Cats are especially prone to
salicylate overdosage.
VETERINARY DOSING INFORMATION
Dosage of aspirin will vary depending on the therapeutic objective to be
attained.
Therapeutic serum concentrations: For salicylate—
Analgesic/antipyretic: 20 to 50 mcg/mL.
Anti-inflammatory/antirheumatic: 150 to 200 mcg/mL.{R-37}
Enteric-coated aspirin products are not recommended because gastric
retention has been noted to occur.{R-23}
ORAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
ASPIRIN BOLUSES USP
Usual dose:
Note: Although veterinary forms of aspirin are marketed with label
indications for treatment of pain, fever, and inflammation, the drug
has never been approved by the Food and Drug Administration Center
for Veterinary Medicine (FDA CVM) for these purposes.
Fever1; or
Pain—Cattle: Oral, 100 mg per kg of body weight every twelve hours.{R-35}
Note: Although ruminants eliminate salicylate rapidly, the slow
absorption of aspirin from the reticulorumen is rate-limiting and
therapeutically effective concentrations are maintained.{R-24}
Fever1; or
Pain1—Pigs: Oral, 10 mg per kg of body weight every six to eight
hours.{R-25} If a water supply is to be used for administration, then
aspirin at 2 mg per kg of body weight per hour (mg/kg/hr) may be
used. For this latter purpose, due to the poor solubility of aspirin in
water, sodium salicylate at 1.8 mg/kg/hr may be considered as a
substitute.
Note: [Escherichia coli diarrhea]1—Piglets, 9 to 20 days of age: Although the
safety and efficacy have not been established, aspirin has been used in
the treatment of Escherichia coli–induced diarrhea in piglets with an oral
dose of 0.5 to 1 gram, once a day in the feed or drinking water.{R-26}
Horses—Although some veterinary aspirin products are labeled for use in
horses, due to the rapid elimination of salicylate by horses, it is
questionable whether therapeutic yet nontoxic concentrations can be
maintained in the horse using conventional dosage intervals.
15.6 grams (240 grains) (OTC) [Asen 240 Bolus; Centra ASA 240;
generic].
Withdrawal times: U.S. and Canada—Aspirin has not been approved
in the United States by the Food and Drug Administration for use in
food-producing animals; therefore, there are no established withdrawal
times. If aspirin is administered to cattle at a dose of 100 mg per kg
every 12 hours, evidence has been compiled by the Food Animal
Residue Avoidance Databank (FARAD) that suggests a meat withdrawal time of 1 day (24 hours) and a milk withholding of 24 hours
would be sufficient to avoid residues.{R-27; 28} The Canadian gFARAD
follows the same recommendations as US FARAD.{R-38} When making
withdrawal recommendations, note that anaphylactoid drug reactions
and Reye’s syndrome have been associated with aspirin exposure in
human beings.{R-19; 28}
Packaging and storage: Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by
manufacturer. Store in a tight container.
USP requirements: Preserve in tight containers. Label Boluses to
indicate that they are for veterinary use only. Contain the labeled
amount, within ±10%. Meet the requirements for Identification, Dissolution (80% in 45 minutes in 0.05 M acetate buffer [pH 4.50 ±
0.05] in Apparatus 1 at 100 rpm), Uniformity of dosage units, and
Limit of salicylic acid (not more than 0.3%).{R-16}
ASPIRIN ORAL GRANULES
Usual dose: See Aspirin Boluses USP.
Strength(s) usually available:{R-33}
U.S.—
Veterinary-labeled product(s):
64.1 mg per cc (2500 mg per 39 cc scoop) (OTC) [Equiphar ArthriBan;
Equi-Spirin].
Canada—
Veterinary-labeled product(s):
725 mg per gram of powder (OTC) [Asen].
Withdrawal times: See Aspirin Boluses USP.
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), unless otherwise specified by
manufacturer. Store in a well-closed container.
USP requirements: Not in USP.{R-16}
ASPIRIN ORAL PASTE
Usual dose: See Aspirin Boluses USP.
Strength(s) usually available:{R-33}
U.S.—
Veterinary-labeled product(s):
3.9 grams (60 grains) (OTC) [generic].
15.6 grams (240 grains) (OTC) [generic].
31.2 grams (480 grains) (OTC) [generic].
Canada—
Veterinary-labeled product(s):
Ó 2004 The United States Pharmacopeial Convention, Inc.
Strength(s) usually available:{R-33}
U.S.—
Veterinary-labeled product(s):
400 mg per cc (2 grams per 5cc mark on syringe) (OTC) [Equi-Prin].
Canada—
Veterinary-labeled product(s):
Not commercially available.
All rights reserved
12 ASPIRIN Veterinary—Systemic
Withdrawal times: See Aspirin Boluses USP.
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), in a well-closed container,
unless otherwise specified by manufacturer. Protect from freezing.
USP requirements: Not in USP.{R-16}
ASPIRIN ORAL POWDER
Usual dose: See Aspirin Boluses USP.
Strength(s) usually available:{R-33}
U.S.—
Veterinary-labeled product(s):
500 mg per gram of powder (OTC) [AniPrin F (molasses flavoring);
generic (apple flavoring or molasses flavoring)].
1 gram per gram of powder (OTC) [AniPrin P; generic].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Withdrawal times: See Aspirin Boluses USP.
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), unless otherwise specified by
manufacturer. Store in a tight container.
USP requirements: Not in USP.{R-16}
ASPIRIN ORAL SOLUTION
Usual dose: See Aspirin Boluses USP.
Note: Poultry—Although products may be labeled for use in poultry, the
USP Veterinary Medicine Committee can make no recommendations
for dosing or drug residue withdrawal when aspirin is administered to
poultry.
Strength(s) usually available:{R-33}
U.S.—
Veterinary-labeled product(s):
12% solution (OTC) [Asp-Rin; Durasol; generic].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Withdrawal times: See Aspirin Boluses USP.
Packaging and storage: Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by
manufacturer. Store in a tight container. Protect from freezing.
USP requirements: Not in USP.{R-16}
Fever1; or
Pain1—
Dogs: Oral, 10 mg per kg of body weight every twelve hours.
[Cats]: Oral, 10 mg per kg of body weight every two days. A convenient
regimen for a cat owner to follow for a nine-pound cat is to administer
one-half an infant aspirin tablet (81 mg) every Monday, Wednesday,
and Friday, with no treatment during the weekend.{R-29; 30}
Note: Aspirin is safe and effective for use in cats if the slow rate of
salicylate elimination in this species is taken into account.
Inflammation1—
Dogs: Oral, 25 to 35 mg per kg of body weight every eight to twelve
hours.{R-31; 32}
[Cats]: Oral, 10 to 20 mg per kg of body weight every two days.{R-22;
30}
A convenient regimen for a cat owner to follow to give a dose of
10 mg per kg to a nine-pound cat is to administer one-half an infant
aspirin tablet (81 mg) every Monday, Wednesday, and Friday, with
no treatment during the weekend; to give a dose of 20 mg per kg, one
infant tablet (81 mg) or one-quarter an adult tablet (325 mg) should
be given to a nine-pound cat on the same Monday, Wednesday, and
Friday schedule.
When a more intense anti-inflammatory effect is required, a dosage of
25 mg per kg of body weight every twenty-four hours may be used.
As this regimen is not well established, careful monitoring for
toxicity, especially GI ulceration, is advised.
Note: Aspirin is safe and effective for use in cats if the slow rate of
salicylate elimination in this species is taken into account.
Note: [Platelet aggregation inhibition]1—Although the ability of aspirin to
effectively prevent thromboembolism is not clearly established and
may be more effective in some diseases than in others, the following
doses have been used to inhibit platelet aggregation:
Cats—The optimal dosage of aspirin in the cat for platelet inhibition
has not been determined. A single dose of 25 mg per kg of body
weight has been demonstrated to have an antiplatelet effect.{R-9}
Many clinicians administer this dose twice weekly for a proposed
antiplatelet effect. Whether lower doses given repetitively would be
effective is unknown.
Dogs—The optimum dosage for platelet inhibition in dogs is
unknown. One study suggested that 0.5 mg per kg of body weight,
administered orally every twelve hours, inhibited platelet aggregation. Another study investigating the ability of aspirin to prevent
platelet aggregation to synthetic shunt materials suggested that
aspirin should be used at 5 mg per kg of body weight, administered
orally every twenty-four hours, for an antithrombotic effect.{R-10;
11; 22}
Horses—The optimal dosage of aspirin in the horse for platelet
inhibition has not been determined. Single doses of 20 mg per kg
of body weight have been demonstrated to have an antiplatelet
effect.{R-8} Whether lower dosages given repetitively would be
effective is unknown.
Note: Gastric retention for long periods of time and therefore lack of
absorption of large enteric-coated aspirin tablets (500 mg) occurs in
healthy dogs; enteric-coated tablets have questionable efficacy in
animals.{R-23}
ASPIRIN TABLETS USP
Usual dose: Note: Although veterinary forms of aspirin are marketed
with label indications for treatment of pain, fever, and inflammation,
the drug has never been approved by the Food and Drug Administration Center for Veterinary Medicine (FDA CVM) for these purposes.
Ó 2004 The United States Pharmacopeial Convention, Inc.
Strength(s) usually available:{R-19; 33}
U.S.—
Veterinary-labeled product(s):
All rights reserved
ASPIRIN Veterinary—Systemic 13
65 mg (Rx) [Palaprin 65 (chewable)].
100 mg (OTC) [Vetrin (chewable)].
150 mg (Rx) [generic (chewable)].
273 mg (Rx) [Arthricare (chewable)].
325 mg [Palaprin 325 (Rx, chewable); Vetrin (OTC, chewable)].
450 mg (Rx) [generic (chewable)].
Human-labeled product(s):
81 mg (OTC) [Aspir-Low; Bayer Children’s Aspirin (chewable);
Healthprin Adult Low Strength (scored); St. Joseph Adult Chewable
Aspirin (chewable); generic].
162.5 mg (OTC) [Healthprin Half-Dose (scored)].
325 mg (OTC) [Aspirtab; Empirin; Genuine Bayer Aspirin Caplets;
Genuine Bayer Aspirin Tablets; Healthprin Full Strength (scored);
Norwich Aspirin; generic].
500 mg (OTC) [Aspirtab-Max; Extra Strength Bayer Aspirin Caplets;
Extra Strength Bayer Aspirin Tablets; Norwich Aspirin; generic].
650 mg (OTC) [generic].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):
80 mg (OTC) [Aspirin Children’s Tablets (chewable)].
300 mg (OTC) [Headache Tablet].
325 mg (OTC) [Apo-ASA; Aspirin Caplets; Aspirin Tablets; PMS-ASA;
generic].
500 mg (OTC) [Aspirin Caplets; Aspirin Tablets; generic].
Note: Strengths of specific products labeled in grains may vary,
depending on the manufacturer.{R-19}
Packaging and storage: Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by
manufacturer. Store in a tight container.
(80% in 30 minutes in 0.05 M acetate buffer [pH 4.5 ± 0.05] in
Apparatus 1 at 50 rpm), Uniformity of dosage units, and Limit of free
salicylic acid (not more than 0.3% for uncoated tablets or not more
than 3.0% for coated tablets).{R-16}
Note—Tablets that are enteric-coated meet the requirements for
Aspirin Delayed-release Tablets USP.{R-16}
ASPIRIN DELAYED-RELEASE TABLETS USP
Usual dose:
Dogs—See Aspirin Tablets USP.
Note: Enteric-coated aspirin products developed for human use are not
recommended for use in animals because gastric retention has been
noted to occur.{R-23}
Strength(s) usually available:{R-33}
U.S.—
Veterinary-labeled product(s):
81 mg (OTC) [Health Measures (enteric-coated)].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), unless otherwise specified by
manufacturer.
USP requirements: Preserve in tight containers. The label indicates
that the Tablets are enteric-coated. Contain the labeled amount, within
±5%. Meet the requirements for Identification, Drug release, Uniformity of dosage units, and Limit of free salicylic acid (not more than
3.0%).{R-16}
1
USP requirements: Preserve in tight containers. Preserve flavored or
sweetened Tablets of 81-mg size or smaller in containers holding not
more than 36 Tablets each. Contain the labeled amount, within
±10%. Tablets of larger than 81-mg size contain no sweeteners or
other flavors. Meet the requirements for Identification, Dissolution
Not included in Canadian product labeling or product not commercially
available in Canada.
Revised: 04/30/93; 09/30/02
Interim revision: 07/19/94; 07/25/95; 07/11/96; 05/07/97; 05/26/
98; 2/6/04
Table 1. Pharmacology/Pharmacokinetics*
Note: Zero-order (dose-dependent) kinetics, especially for the elimination half-life, have been reported in dogs and cats. Such an occurrence cannot be discounted as possible
in other species. For such drugs, larger doses typically lead to longer elimination half-lives.
Species
Cats{R-34}
{R-30}
Cattle{R-35}
Dogs{R-34}
{R-36}
Goats{R-34}
Horses
{R-34}
Pigs{R-34}
Drug
Dosed
Protein
Binding (%)
Half-life of
Elimination (hr)
Vd (L/kg)
Clearance
(mL/min/kg)
Route; Dose
(mg/kg)
Half-life of
Absorption (hr)
Tmax (hr)
Cmax
(mcg/mL)
F (%)
Sodium salicylate
Aspirin
Aspirin
Sodium salicylate
Aspirin
Sodium salicylate
Aspirin
Aspirin
Sodium salicylate
60%
37.6
26.8
44.6
0.54
0.21
0.065
0.24
5.13
2.91
3
45
70
60%
8.6
4.49
0.19
Vdss 0.285
0.255
0.683
2
95.9
100
60%
0.8
0.13
1.88
IV; 44
Oral; 2.5
Oral; 25
IV; 50
Oral; 100
IV; 44
IV; 17.5
Oral; 35
IV; 44
Sodium salicylate
Sodium salicylate
54%
70%
1.0
5.9
0.18
0.18
2.08
0.352
IV; 44
IV; 44
60%
*
Abbreviations: Vd = Volume of distribution, IV = Intravenous, Tmax = Time to peak serum concentration, Cmax = Peak serum concentration, F = Bioavailability; percent
absorbed
Estimated from graph
Ó 2004 The United States Pharmacopeial Convention, Inc.
All rights reserved
14 ASPIRIN Veterinary—Systemic
REFERENCES
1. Fox, PR. Feline cardiomyopathies. In: Ettinger SJ, Feldman E, editors. Textbook
of veterinary internal medicine, 5th ed. Philadelphia: W.B. Saunders Company,
2000. p. 896–918.
2. Schaub RG, Gates KA, Roberts RE. Effect of aspirin on collateral blood flow
after experimental thrombosis of the feline aorta. Am J Vet Res 1982; 43:
1648–50.
3. Knight, DH. American Heartworm Society: 1999 guidelines for the diagnosis,
treatment and prevention of heartworm infection in cats. Batavia, IL:
American Heartworm Society, 1999.
4. American Heartworm Society. American Heartworm Society recommended
procedures for the diagnosis, prevention, and management of heartworm
(Dirofilaria immitis) infection in dogs. Canine Practice 1997; 22(2–3): 8–15.
5. Rawlings CA. Pulmonary arteriography and hemodynamics during feline
heartworm disease. Effect of aspirin. J Vet Int Med 1990; 4(6): 285–91.
6. Schaub RG, Rawlings CA, Keith JC. Effect of long-term aspirin treatment on
platelet adhesion to chronically damaged canine pulmonary arteries. Thromb
Haemostas (Stuttgart) 1981; 46(4): 680–3.
7. Cambridge H, Lees P, Hooke RE, et al. Antithrombotic actions of aspirin in the
horse. Eq Vet J 1991; 23(2): 123–7.
8. Judson DG, Barton M. Effect of aspirin on haemostasis in the horse. Res Vet Sci
1981; 30: 241–2.
9. Greene CE. Effects of aspirin and propranolol on feline platelet aggregation. Am
J Vet Res 1985; 46(9): 1820–3.
10. Escudero MC, Alvarez L, Haro JD, et al. Prevention of thrombus formation on
biomaterials exposed to blood using different antiplatelet drugs: experimental
study in dogs. J Biomed Mat Res 1994; 28(1): 1–6.
11. Rackear D, Feldman B, Farver T, et al. The effect of three different dosages of
acetylsalicylic acid on canine platelet aggregation. J Am Anim Hosp Assoc
1988: 24(1): 23–6.
12. Gentry PA, Tremblay RRM, Ross ML. Failure of aspirin to impair bovine
platelet function. Am J Vet Res 1989; 50(6): 919–22.
13. Panel comment, 3/9/95.
14. O’Neil MJ, editor. The merck index: an encyclopedia of chemicals, drugs, and
biologicals, 13th ed. Whitehouse Station, NJ: Merck & Company, Inc., 2001.
p. 145, 146.
15. USP dictionary of USAN and international drug names, 2002 ed. Rockville,
MD: The United States Pharmacopeial Convention, Inc., 2002.
16. The United States pharmacopeia. The national formulary. USP 26th revision
(January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United
States Pharmacopeial Convention, Inc., 2002. p.173, 175–7, 2549.
17. McEvoy GK, editor. AHFS Drug information 93. Bethesda, MD: American
Society of Hospital Pharmacists, 1992; (28:08.04): 1053.
Ó 2004 The United States Pharmacopeial Convention, Inc.
18. Katzung, BG. Basic and clinical pharmacology. 6th ed. Norwalk, Connecticut:
Appleton and Lange, 1995.
19. Klasco RK, editor. USP DI Drug information for the healthcare professional.
Volume I. Greenwood Village, CO: Thomson MICROMEDEX, Inc., 2003.
20. Panel comment, 02/17/95.
21. Lipowitz AJ, Boulay J, Klausner JS. Serum salicylate and endoscopic evaluation
of the gastric mucosa in dogs after oral administration of aspirin-containing
products. Am J Vet Res 1986; 27(7): 1586–9.
22. Panel comment, 3/9/95.
23. Nap RC, Breen DJ, Lam TJGM, et al. Gastric retention of enteric-coated aspirin
tablets in beagle dogs. J Vet Pharmacol Ther 1990; 13(2): 148–53.
24. Langston VC. Therapeutic management of inflammation. In: Howard JL,
editor. Current veterinary therapy 3: food animal practice. Philadelphia: W.B.
Saunders, 1993. p. 9.
25. Per phone call (Veratex—US), 12/3/93.
26. Davis L. Drugs affecting the digestive system. In: Howard JL, editor. Current
veterinary therapy 3: food animal practice. Philadalphia: W.B. Saunders,
1993. p. 758–61.
27. Committee consensus, 4/15/02.
28. Payne MA. Anti-inflammatory therapy in dairy cattle: therapeutic and
regulatory considerations. California Veterinarian 2001; 55(2): 10–12.
29. McDonald RK, Langston VC. Use of corticosteroids and nonsteroidal antiinflammatory agents. In: Ettinger SJ, editor. Textbook of Veterinary Internal
Medicine, 4th edition. Philadelphia: W.B. Saunders, 1995: 284–93.
30. Yeary RA, Swanson W. Aspirin dosages for the cat. J Am Vet Med Assoc 1973;
163(10): 1177–8.
31. Yeary RA, Brant RJ. Aspirin dosages for the dog. J Am Vet Med Assoc 1975;
167(1): 63–64.
32. Lipowitz AJ. Serum salicylate concentrations and endoscopic evaluation of the
gastric mucosa in dogs after oral administration of aspirin-containing
products. Am J Vet Res 1986; 47(7): 1586–9.
33. Arrioja-Dechert A, editor. Compendium of veterinary products, CD ed. Port
Huron, MI: North American Compendiums, Inc. 2003.
34. Davis LE, Westfall BA. Species differences in biotransformation and excretion of
salicylate. Am J Vet Res 1972 Jun; 33(6): 1253–62.
35. Gingerich DA, Baggot JD, Yeary RA. Pharmacokinetics and dosage of aspirin
in cattle. J Am Vet Med Assoc 1975 Nov 15; 167(10): 945–8.
36. Waters DJ, Bowers LD, Cipolle RJ, et al. Plasma salicylate concentrations in
immature dogs following aspirin administration: comparison with adult dogs.
J Vet Pharmacol Ther 1993; 16(3): 275–282.
37. Davis LE. Clinical pharmacology of salicylates. J Am Vet Med Assoc 1980 Jan
1; 176(1): 65.
38. The Canadian gFARAD. Personal communication, 12/12/03.
All rights reserved
CARPROFEN Veterinary—Systemic 15
CARPROFEN Veterinary—Systemic
A commonly used brand name for a veterinary-labeled product is Rimadyl.
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
CATEGORY:
REGULATORY CONSIDERATIONS
U.S. and Canada—
Carprofen is labeled for use only by or on the order of a licensed
veterinarian.{R-1; 2; 40; 41} It is not labeled for use in food-producing
animals.
Anti-inflammatory (nonsteroidal); analgesic; antipyretic.
CHEMISTRY
INDICATIONS
Note: Bracketed information in the Indications section refers to uses that
either are not included in U.S. product labeling or are for products not
commercially available in the U.S.
Chemical group: Aryl-propionic acid class of non-steroidal anti-inflammatory drug.{R-7} The proprionic acid derivatives include ketoprofen, ibuprofen, and naproxen.{R-1}
Chemical name: (±)-6-Chloro-alpha-methylcarbazole-2-acetic acid.{R-1}
GENERAL CONSIDERATIONS
The relative anti-inflammatory activity of carprofen is approximately:
carprofen indomethacin, piroxicam, diclofenac > phenylbutazone >
ibuprofen > aspirin.{R-7} Analgesic and antipyretic activities have also
been shown to be similar to indomethacin and greater than
phenylbutazone or aspirin.{R-26}
Carprofen is reported to be 16 times less active than indomethacin in
producing gastric ulcers in mice.{R-8; 26} Carprofen causes significantly
less platelet aggregation inhibition than aspirin does; carprofen does
not alter buccal mucosal bleeding time in healthy dogs when
administered at recommended dosages.{R-4; 8; 53}
Molecular formula: C15H12ClNO2.{R-1}
Molecular weight: 273.72.{R-1}
Description: White, crystalline compound.{R-1}
Solubility: Freely soluble in ethanol, but practically insoluble in water at
25 C.{R-1}
PHARMACOLOGY/PHARMACOKINETICS
ACCEPTED
Inflammation, musculoskeletal (treatment); or
Pain, musculoskeletal (treatment)—Dogs: Carprofen caplets, chewable
tablets, and injection1 are indicated in the control of inflammation and
pain associated with osteoarthritis.{R-1; 2; 9; 40; 41; 61}
Pain, postoperative (treatment)1—Dogs: Carprofen caplets, chewable
tablets, and injection are indicated in the control of postoperative pain
associated with soft tissue or orthopedic surgery.{R-1; 2; 61}
Preoperative administration is recommended because it can be more
effective than postoperative administration alone in the control of
postoperative pain;{R-1; 45; 46} however, some clinicians do not
recommend routine preoperative administration of NSAIDs for the
control of pain. General health and age of the animal are considered in
choice of analgesic, timing of administration, anesthetic regimen, and
use of perioperative supportive therapy (see also Veterinary Dosing
Information in this monograph). Preoperative carprofen administration
would not be expected to significantly decrease minimum alveolar
concentration of halothane or isoflurane required for anesthesia in
dogs.{R-47; 48}
ACCEPTANCE NOT ESTABLISHED
Inflammation (treatment); or
Pain (treatment)—[Horses]1: Although the safety and efficacy have not
been established, there is evidence to suggest that oral or parenteral
carprofen can be effective in the treatment of pain and inflammation in
horses.{R-6; 20; 27-29; 58; 59}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
2004 The United States Pharmacopeial Convention, Inc.
Mechanism of action/Effect: The mechanisms of action of carprofen
are not completely understood. This lack of clarity may be due to
species differences, to differing methodologies in the studies performed, and to the evolving understanding of anti-inflammatory activity and tests for measuring it.
Inhibition of cyclooxygenase is believed to be the mechanism of action for
the anti-inflammatory effect of carprofen.{R-30; 31; 61} Research
suggests carprofen selectively inhibits cyclooxygenase 2 (COX-2) over
cyclooxygenase 1 (COX-1) in dogs.{R-31; 63; 64} Because COX-1,
present in most cells and tissues, is believed to produce cytoprotective
prostaglandins{R-8} active in maintaining normal gastrointestinal and
renal function in mammals while COX-2 produces prostaglandins
involved in inflammation, selectivity would minimize adverse gastrointestinal and renal effects while effectively reducing inflammation.
The potency of carprofen in inhibiting cyclooxygenase and its
selectivity for COX-2 over COX-1 in dogs has not been consistently
supported by all published research.{R-12; 63; 65} In the future, a clearer
picture of anti-inflammatory mechanisms and their relationship to
clinical effects may emerge.
Cyclooxygenase inhibition has also been investigated in other animal
species. Carprofen has been described as a potent cyclooxygenase
inhibitor in sheep, based on an in vivo study, but isozyme selectivity
was not determined.{R-24} Carprofen inhibited cyclooxygenase in an
in vitro study of equine blood but it did not appear to be very selective
for COX-2.{R-63} In vitro tests of feline blood showed that carprofen
may be a selective inhibitor of COX-2 in that species.{R-63}
Carprofen has been shown to inhibit the release of prostagladins from rat
polymorphonuclear leucocytes, an acute inflammatory reaction, and
human rheumatoid synovial cells, a chronic inflammatory reaction.{R-1}
All rights reserved
16 CARPROFEN Veterinary—Systemic
Carprofen has also been shown to modulate humoral and cellular
immune responses.{R-1}
Chirality: Carprofen contains an asymmetrical carbon atom and exists
in two enantiomeric forms. Differences in pharmacokinetics and
pharmacodynamics between the two enantiomers occur in animals
and can also vary significantly among species.{R-13} Currently, commercially available products contain a racemic (50:50) mixture of the
two enantiomers, S(+) and R(–).{R-12}
An in vitro study using canine cyclooxygenases showed evidence that the
S(+)-enantiomer of carprofen is the anti-inflammatory eutomer, being
more than 100 times more active against COX-2 than the R(–)enantiomer.{R-31} In vitro studies using equine chondrocytes have
demonstrated the ability of the S(+)-enantiomer to produce 10 to 100
times the suppression of prostaglandin E2 production and 10 times the
stimulation of proteoglycan synthesis produced by the R(–)-enantiomer.{R-22} In sheep, the R(–)-enantiomer was demonstrated in vivo to
have little effect on prostaglandin E2 generation in exudate, also
pointing to the S(+)-enantiomer, equivalent to the racemic mixture in
inhibiting exudate PGE2, as the source of anti-inflammatory effect in
that species.{R-24}
Plasma concentrations of the R(–)-enantiomer have been reported as
consistently higher than the S(+)-enantiomer after administration of
racemic carprofen in calves, cats, cows, and horses.{R-12; 20; 21; 23; 25;
26; 28; 32}
The ratio of R to S in the plasma varies by species, from as
low as 1.2 in lactating dairy cows to greater than 5 in horses.{R-20; 23}
In rats, the S(+)-enantiomer predominates in the plasma.{R-19} In
dogs, one study reported the R(–)-enantiomer predominated in plasma
while another noted no significant difference in concentrations of the R
and S forms.{R-12; 37}
Conversion of one enantiomer to another does not appear to occur to any
significant degree in dogs, horses, human beings, and rats; therefore, it
should not affect the ratio of enantiomers in plasma.{R-12; 19; 20}
Plasma concentrations of each enantiomer is not affected by
concurrent administration in the racemic mixture in dogs.{R-12}
Absorption: Dogs—
Oral: Carprofen is rapidly and almost completely absorbed; greater
than 90% bioavailability.{R-1; 10; 11}
Subcutaneous: When administered subcutaneously at a dose of about
2 mg per kg of body weight (mg/kg), carprofen has a slower rate of
absorption than when administered orally. But total drug absorption
in the first 12 hours after a single dose and at steady state with
repeated doses is similar for the two routes of administration.{R-62}
Distribution: Racemic form does not appear to affect transfer from
plasma to transudate or exudate, as demonstrated in calves and dogs;
the R(–)-enantiomer continues to predominate.{R-12; 25} In dogs and
horses, concentration of carprofen was greater in transudate and
exudate in tissue cages or pouches than in plasma twenty-four to fortyeight hours after administration.{R-12; 29} However, penetration into
transudate is limited until inflammation is present.{R-12; 25; 29} Penetration of carprofen into the synovial fluid of healthy joints of horses
is also limited but is expected to be significantly higher with
inflammation.{R-21}
Volume of distribution—Limited, considered to be constrained by high
protein binding.
Calves, 8 to 10 weeks of age:
Area—
2004 The United States Pharmacopeial Convention, Inc.
R(–)-carprofen: 0.145 ± 0.005 liters per kilogram (L/kg).{R-26}
S(+)-carprofen: 0.163 ± 0.003 L/kg.{R-26}
Steady state:
R(–)-carprofen: 0.147 ± 0.003 L/kg.{R-26}
S(+)-carprofen: 0.163 ± 0.002 L/kg.{R-26}
Calves, 16 to 17 weeks of age:
Area—
R(–)-carprofen: 0.136 ± 0.003 L/kg.{R-25}
S(+)-carprofen: 0.154 ± 0.005 L/kg.{R-25}
Steady state—
R(–)-carprofen: 0.140 ± 0.004 L/kg.{R-25}
S(+)-carprofen: 0.154 ± 0.008 L/kg.{R-25}
Cats:
Area—
Racemic mixture: 0.15 ± 0.04 L/kg;{R-32} 0.17 ± 0.09 L/kg.{R-38}
R(–)-carprofen: 0.24 ± 0.05 L/kg.{R-32}
S(+)-carprofen: 0.35 ± 0.10 L/kg.{R-32}
Steady state—Racemic mix: 0.14 ± 0.05 L/kg.{R-38}
Cows, lactating: Steady state—Racemic mix: 0.091 ± 0.003 L/kg.{R-35}
Dogs:
Area—Racemic mix: 0.18 ± 0.04 L/kg.{R-10}
Steady-state—
Racemic mix: 0.14 ± 0.02 L/kg;{R-10} 0.18 ± 0.06 L/kg.{R-11}
R(–)-carprofen: 0.12 ± 0.03 L/kg.{R-15}
S(+)-carprofen: 0.19 ± 0.05 L/kg.{R-15}
Horses:
Area—Racemic mixture: 0.23 ± 0.04 L/kg;{R-27} 0.25 ± 0.02 L/kg.{R-29}
Steady-state—
Racemic mixture: 0.22 ± 0.01 L/kg.{R-29}
R(–)-carprofen: 0.10 ± 0.01 L/kg.{R-21}
S(+)-carprofen: 0.29 ± 0.04 L/kg.{R-21}
Rats:
Steady-state—
R(–)-carprofen: 0.228 ± 0.043 L/kg.{R-19}
S(+)-carprofen: 0.242 ± 0.030 L/kg.{R-19}
Sheep:
Racemic mixture—
Area: 0.096 ± 0.006 L/kg.{R-33}
Steady-state: 0.093 ± 0.006 L/kg.{R-33}
Protein binding: Dogs—Greater than 99%.{R-1}
Half-life: Elimination—
Calves, 8 to 10 weeks of age:
R(–)-carprofen—49.7 ± 3.9 hours.{R-26}
S(+)-carprofen—37.4 ± 2.4 hours.{R-26}
Calves, 16 to 17 weeks of age:
R(–)-carprofen—37.7 ± 1.8 hours.{R-25}
S(+)-carprofen—37.4 ± 2.4 hours.{R-25}
Cats:
Racemic mix—19.4 ± 7.25 hours;{R-32} 20.0 ± 16.6 hours.{R-38}
R(–)-carprofen—21.3 ± 9.09 hours.{R-32}
S(+)-carprofen—14.6 ± 5.78 hours.{R-32}
Cows, lactating: Racemic mixture—30.7 ± 2.3 hours.{R-35}
Dogs: Racemic mixture—8.00 ± 1.18 hours;{R-10} 11.7 ± 3.05.{R-11}
Horses:
Racemic mixture—21.9 ± 2.3 hours;{R-27} 18.1 ± 1.3 hours.{R-29}
All rights reserved
CARPROFEN Veterinary—Systemic 17
R(–)-carprofen—18.36 ± 1.02 hours;{R-20} 20.6 ± 2.55 hours.{R-21}
S(+)-carprofen—9.86 ± 1.29 hours;{R-20} 16.8 ± 1.77 hours.{R-21}
Sheep: Racemic mixture—26.1 ± 1.14 hours.{R-33}
Peak concentration: Dogs—
Oral administration:
Dose of approximately 2 mg/kg—Peak plasma concentration of 16.47
± 3.95 mcg/mL at 1.05 ± 0.76 hours after administration.{R-62}
Dose of 4 mg/kg—Peak plasma concentration of 35.30 ± 2.70 mcg/
mL at 1.25 ± 0.25 hours.{R-10}
Dose of approximately 7.5 mg/kg—Peak plasma concentration of 57.3
± 9.68 mcg/mL at 0.70 ± 0.48 hour.{R-11}
Subcutaneous administration: Dose of approximately 2 mg/kg—Peak
plasma concentration of 8.08 ± 1.46 mcg/mL at 2.58 ± 1.64
hours.{R-62}
Onset of action: Dogs—Because carprofen is absorbed more slowly
when administered subcutaneously than when administered orally,
onset of action may be slightly delayed in comparison.{R-61}
Duration of action: Postoperative analgesia—Cats: A minimum of 18
to 24 hours (as assessed by visual analogue scale) after a subcutaneous
4-mg/kg dose administered either preoperatively or at extubation.{R-54-57}
Elimination: Eliminated primarily by biotransformation, as demonstrated in dogs, horses, humans, rats, and sheep.{R-1; 15; 17; 18} In
these species, both R(–)- and S(+)-enantiomers are converted to glucuronide metabolites; relative rates of enantiomer metabolism vary
among species.{R-17; 20} In vitro testing showed the R(–)-enantiomer to
be glucuronidated at a higher rate than the S(+)-enantiomer in liver
microsomes of several species;{R-17} however, in vivo tests of horses
demonstrated that glucuronidation of the S(+)-enantiomer is favored
over the R(–)-enantiomer.{R-20} Researchers have not been able to
consistently link stereospecific glucuronidation rates to the differences
in pharmacokinetics between enantiomers;{R-17} however, in horses,
the clearly predominant S(+)-enantiomer glucuronidation may explain
the higher R(–)-enantiomer concentrations in plasma samples.{R-20}
Dogs—70 to 80% of carprofen metabolites are eliminated in the feces and
10 to 20% in the urine.{R-1; 15; 18} Identified metabolites include an
ester glucuronide and ether glucuronides of 2 phenolic metabolites,
7-hydroxy carprofen and 8-hydroxy carprofen.{R-1} Some enterohepatic circulation of the S(+)-enantiomer metabolites occurs; about
34% of the dose is recirculated.{R-17}
Human beings—Unlike rats and dogs, humans excrete most of an oral
dose (65 to 70%) as ester glucuronide in the urine; the remaining
drug is eliminated in the bile with subsequent enterohepatic
circulation.{R-18} Neither enantiomer is favored in glucuronidation.{R-20}
Rats—In rats, biliary secretion and fecal elimination account for 60 to
75% of an intravenous dose while 20 to 30% is excreted in the
urine.{R-18} In rats, the S(+)-enantiomer is predominant in the plasma
while the R(–)-enantiomer is glucuronidated at a higher rate.{R-20}
Less than 5% of the dose is eliminated as free, intact drug.{R-18}
Clearance—
Calves, 8 to 10 weeks of age:
R(–)-carprofen—0.035 ± 0.002 mL/minÆkg.{R-26}
S(+)-carprofen—0.052 ± 0.004 mL/minÆkg.{R-26}
2004 The United States Pharmacopeial Convention, Inc.
Calves, 16 to 17 weeks of age:
R(–)-carprofen—0.042 ± 0.002 mL/minÆkg.{R-25}
S(+)-carprofen—0.062 ± 0.002 mL/minÆkg.{R-25}
Cats:
Racemic mix—0.10 ± 0.03 mL/minÆkg;{R-32} 0.12 ± 0.05 mL/
minÆkg.{R-38}
R(–)-carprofen—0.13 ± 0.03 mL/minÆkg.{R-32}
S(+)-carprofen—0.32 ± 0.07 mL/minÆkg.{R-32}
Cows, lactating: Racemic mixture—0.04 ± 0.003 mL/minÆkg.{R-25}
Dogs:
Racemic mix—0.28 ± 0.05 mL/minÆkg.{R-11}
R(–)-carprofen—0.28 ± 0.07 mL/minÆkg.{R-15}
S(+)-carprofen—0.47 ± 0.16 mL/minÆkg.{R-15}
Horses:
Racemic mixture (as calculated from reported data): 0.10 mL/
minÆkg;{R-27} 0.20 mL/minÆkg.{R-29}
R(–)-carprofen—0.04 ± 0.01 mL/minÆkg;{R-20} 0.06 ± 0.02 mL/
minÆkg.{R-21}
S(+)-carprofen—0.23 ± 0.02 mL/minÆkg;{R-20} 0.25 ± 0.02 mL/
minÆkg.{R-21}
Rats:
R(–)-carprofen—1.48 ± 0.13 mL/minÆkg.{R-19}
S(+)-carprofen—0.49 ± 0.08 mL/minÆkg.{R-19}
Sheep: Racemic mix—0.042 ± 0.002 mL/minÆkg.{R-19}
PRECAUTIONS TO CONSIDER
PREGNANCY/REPRODUCTION
Dogs—Studies have not been performed to establish the safety of
carprofen in the treatment of breeding animals, or pregnant or
lactating dogs.{R-1; 40}
Rats—Reproduction studies in rats with doses of 2, 6, or 20 mg/kg
showed little evidence of teratogenicity but did demonstrate effects
characteristic of prostaglandin synthetase inhibitors on parturition,
including slightly prolonged gestation and a small increase in fetal
deaths at birth with the highest dose.{R-36}
LACTATION
Cows: Carprofen has limited distribution into milk in healthy animals.
With a single low intravenous dose (0.7 mg/kg), concentration in milk
has been reported to be less than 0.02 mcg/mL of milk and, with five
daily doses, concentrations increased to only 0.03 mcg/mL.{R-34; 35}
However, in the milk of cows with acute or induced mastitis,
concentrations in milk rose to 0.164 mcg/mL within twelve hours,
dropping again as the inflammation resolved.{R-34; 35}
Rats: One study suggests gastrointestinal toxicity may be increased
during lactation. Eighty-five percent of the dams treated with
carprofen at a dose of 20 mg/kg died during the second week of
lactation, with evidence of intestinal toxicity; most pups were found
alive.{R-36} Mortality rates for lactating dams were much higher than
in pregnant or nonpregnant female rats.{R-36}
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily
inclusive (» = major clinical significance):
All rights reserved
18 CARPROFEN Veterinary—Systemic
Note: Combinations containing any of the following medications,
depending on the amount present, may also interact with this
medication.
Angiotensin converting enzyme inhibitors (ACE inhibitors) or
Furosemide{R-4; 7}
(because ACE inhibitors and furosemide act through the effects of
vasodilatory prostaglandins on renal function, NSAIDS may decrease
their effectiveness; there is not yet any evidence that this is clinically
significant, but blood pressure monitoring is recommended)
Anti-inflammatory medications,{R-1} such as
Corticosteroids{R-7}
Other nonsteroidal anti-inflammatory drugs{R-7}
(concurrent administration with carprofen can increase risk of
toxicity, including the risk of gastrointestinal ulceration)
Nephrotoxic medications{R-1}
(could exacerbate renal effects of carprofen)
Phenobarbital{R-4; 7}
(because phenobarbital can cause elevations in liver enzymes,
baseline serum chemistries should be established before beginning
treatment with any NSAID)
HUMAN DRUG INTERACTIONS AND/OR RELATED
PROBLEMS{R-60}
In addition to the above drug interactions reported in animals, the
following drug interactions have been reported in humans, and are
included in the human monograph Anti-inflammatory Drugs, Nonsteroidal (Systemic) in USP DI Volume I; these drug interactions are
intended for informational purposes only and may or may not be
applicable to the use of carprofen in the treatment of animals:
Note: There are no carprofen products labeled for use in human beings;
the following are those listed for all systemic nonsteroidal antiinflammatory drugs.
Anticoagulants, coumarin- or indanedione-derivative
Heparin or
Thrombolytic agents, such as:
Alteplase
Anistreplase
Streptokinase
(inhibition of platelet aggregation by nonsteroidal anti-inflammatory drugs [NSAIDs], and the possibility of NSAID-induced
gastrointestinal ulceration or bleeding, may be hazardous to
patients receiving anticoagulant or thrombolytic therapy)
Antidiabetic agents, oral or
Insulin
(NSAIDs may increase the hypoglycemic effect of these medications
because prostaglandins are directly involved in regulatory mechanisms of glucose metabolism)
Antihypertensives, including angiotensin-converting enzyme (ACE)
inhibitors, or
Diuretics
(NSAIDs may decrease the diuretic, natriuretic, and antihypertensive
effects of diuretics, probably by inhibiting renal prostaglandin
synthesis)
(concurrent use of an NSAID and a diuretic may increase the risk of
renal failure secondary to a decrease in renal blood flow caused by
inhibition of renal prostaglandin synthesis)
Cyclosporine or
2004 The United States Pharmacopeial Convention, Inc.
Nephrotoxic medications, other
(inhibition of renal prostaglandin activity by NSAIDs may increase
the plasma concentration of cyclosporine and/or the risk of
cyclosporine-induced nephrotoxicity)
(the risk of adverse effects may also be increased when an NSAID is
used concurrently with other nephrotoxic medications)
Digitalis glycosides
(diclofenac and ibuprofen have been shown to increase serum digoxin
concentrations, and indomethacin has increased digitalis concentrations in neonates being treated for patent ductus arteriosus; the
possibility should be considered that some of the other NSAIDs also
may increase digoxin concentrations, leading to an increased risk of
digitalis toxicity; increased monitoring and dosage adjustments of the
digitalis glycoside may be necessary during and following concurrent
NSAID therapy; however, studies have failed to show that flurbiprofen,
ketoprofen, piroxicam, or tenoxicam increase digoxin concentrations,
and phenylbutazone may decrease digitalis concentrations)
Methotrexate
(NSAIDs may decrease protein binding and/or renal elimination of
methotrexate, resulting in increased and prolonged methotrexate
plasma concentrations and an increased risk of toxicity, especially
during high-dose methotrexate infusion therapy)
Photosensitizing medications, other
(concurrent use with photosensitizing NSAIDs may cause additive
photosensitizing effects)
Platelet aggregation inhibitors, other
(concurrent use with an NSAID may increase the risk of bleeding
because of additive inhibition of platelet aggregation, as well as the
potential for NSAID-induced gastrointestinal ulceration or hemorrhage)
(concurrent use of sulfinpyrazone with NSAIDs may also increase the
risk of gastrointestinal ulceration or hemorrhage)
LABORATORY VALUE ALTERATIONS
The following have been selected on the basis of their potential clinical
significance (possible effect in parentheses where appropriate)—not
necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alkaline aminotransferase (ALT [SGPT]){R-1} and
Alkaline phosphatase{R-53}
(values may be increased; see Patient monitoring below for more
information)
HUMAN LABORATORY VALUE ALTERATIONS{R-60}
The following laboratory value alterations have been reported in humans,
and are included in the human monograph Anti-inflammatory Drugs,
Nonsteroidal (Systemic) in USP DI Volume I; these laboratory value
alterations are intended for informational purposes only and may or may
not be applicable to the use of carprofen in the treatment of animals:
Note: There are no carprofen products labeled for use in human beings;
the following are those listed for all nonsteroidal anti-inflammatory
drugs (NSAIDs).
With physiology/laboratory test values
Bleeding time
(may be prolonged by many NSAIDs because of suppressed platelet
aggregation)
Hematocrit or
Hemoglobin
All rights reserved
CARPROFEN Veterinary—Systemic 19
(values may be decreased, possibly because of gastrointestinal
bleeding or microbleeding and/or hemodilution caused by fluid
retention)
Leukocyte count and
Platelet count
(may be decreased)
Liver function tests, including:
Alkaline phosphatase and
Lactate dehydrogenase (LDH) and
Transaminases, serum
(values may be increased; liver function test abnormalities may
return to normal despite continued use; however, if significant
abnormalities occur, clinical signs and symptoms consistent with
liver disease develop, or systemic manifestations such as eosinophilia
or rash occur, the medication should be discontinued)
Potassium, serum
(concentrations may be increased)
Renal function tests, including:
Blood urea nitrogen (BUN)
Creatinine, serum
Electrolytes, blood and urine
Urine volume
(NSAIDs may decrease renal function, resulting in increased BUN,
serum creatinine, and serum electrolyte concentrations and in
decreased urine volume and urine electrolyte concentrations;
however, in some cases, water retention may exceed that of sodium,
resulting in dilutional hyponatremia)
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
given in parentheses where appropriate)—not necessarily inclusive (»
= major clinical significance).
Except under special circumstances, this medication should not be
used when the following medical problems exist:
» Hypersensitivity to carprofen{R-1}
(a previous episode of hypersensitivity is a contraindication)
Risk-benefit should be considered when the following medical
problems exist:
Bleeding disorders{R-1}
(the safety of carprofen in dogs with bleeding disorders, such as Von
Willebrand’s disease, has not been studied)
(in healthy Labrador Retrievers, carprofen administered for 5 days
was shown to have no effect on buccal mucosal bleeding time; there
were indications of minor changes in platelet aggregation that may
have more significance when other risk factors for impaired
hemostasis are present){R-53}
Cardiovascular disease or
Dehydration
(animals with cardiovascular disease or dehydration can be at higher
risk for renal toxicity)
Gastrointestinal disease
(may be exacerbated by carprofen administration)
Hypoproteinemia{R-7}
(because carprofen is highly protein bound, dosages recommended for
animals with average blood protein content could produce higher
free-drug concentrations in hypoproteinemic animals)
2004 The United States Pharmacopeial Convention, Inc.
Renal disease
(occult or overt renal disease can be exacerbated by nonsteroidal antiinflammatory drugs that inhibit prostaglandins responsible for
maintaining normal organ function){R-1; 61}
PATIENT MONITORING
The following may be especially important in patient monitoring (other
tests may be warranted in some patients, depending on condition; » =
major clinical significance):
Alkaline aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) and
Serum bilirubin and
Urine bilirubin
(an increase in alkaline phosphatase activity alone may occur with
medications, such as carprofen, or with liver changes, as in nodular
hyperplasia){R-7}
(for hepatoxicity—ALT and AST provide better assessment of acute
hepatoxicity than alkaline phosphatase; elevations in alkaline
phosphatase can lag behind ALT and AST; an elevation of ALT that
is three- to four-times normal may be an early sign of acute
hepatopathy; dogs reported to have liver dysfunction in association
with carprofen administration have also had bilirubinemia, bilirubinuria, and abnormal liver function tests){R-4}
Blood chemistry, including urea nitrogen (BUN) and
Complete blood count (CBC) and
Urinalysis
(exacerbation of occult or overt chronic renal failure can occur with
NSAID administration; in a few cases, acute tubular necrosis or
glomerular disease has been reported)
(particularly in older dogs, dogs with a history of liver or renal disease,
or dogs expected to receive long-term therapy, baseline CBC and blood
chemistry testing before initiation of carprofen administration and
regular follow-up blood chemistry testing should be considered)
SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their
potential clinical significance (possible signs and, for humans, symptoms
in parentheses where appropriate)—not necessarily inclusive:
Note: No clinically significant adverse effects were observed in dogs
during investigational studies of treatment of osteoarthritis with
carprofen. In field studies, reported clinical signs were similar for dogs
receiving the placebo (product vehicle) control and dogs that received
the labeled dose of 4.4 mg of carprofen per kg of body weight a day.{R-1}
However, as with other nonsteroidal anti-inflammatory drugs
(NSAIDS), adverse effects may occur in individual animals with
administration of carprofen.{R-1} Side effects appear to be rare but can
be serious and should be recognized as early as possible. Incidence of
reported adverse events associated with carprofen administration was
0.18% in 1998 and in 1999.{R-4}
THOSE INDICATING NEED FOR MEDICAL ATTENTION
Note: Unless otherwise noted, the following are drawn from postapproval adverse drug experience reporting for dogs.
Dogs (categories listed in decreasing order of frequency){R-1}
Gastrointestinal effects (vomiting, diarrhea, constipation, inappetence, melena, hematemesis, gastrointestinal ulceration, gastrointestAll rights reserved
20 CARPROFEN Veterinary—Systemic
inal bleeding, pancreatitis); hepatic effects (inappetence, vomiting,
jaundice, acute hepatic toxicity, hepatic enzyme elevation, abnormal
liver function tests, hyperbilirubinemia, bilirubinuria, hypoalbuminemia); neurologic effects (ataxia, paresis, paralysis, seizures,
vestibular signs, disorientation); urinary effects (hematuria, polyuria, polydipsia, urinary incontinence, urinary tract infection,
azotemia, acute renal failure, tubular abnormalities, including acute
tubular necrosis, renal tubular necrosis, glucosuria); behavioral
effects (sedation, lethargy, hyperactivity, restlessness, aggressiveness); hematologic effects (immune-mediated hemolytic anemia,
immune-mediated thrombocytopenia, blood loss anemia, epistaxis);
dermatologic effects (pruritis, increased shedding, alopecia, pyotraumatic moist dermatitis, necrotizing panniculitis/vasculitis, ventral ecchymosis); immunologic effects or hypersensitivity (facial
swelling, hives, erythema)
Note: Behavioral effects associated with carprofen administration usually
resolve when treatment is discontinued.
The majority of reported cases of gastrointestinal signs resolved with
discontinuation of medication and/or treatment of underlying
disease.{R-4} Gastrointestinal ulceration or perforation is reported
rarely in association with carprofen administration.{R-4}
Elevated liver enzymes without clinical evidence of liver dysfunction is
the most commonly reported hepatic effect seen in association with
carprofen administration.{R-4} However, about 1.4 in 10,000 dogs
treated with carprofen in 1999 were reported to develop hepatotoxicity,
including clinical signs of liver disease, elevation of serum bilirubin,
abnormal liver function tests, and histopathologic evidence of hepatic
necrosis and cholestasis.{R-4; 7} Anorexia is often the first sign of
hepatopathy{R-4} and the last sign to resolve, in some cases requiring 1
to 3 weeks after discontinuation of therapy.{R-39} Vomiting, icterus,
lethargy, diarrhea, polydipsia, polyuria, ascites, and hematuria have
also been reported with toxicosis.{R-39} See also Patient monitoring
above in this monograph for information on laboratory tests. For dogs
with hepatic dysfunction, discontinuation of carprofen therapy and
immediate supportive treatment for liver disease is indicated. Severity
of hepatic dysfunction and prognosis for recovery do not appear to be
correlated with the dose of carprofen or length of time it was
administered; these appear to be idiosyncratic reactions.{R-4}
Immune-mediated diseases, including thrombocytopenia, anemia, and
skin disease have been reported in association with carprofen administration.{R-4} Thrombocytopenia and anemia are usually regenerative.{R-4}
Neurologic signs reported to be associated with carprofen administration have resolved with discontinuation of therapy.{R-4}
Renal effects that have been reported in a few cases in association with
carprofen administration include acute tubular necrosis and glomerular disease, such as glomerulonephritis.{R-4} Pre-existing renal disease
may be exacerbated by administration of carprofen.{R-4}
Horses
Edema, subcutaneous, temporary—with a dose of 1.4 mg/kg a day
for 14 days{R-27}
THOSE INDICATING NEED FOR MEDICAL ATTENTION
ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Incidence unkown
Dogs
Swelling and warmth at the injection site—with subcutaneous
administration{R-61}
2004 The United States Pharmacopeial Convention, Inc.
OVERDOSE
For information in cases of overdose or unintentional ingestion, contact
the American Society for the Prevention of Cruelty to Animals
(ASPCA) National Animal Poison Control Center (888-426-4435
or 900-443-0000; a fee may be required for consultation) and/or the
drug manufacturer.
CLINICAL EFFECTS OF OVERDOSE
The following effects have been selected on the basis of their potential
clinical significance (possible signs in parentheses where appropriate)—not necessarily inclusive:
Note: Hepatocellular toxicosis appears to be an idiosyncratic reaction to
carprofen administration rather than being clearly associated with
overdosage or prolonged therapy.{R-4; 39}
Dogs
With a dose of up to 25 mg per kg of body weight (mg/kg) a day (5.7 times
the labeled dose) for 13 or 52 weeks, the following were reported:
Elevated L-alanine aminotransferase (ALT [SGPT])—with the
highest dose, elevations averaged 20 IU; mild dermatitis—reported as not dose-related and not clearly linked to medication{R-1}
With a dose of 22 mg/kg every twelve hours (10 times the labeled
dose) or 2.2 to 11 mg/kg every twelve hours for 42 days:
Black or bloody stools—observed in 1 of 8 dogs; hypoalbuminenia—observed in 2 of 8 dogs{R-1}
With a dose of 80 or 160 mg/kg a day for 5 days:{R-16}
Elevated L-alanine aminotransferase (ALT [SGPT]); hematocrit, decreased; hemoglobin, decreased; hemorrhagic erosions
of the small intestine
TREATMENT OF OVERDOSE
Recommended treatment consists of the following:{R-7}
• If within 4 hours of ingestion, induce emesis
• Gastric lavage
• Administer activated charcoal in a water slurry
• Supportive care, including intravenous fluids
• Administer gastric protectants
• Perform baseline blood values, including CBC and chemistry
CLIENT CONSULTATION
A package insert developed specifically for dog owners, the Owner
Information Sheet, is provided by the United States manufacturer for
clients administering oral carprofen to their dogs.{R-5}
In providing consultation, consider emphasizing the following selected
information:
Keeping chewable tablets out of the reach of children, cats and dogs.
Cats and dogs may be attracted to the flavoring and be at risk of
overdosage.{R-2}
Keeping water readily available to animals receiving carprofen to avoid
dehydration.
Counseling clients to contact their veterinarian and discontinue
medication if any of the following are observed: decreased appetite;
vomiting, diarrhea, or dark or tarry stools; increased water
consumption; change in urination, such as increased or decreased
frequency, change in color or odor; pale gums or yellowing of gums,
skin, or whites of the eyes; changes in skin, such as redness, scabs, or
scratching; or behavioral changes, such as decreased or increased
activity, incoordination, seizure, or aggression.{R-5}
All rights reserved
CARPROFEN Veterinary—Systemic 21
been recommended in the treatment of pain in horses.{R-27} This dose
also reduces some experimental markers of inflammation, but higher
dosages may be necessary in the treatment of inflammation and pain.
A comparison of high and low doses of carprofen (4 mg/kg and 0.7
mg/kg, respectively), administered to horses with induced inflammation, demonstrated that more definitive suppression of inflammatory
mediators and reduction in signs of inflammation occur with the 4mg-per-kg dose.{R-59}
VETERINARY DOSING INFORMATION
CHANGING ANTI-INFLAMMATORY MEDICATIONS
Because concurrent administration of nonsteroidal anti-inflammatory
drugs (NSAIDS) with corticosteroids or other NSAIDS may increase the
potential for adverse effects, recommendations have been made for
withdrawal or washout times for the medication being discontinued
before beginning another therapy. The decision to change medication
should take into account the potential for a resurgence of signs being
controlled by the anti-inflammatory during the transition period.
Table 1. Washout time when switching to a(nother) NSAID{R-7}
Medication being discontinued
Minimum washout time
NSAID
Aspirin*
Prednisone
Long-acting corticosteroid
48 to 72 hours
10 to 14 days
1 week
3 to 4 weeks
*
The prolonged washout time recommended for aspirin is to minimize carryover of
platelet dysfunction.
FOR PERIOPERATIVE ADMINISTRATION
Because NSAIDs can produce renal disturbances in animals prone to
them, intravenous fluid therapy may be an appropriate precaution in
some animals at risk for renal disease.{R-1} While young healthy dogs
showed no evidence of renal dysfunction from carprofen administered
before a period of anesthesia,{R-51; 52} carprofen, like other NSAIDs,
may contribute to a decrease in glomerular filtration rate for up to 48
hours when administered before surgery without the benefit of
intravenous fluid support.{R-49; 50}
Carprofen causes significantly less platelet aggregation inhibition
than aspirin does; when administered at recommended dosages,
carprofen does not alter buccal mucosal bleeding time in healthy
dogs.{R-4; 8; 53} However, preoperative administration of an NSAID
should be considered with caution for animals with bleeding
disorders.
Strength(s) usually available:
U.S.—{R-1 ; 2}
Veterinary-labeled product(s):
25 mg (Rx) [Rimadyl Caplets (scored); Rimadyl Chewable Tablets
(scored)].
75 mg (Rx) [Rimadyl Caplets (scored); Rimadyl Chewable Tablets
(scored)].
100 mg (Rx) [Rimadyl Caplets (scored); Rimadyl Chewable Tablets
(scored)].
Canada—{R-40; 41}
Veterinary-labeled product(s):
25 mg (Rx) [Rimadyl Caplets (scored); Rimadyl Chewable Tablets
(scored)].
75 mg (Rx) [Rimadyl Caplets (scored); Rimadyl Chewable Tablets
(scored)].
100 mg (Rx) [Rimadyl Caplets (scored); Rimadyl Chewable Tablets
(scored)].
Packaging and storage: Store between 15 and 30 C (59 and 86 F),
unless otherwise specified by the manufacturer.{R-1; 2; 40; 41}
Caution: Chewable tablets should be kept out of the reach of children.{R-2}
They should also be stored out of the reach of cats and dogs; they
can be attracted to the flavoring and be at risk of accidental overdosage.{R-2}
USP requirements: Not in USP.
FOR TREATMENT OF ADVERSE EFFECTS
1
Not included in Canadian product labeling or product not commercially
available in Canada.
Recommended treatment consists of the following:
For anaphylaxis
• Parenteral epinephrine.
• Oxygen administration and respiratory support.
PARENTERAL DOSAGE FORMS
ORAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
CARPROFEN INJECTION
CARPROFEN TABLETS
Usual dose:
Inflammation, musculoskeletal; or
Pain, musculoskeletal—Dogs: Oral, 4.4 mg per kg of body weight every
twenty-four hours or 2.2 mg per kg of body weight every twelve
hours.{R-1}
Pain, postoperative1—Dogs: Oral, 2.2 to 4.4 mg per kg of body weight,
administered 2 hours prior to procedure.{R-1; 45; 46}
Note: [Horses]1—Although the safety and efficacy have not been
established, an oral dose of 0.7 mg per kg of body weight a day has
2004 The United States Pharmacopeial Convention, Inc.
Usual dose:
Inflammation, musculoskeletal1; or
Pain, musculoskeletal1—Dogs: Subcutaneous, 4.4 mg per kg of body
weight every twenty-four hours or 2.2 mg per kg of body weight every
twelve hours.{R-61}
Pain, postoperative1—Dogs: Subcutaneous, 2.2 to 4.4 mg per kg of
body weight, administered 2 hours prior to surgery. The initial dose
may be followed by 2.2 mg per kg of body weight every twelve
hours or 4.4 mg per kg of body weight every twenty-four hours, to
provide a maximum of 4.4 mg per kg of body weight within a
twenty-four hour period.{R-61} In field studies, carprofen was
All rights reserved
22 CARPROFEN Veterinary—Systemic
administered for a total of three days to animals undergoing soft
tissue surgery and a total of four days to animals undergoing
orthopedic surgery, producing statistically significant reductions in
pain scores.{R-61}
It is recommended that different sites be used when more than one
injection is administered.{R-61}
Note: [Horses]1—Although the safety and efficacy have not been
established, an intravenous dose of 0.7 mg per kg of body weight a
day has been recommended in the treatment of pain in horses.{R-6; 29;
58}
This dose also reduces some experimental markers of inflammation,
but higher dosages may be necessary in the treatment of inflammation
and pain. A comparison of high and low doses of carprofen (4 mg/kg
and 0.7 mg/kg, respectively), administered to horses with induced
inflammation, demonstrated that more definitive suppression of
inflammatory mediators and reduction in signs of inflammation occur
with the 4-mg-per-kg dose.{R-59}
Strength(s) usually available:
U.S.—{R-61}
Veterinary-labeled product(s):
50 mg per mL (Rx) [Rimadyl].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Packaging and storage: Store under refrigeration, between 2 and 8 C
(36 and 46 F),{R-61} unless otherwise specified by the manufacturer.
USP requirements: Not in USP.
1
Not included in Canadian product labeling or product not commercially
available in Canada.
Developed: 2/6/04
REFERENCES
1. Rimadyl Caplets package insert (Pfizer—US). Available at www.pfizerah.com.
Accessed January 26, 2004.
2. Rimadyl Chewable Tablets package insert (Pfizer—US). Available at www.pfizerah.com. Accessed Janaury 26, 2004.
3. Food and Drug Administration Center for Veterinary Medicine. CVM Update on
Rimadyl. December 1, 1999. Available at www.fda.gov/cvm. Accessed
October 11, 2002.
4. Fox SM, Campbell S. Update: two year (1997-1998) clinical experience with
rimadyl (carprofen). Pfizer Animal Health Technical Bulletin. August 1999.
5. Dog owner information about Rimadyl caplets (Pfizer—US). Issued 2/00, Rec
10/4/02.
6. Schatzmann U, Gugelmann M, von Cranach J, et al. Pharmacodynamic
evaluation of the peripheral pain inhibition by carprofen and flunixin in the
horse. Schweiz Arch Tierheilkd 1990; 132(9): 497–504.
7. Hodge TM, Wahlstrom T. Three years (1997–1999) of US clinical
experience with Rimadyl. Pfizer Animal Health Technical Bulletin. December
2000.
8. Fox SM, Johnston SA. Use of carprofen for the treatment of pain and
inflammation in dogs. J Am Vet Med Assoc 1997 May 15; 210(10): 1493.
9. Vasseur PB, Johnson AL, Budsberg SC, et al. Randomized, controlled trial of
the efficacy of carprofen, a nonsteroidal anti-inflammatory drug, in the
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2004 The United States Pharmacopeial Convention, Inc.
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28. Lees P, Delatour P, Enoit E, et al. Pharmacokinetics of carprofen enantiomers
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carprofen in the horse. Equine Vet J 1994; 26(3): 203–8.
30. Benton HP, Vasseur PB, Broderick-Villa GA, et al. Effect of carprofen on
sulfated glycosaminoglycan metabolism, protein synthesis, and prostaglandin
release by cultured osteoarthritic canine chondrocytes. Am J Vet Res 1997
Mar; 58(3): 286–92.
31. Ricketts AP, Lundy KM, Seibel SB. Evaluation of selective inhibition of canine
cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J Vet Res 1998 Nov; 59(11): 1441–2.
32. Taylor PM, Delatour P, Landoni FM, et al. Pharmacodynamics and
enantioselective pharmacokinetics of carprofen in the cat. Res Vet Sci 1996;
60: 144–51.
33. Welsh EM, Baxter P, Nolan AM. Pharmacokinetics of carprofen administered
intravenously to sheep. Res Vet Sci 1992 Sep; 53(2); 264–6.
34. Ludwig B. Jordan JC, Rehm WF, et al. Carprofen in veterinary medicine I.
Plasma disposition, milk excretion and tolerance in milk-producing cows.
Schweiz Arch Tierheilkd 1989; 131(2): 99–106.
35. Lohuis JA, van Werven T, Brand A, et al. Pharmacodynamics and
pharmacokinetics of carprofen, a non-steroidal anti-inflammatory drug, in
healthy cows and cows with Escherichia coli endotoxin-induced mastitis. J Vet
Pharmacol Ther 1991 Sep; 14(3): 219–29.
36. McClain RM, Hoar RM. Reproduction studies with carprofen, a nonsteroidal
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37. Lipscomb VJ, AliAbadi FS, Lees P, et al. Clinical efficacy and pharmacokinetics
of carprofen in the treatment of dogs with osteoarthritis. Vet Rec 2002 Jun 1;
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38. Parton K, Balmer TV, Boyle J, et al. The pharmacokinetics and effects of
intravenously administered carprofen and salicylate on gastrointestinal
All rights reserved
CARPROFEN Veterinary—Systemic 23
mucosa and selected biochemical measurements in healthy cats. J Vet
Pharmacol Ther 2000; 23: 73–9.
39. MacPhail CM, Lappin MR, Meyer DJ, et al. Hepatocellular toxicosis associated
with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998 Jun
15, 212(12): 1895–1901.
40. Rimadyl Caplets package insert (Pfizer—Canada), Rev 4/4/02, Rec 10/17/02.
41. Rimadyl Chewable Tablets package insert (Pfizer—Canada), Rev 4/17/02, Rec
10/17/02.
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43. Reimer ME, Johnston SA, Leib MS, et al. The gastroduodenal effects of buffered
aspirin, carprofen, and etodolac in healthy dogs. J Vet Intern Med 1999; 13:
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44. Runk A, Kyles AE, Downs MO. Duodenal perforation in a cat following the
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45. Lascelles BD, Cripps PJ, Jones A, et al. Efficacy and kinetics of carprofen,
administered preoperatively or postoperatively, for the prevention of pain in
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46. Welsh EM, Nolan AM, Reid J. Beneficial effects of administering carprofen
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47. Alibhai HI, Clarke KW. Influence of carprofen on minimum alveolar
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48. Ko JC, Lange DN, Mandsager RE, et al. Effects of butorphanol and carprofen on
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49. Forsyth SF, Guilford WG, Pfeiffer DU, et al. Effect of NSAID administration on
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50. Lobetti RG, Joubert KE. Effect of administration of nonsteroidal antiinflammatory drugs before surgery on renal function in clinically normal
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51. Bostrom IM, Nyman GC, Lord PF, et al. Effects of carprofen on renal function
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2004 The United States Pharmacopeial Convention, Inc.
52. Ko JC, Miyabiyashi T, Mandsager RE, et al. Renal effects of carprofen
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54. Lascelles BD, Cripps P, Mirchandani S, et al. Carprofen as an analgesic for
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55. Balmer TV, Irvine D, Jones RS, et al. Comparison of carprofen and pethidine as
postoperative analgesics in the cat. J Small Anim Pract 1998 Apr; 39: 158–64.
56. Slingsby LS, Waterman-Pearson AE. Postoperative analgesia in the cat after
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acid. J Small Anim Pract 2000 Oct; 41: 447–50.
57. Slingsby LS, Waterman-Pearson AE. Comparison between meloxicam and
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58. Johnson CB, Taylor PM, Young SS, et al. Postoperative analgesia using
phenylbutazone, flunixin or carprofen in horses. Vet Rec 1993; 133: 336–8.
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60. Klasco RK, editor. USP DI Drug Information for the health care professional.
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65. Kay-Mugford P, Benn SJ, LaMarre J, et al. In vitro effects of nonsteroidal antiinflammatory drugs on cyclooxygenase activity in dogs. Am J Vet Res 2000
July; 61(7): 802–10.
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24 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
This monograph contains information on the following: Dexamethasone;
Flumethasone; Hydrocortisone; Isoflupredone; Methylprednisolone;
Prednisolone; Prednisone; Triamcinolone.
Some commonly used brand names are:
For veterinary-labeled products—
Azium Powder [Dexamethasone]
Azium Solution [Dexamethasone]
Cortalone [Triamcinolone]
Depo-Medrol [Methylprednisolone]
Dexaject [Dexamethasone]
Dexaject SP [Dexamethasone]
Dexamethasone 2 [Dexamethasone]
Dexamethasone 5 [Dexamethasone]
Dexasone [Dexamethasone]
Dexazone 2 mg [Dexamethasone]
Dexone [Dexamethasone]
Dextab [Dexamethasone]
Flucort [Flumethasone]
Medrol [Methylprednisolone]
Methysone 40 [Methylprednisolone]
Predef 2X [Isoflupredone]
PrednisTab [Prednisolone]
Predsone-5 [Prednisone]
Rafter Dex [Dexamethasone]
Solu-Delta-Cortef [Prednisolone]
Triamtabs [Triamcinolone]
Uni-Dex [Dexamethasone]
Unimed [Methylprednisolone]
Uni-Pred 50 [Prednisolone]
Vetacortyl [Methylprednisolone]
Vetalog [Triamcinolone]
ACCEPTED
For human-labeled products—
A-methaPred [Methylprednisolone]
Cortef [Hydrocortisone]
Decadron [Dexamethasone]
Dexasone [Dexamethasone]
state that a product is for use when an anti-inflammatory drug or
adrenal glucocorticoid is needed or, alternatively, the label may list
relatively specific indications for use.{R-18; 23} Many product labels
state that treatment of conditions known to be responsive to antiinflammatory glucocorticoids is indicated but then also list specific
disorders for which the medication is known to be effective.{R-4; 6; 8; 11;
12; 14; 16; 17; 20; 22}
For clarity, specific indications noted on product
labeling are listed in this section as unbracketed Accepted indications
and those not specifically named in U.S. or Canadian labeling are
bracketed or marked with a superscript 1, respectively. However, it
should be noted that products that are labeled for use in the treatment
of general inflammation might also be considered efficacious in the
treatment of more specific indications, such as musculoskeletal
inflammation, for which it may not be listed because that specific
type of inflammation is not mentioned on product labeling.
Hexadrol [Dexamethasone]
Hydrocortone [Hydrocortisone]
Solu-Medrol [Methylprednisolone]
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
CATEGORY:
Abortifacient—Dexamethasone.
Anti-inflammatory agent (steroidal)—Dexamethasone; Flumethasone;
Hydrocortisone; Isoflupredone; Methylprednisolone; Prednisolone;
Prednisone; Triamcinolone.
Diagnostic aid (hyperadrenocorticism)—Dexamethasone.
Gluconeogenic agent—Dexamethasone; Flumethasone; Isoflupredone;
Prednisolone.
Immunosuppressant—Prednisolone; Prednisone.
Parturifacient—Dexamethasone; Flumethasone.
INDICATIONS
Note: Bracketed information in the Indications section refers to uses that
either are not included in U.S. product labeling or are for products not
commercially available in the U.S.
Information identified by a superscript 1 refers to uses that either are not
included in Canadian product labeling or are for products not
commercially available in Canada.
GENERAL CONSIDERATIONS
Glucocorticoids potentially affect every cell in the body and produce a
wide spectrum of effects depending on tissue concentration and cell
type.{R-30} A variety of glucocorticoids have been developed in an effort
to vary the intensity and duration of effects and to decrease
mineralocorticoid effects. However, systemic administration of these
drugs is not a specifically targeted therapy and should be structured to
minimize unwanted effects and to maximize therapeutic benefits.
Guidelines for use of glucocorticoids provided by product labeling range
from broad to specific, depending on the product. A label may only
2004 The United States Pharmacopeial Convention, Inc.
Adrenocortical insufficiency, acute (treatment)—Glucocorticoids are
indicated in the treatment of acute adrenocortical insufficiency
(Addison’s disease); however, the mineralocorticoid effect will vary
from product to product. For that small percentage of dogs with only
glucocorticoid deficiency, long-term replacement can be performed
without a need for mineralocorticoid; however, for the majority of
dogs, mineralocorticoid replacement is necessary. Hydrocortisone,
methylprednisolone, prednisolone, and prednisone{R-34; 145} produce
minor mineralocorticoid effects in addition to their glucocorticoid
effects and may adequately reverse electrolyte imbalances when
administered in conjunction with intravenous sodium chloride solution; however, methylprednisolone, prednisolone, and prednisone are
considered insufficient for long-term control of the potassium-retention
or sodium and chloride losing effects of most cases of primary
adrenocortical insufficiency{R-8} and a mineralocorticoid-specific medication is generally indicated.
In acute adrenocortical insufficiency, a rapidly acting parenteral corticosteroid with the most mineralocorticoid effect available should be
administered in conjunction with vascular volume expansion using
isotonic saline.{R-213} Relative mineralocorticoid effect from the most
to the least potency is hydrocortisone > prednisolone/prednisone >
methylprednisolone > dexamethasone.{R-38; 188}
Cats: Methylprednisolone tablets1,{R-14; 192} [hydrocortisone tablets]1,
{R-193}
prednisolone sodium succinate injection, [prednisolone tablets]1,{R-193} and [prednisone tablets]1{R-193} are indicated in the
treatment of acute adrenocortical insufficiency.
Dogs: Prednisolone sodium succinate{R-7; 9} is indicated in the
treatment of acute adrenocortical insufficiency when a rapid effect
is necessary. Methylprednisolone tablets1,{R-14; 192} prednisolone
tablets1,{R-8} [hydrocortisone tablets]1,{R-193} and [prednisone tablets]1{R-100; 195} are also indicated in the treatment of acute
adrenocortical insufficiency.
Horses: Dexamethasone sodium phosphate{R-11} is indicated for use in
situations in which a rapid adrenocortical effect is needed; however,
it provides no significant mineralocorticoid effect. [Prednisolone]1
and [prednisone]1 have been used in the treatment of adrenocortical
insufficiency.
All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 25
Allergic disorders (treatment)—Many glucocorticoids are likely to be
effective in the treatment of allergic reactions; however, the
formulation should be chosen carefully to provide the onset of
action, duration of action, and side effect profile to fit the type of
reaction being treated. For example, for anaphylactic reactions,
corticosteroids play a secondary role to epinephrine and fluid
therapy. If corticosteroids are employed in the treatment of
anaphylaxis, short-acting water soluble formulations are recommended.
Cats: Dexamethasone injection, methylprednisolone acetate injectable
suspension,{R-15; 16} methylprednisolone tablets1,{R-14; 192} prednisolone sodium succinate,{R-7; 9} triamcinolone acetonide injectable
suspension1,{R-22} and triamcinolone tablets1{R-20} are indicated in
the treatment of allergic conditions. [Flumethasone]1, [prednisolone]1, and [prednisone] should also be effective in the treatment of
allergic disorders.{R-100; 194}
Cattle: Isoflupredone acetate injectable suspension{R-23; 24} and dexamethasone injection{R-6} are indicated in the treatment of allergic
conditions. Although they are not labeled for use in cattle in the U.S.,
[flumethasone]1, [prednisolone]1, and [prednisone]1 should also be
effective in the treatment of allergic disorders.
Dogs: Dexamethasone injection, flumethasone injection,{R-18} methylprednisolone acetate injectable suspension,{R-15; 16; 17} methylprednisolone tablets1,{R-14; 192} prednisolone sodium succinate,{R-7; 9}
prednisolone tablets1,{R-8} triamcinolone acetonide injectable suspension1,{R-22} and triamcinolone tablets1{R-20} are indicated in the
treatment of allergic conditions. [Prednisone] should also be effective
in the treatment of allergic disorders.{R-100}
Horses: Dexamethasone injection, flumethasone injection1,{R-18} isoflupredone acetate injectable suspension,{R-23; 24} and prednisolone
sodium succinate{R-7; 9} are indicated in the treatment of allergic
conditions. [Methylprednisolone]1 and [prednisone]1 should also be
effective in the treatment of allergic disorders.{R-100; 194}
Pigs: Isoflupredone acetate injectable suspension{R-23; 24} is indicated
in the treatment of allergic conditions. Although they are not labeled
for use in pigs, [dexamethasone]1, [flumethasone]1, [methylprednisolone]1, [prednisolone]1, and [prednisone]1 should also be effective in
the treatment of allergic disorders.
Asthma, bronchial (treatment)—Cats: Methylprednisolone acetate injection or tablets1,{R-14; 192} [prednisolone]1,{R-100; 193} or [prednisone
tablets]{R-28; 100; 193} are indicated in the treatment of bronchial
asthma. Once initial inflammation is controlled, other methods of
controlling this disease should be pursued. If corticosteroid treatment
must be continued, the lowest dose necessary and, if possible, alternate
day therapy should be instituted.{R-213}
Colitis, ulcerative (treatment)1—Dogs: Methylprednisolone tablets,{R-14;
192}
prednisolone tablets,{R-8} and [prednisone]{R-100} are indicated in
the treatment of ulcerative colitis in dogs; however, use typically is
reserved for cases that are not responsive to other therapies.
Dermatitis, allergic (treatment);
Dermatoses, nonallergic (treatment);
Otitis (treatment); or
Pruritus (treatment)—Once initial inflammation is controlled, other
methods of controlling disease should be pursued. If corticosteroid
treatment must be continued, the lowest dose necessary or, if possible,
alternate day therapy with either prednisolone, prednisone, methylprednisolone, or triamcinolone should be instituted.{R-213} Repeated
injections of acetate or acetonide repository injections are not
2004 The United States Pharmacopeial Convention, Inc.
recommended for control of chronic skin disease because of the risk
of iatrogenic hyperadrenocorticism.
Cats: Dexamethasone injection,{R-4} [dexamethasone tablets],{R-12}
flumethasone injection,{R-18} methylprednisolone acetate injectable
suspension,{R-15; 16; 17} methylprednisolone tablets1,{R-14; 192}
prednisolone sodium succinate,{R-9} [prednisolone tablets]1, [prednisone tablets],{R-28} triamcinolone acetonide injectable suspension1,{R-22} and triamcinolone tablets1{R-20} are indicated in the
treatment of acute and chronic dermatoses of varying etiologies and
the associated inflammation, irritation, and pruritus. Methylprednisolone tablets1{R-14; 192} are labeled for the treatment of otitis
externa.
Dogs: Dexamethasone injection,{R-4} [dexamethasone tablets],{R-12}
flumethasone injection,{R-18} methylprednisolone acetate injectable
suspension,{R-15; 16; 17} methylprednisolone tablets1,{R-14; 192}
[prednisolone acetate injectable suspension],{R-10} prednisolone
sodium succinate,{R-9} prednisolone tablets1,{R-8} [prednisone tablets],{R-28} triamcinolone acetonide injectable suspension1,{R-22} and
triamcinolone tablets1{R-20} are indicated in the treatment of acute
and chronic dermatoses of varying etiologies and the associated
inflammation, irritation, and pruritus. Flumethasone injection,{R-18}
methylprednisolone acetate injectable suspension,{R-15; 16; 17}
methylprednisolone tablets1,{R-14; 192} and prednisolone tablets1{R8}
are labeled for the treatment of otitis externa.
Disk disease, intervertebral (treatment)—Dogs: Dexamethasone injection{R-4} and flumethasone injection{R-18} are indicated as supportive
therapy in the treatment of intervertebral disk disease (disk syndrome).
But it should be noted that high dosages of dexamethasone carry a risk
of severe adverse effects.{R-166} Therapy should be tailored to the type
of disk dysfunction and clinical signs. [Methylprednisolone]1, [prednisolone]1, or [prednisone]1, administered at an anti-inflammatory
dosage, may be a more appropriate choice of therapy in many cases.
However, acute paralysis due to intervertebral disk disease is an
emergency usually requiring surgery and/or anti-inflammatory dosages much higher than those typically used for inflammation. For this
form of the disease, see [Spinal cord trauma, acute] listed in this section.
Inflammation, general (treatment)—
Cats: Dexamethasone injection,{R-4; 181} [dexamethasone sodium
phosphate injection],{R-176} [dexamethasone tablets],{R-12} [flumethasone injection],{R-18; 185} methylprednisolone acetate injectable
suspension,{R-15; 16; 17} methylprednisolone tablets1,{R-14} prednisolone sodium succinate,{R-7; 9} [prednisolone tablets]1, [prednisone
tablets],{R-28} triamcinolone acetonide injectable suspension1,{R-22}
and triamcinolone tablets1{R-20} are indicated in the treatment of
inflammation known to be responsive to glucocorticoids.
Cattle: Dexamethasone injection,{R-4; 6; 176; 181} dexamethasone oral
powder,{R-3; 5} [dexamethasone sodium phosphate injection],{R-176}
and [flumethasone injection]{R-185} are indicated in the treatment of
inflammation known to be responsive to glucocorticoids. Although
they are not labeled for use in cattle in the U.S., [prednisolone]1 and
[prednisone]1 should also be effective in the treatment of general
inflammation.
Dogs: Dexamethasone injection,{R-181} dexamethasone sodium phosphate injection,{R-176} [dexamethasone tablets],{R-12} flumethasone
injection,{R-18; 185} methylprednisolone acetate injectable suspension,{R-15; 16; 17} methylprednisolone tablets1,{R-14} prednisolone
sodium succinate,{R-7; 9} prednisolone tablets1,{R-8} [prednisone
tablets],{R-28} triamcinolone acetonide injectable suspension1,{R-22}
All rights reserved
26 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
and triamcinolone tablets1{R-20} are indicated in the treatment of
inflammation known to be responsive to glucocorticoids.
Horses: Dexamethasone injection,{R-4; 6; 11; 176; 181} dexamethasone
sodium phosphate injection, dexamethasone oral powder,{R-5} flumethasone injection,{R-18; 185} methylprednisolone acetate injectable
suspension1,{R-15; 16; 17} prednisolone sodium succinate,{R-7; 9} and
triamcinolone acetonide injectable suspension1{R-22} are indicated in
the treatment of inflammation known to be responsive to glucocorticoids.
Inflammation, musculoskeletal (treatment)—Corticosteroids are indicated for symptomatic treatment of musculoskeletal disorders by
reduction of pain, inflammation, and swelling. Clinical response is
limited by the degree of irreversible pathologic change present.
Cats: Dexamethasone injection,{R-4} [dexamethasone tablets],{R-12}
[flumethasone injection], methylprednisolone acetate injectable suspension,{R-15; 16; 17} methylprednisolone tablets1,{R-14; 192} prednisolone sodium succinate,{R-9} [prednisolone tablets]1,{R-28; 31; 189}
[prednisone tablets],{R-28} triamcinolone acetonide injectable suspension1,{R-22} and triamcinolone tablets1{R-20} are indicated in the
treatment of joint and musculoskeletal inflammation.
Intra-articular administration of triamcinolone injectable suspension1{R-22} is indicated in the treatment of joint inflammation;
however, the risk of local adverse effects, including postinjection
flare-up and septic arthritis, is increased, particularly with repeated
injections. There is some concern that high dose regimens may cause
articular surface damage.{R-197} Use of the lowest dose at the longest
dosing interval possible is recommended if intra-articular injection is
necessary.{R-197}
Cattle: Dexamethasone injection,{R-4} dexamethasone oral powder,{R-5}
[dexamethasone 21 phosphate injection],{R-1} [flumethasone injection],{R-185} and isoflupredone acetate injectable suspension{R-23; 24}
are indicated in the treatment of joint and musculoskeletal inflammation. Although they are not labeled for use in cattle in the U.S.,
[prednisolone]1 and [prednisone]1 should also be effective in the
treatment of musculoskeletal inflammation.
Dogs: Dexamethasone injection,{R-4} [dexamethasone tablets],{R-12}
flumethasone injection,{R-18} methylprednisolone acetate injectable
suspension,{R-15; 16; 17} methylprednisolone tablets1,{R-14; 192}
[prednisolone acetate injectable suspension],{R-10} prednisolone
sodium succinate,{R-7; 9} prednisolone tablets1,{R-8} [prednisone
tablets],{R-28} triamcinolone acetonide injectable suspension1,{R-22}
and triamcinolone tablets1{R-20} are indicated in the treatment of
joint and musculoskeletal inflammation, including arthritis,{R-17; 99}
bursitis,{R-14; 192} myositis,{R-14; 192} and osteoarthritis.{R-17}
Intra-articular administration of flumethasone injection,{R-18} methylprednisolone acetate injectable suspension,{R-15; 16; 17} and
triamcinolone acetonide injectable suspension1{R-22} are indicated
in the treatment of joint inflammation; however, the risk of local
adverse effects, including postinjection flare-up and septic arthritis,
is increased, particularly with repeated injections, and there is some
concern that high dose regimens may cause articular surface
damage.{R-197} Use of the lowest dose at the longest dosing interval
possible is recommended if intra-articular injection is necessary.{R-197}
Horses: Dexamethasone injection,{R-4; 176} dexamethasone oral
powder,{R-5} [dexamethasone 21 phosphate injection],{R-1}
flumethasone injection,{R-18} isoflupredone acetate injectable
suspension,{R-23; 24} methylprednisolone acetate injectable suspen-
2004 The United States Pharmacopeial Convention, Inc.
sion,{R-15; 16; 17} [prednisolone acetate injectable suspension],{R-10}
prednisolone sodium succinate,{R-7; 9} and triamcinolone acetonide
injectable suspension1{R-22} are indicated in the treatment of joint
and musculoskeletal inflammation, including bursitis,{R-6; 16} carpitis,{R-6; 16} osselets,{R-6; 16} myositis,{R-6; 16} osteoarthritis,{R-16; 17}
periostitis,{R-16; 17} sprains,{R-6; 16} synovitis,{R-16; 17} or tenosynovitis.{R-16; 17}
Intra-articular administration of flumethasone injection,{R-18} isoflupredone acetate injectable suspension,{R-23; 24} methylprednisolone
acetate injectable suspension,{R-15; 16; 17} or triamcinolone acetonide
injectable suspension1{R-22} is indicated in the treatment of joint
inflammation to avoid the systemic side effects of these medications;{R-122} however, joint tissue repair is delayed,{R-122} some
systemic absorption and adrenal suppression occurs,{R-121; 129} and
the risk of local adverse effects, including postinjection flare up and
septic arthritis,{R-121} is increased, particularly with repeated injections.{R-121-126} Intra-articular glucocorticoids, such as methylprednisolone, also can mask the clinical signs of infectious arthritis for
up to 3 days.{R-128} Use of the lowest dose at the longest dosing
interval possible is recommended if intra-articular injection is
necessary.{R-197}
Pigs: Isoflupredone acetate injectable suspension{R-23} is indicated in
the treatment of joint and musculoskeletal inflammation. Although
they are not labeled for use in pigs, [dexamethasone]1, [flumethasone]1, [prednisolone]1, and [prednisone]1 should also be effective in
the treatment of musculoskeletal inflammation.
Inflammation, ocular (treatment)—
Cats: Methylprednisolone tablets1,{R-14; 192} prednisolone sodium
succinate,{R-7; 9} [prednisolone tablets]1, and [prednisone tablets]1{R-193} are indicated in the treatment of inflammatory conditions of the eye, including chorioretinitis, secondary glaucoma,
iriditis, iridocyclitis, and uveitis. [Dexamethasone]1 and [flumethasone]1 should also be effective in the treatment of ocular inflammation.
Cattle: Isoflupredone acetate injectable suspension{R-23} and [dexamethasone injection]1 are indicated in the treatment of inflammatory
conditions of the eye. Although not labeled for use in cattle in the
U.S., [flumethasone]1, [prednisolone]1, and [prednisone]1 should also
be effective in the treatment of ocular inflammation.
Dogs: Methylprednisolone tablets1,{R-14; 192} prednisolone sodium
succinate,{R-7; 9} prednisolone tablets1,{R-8} and [prednisone tablets]1{R-100} are indicated in the treatment of inflammatory conditions of the eye, including chorioretinitis, secondary glaucoma,
iriditis, iridocyclitis, and uveitis. [Dexamethasone]1 and [flumethasone]1 should also be effective in the treatment of ocular inflammation.
Horses: Isoflupredone acetate injectable suspension{R-23} and prednisolone sodium succinate{R-7; 9} are indicated in the treatment of
inflammatory conditions of the eye. [Dexamethasone]1, [flumethasone]1, and [prednisone]1 should also be effective in the treatment of
ocular inflammation.
Pigs: Isoflupredone acetate injectable suspension{R-23} is indicated in
the treatment of inflammatory conditions of the eye. Although not
labeled for use in pigs in the U.S., [dexamethasone]1, [flumethasone]1, [prednisolone]1, and [prednisone]1 should also be effective in
the treatment of ocular inflammation.
Ketosis (treatment)—Cattle: Dexamethasone injection,{R-4; 6} [dexamethasone 21 phosphate injection],{R-1} [dexamethasone sodium phos-
All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 27
phate injection],{R-176} dexamethasone oral powder,{R-5} [flumethasone injection],{R-185} isoflupredone acetate injectable suspension,{R-23} and [prednisolone acetate injectable suspension]{R-10} are
indicated in the treatment of primary bovine ketosis and are likely to
be more effective when administered with intravenous glucose
solutions.{R-57} For secondary bovine ketosis, corticosteroids should be
used concurrently with other therapies for underlying disease, including
local and systemic antibacterials to treat primary bacterial infections.{R-23} A significant decrease in milk production should be expected
when a corticosteroid is administered to lactating cattle.{R-213}
Shock, septic (treatment adjunct)—The primary treatment of septic
shock (endotoxemia) includes antimicrobial therapy and supportive
parenteral fluid therapy. In the search for other medications to block
the mediators of endotoxemic shock,{R-47} a wide variety of research
has been done, often with contradictory results.{R-47-52} The use of
glucocorticoids in the treatment of septic shock is therefore controversial and several criteria must be met for treatment to possibly be
effective. High doses of a rapidly-acting glucocorticoid, preferably of
short duration, should be given in conjunction with fluid and
electrolyte therapy within a short period of time, possibly less than
1 hour, after the onset of sepsis.{R-47-50} Because studies have shown
flunixin to be at least as effective as or superior to glucocorticoids in the
treatment of endotoxemia in calves and ponies{R-47-51} without the
risk of attenuation of immune defenses, its use may be preferred in
some situations.
Cats: Methylprednisolone acetate injectable suspension is indicated in
the treatment of septic shock;{R-15; 16} however, the rapid-acting
corticosteroid formulations, such as [dexamethasone sodium phosphate]1 and prednisolone sodium succinate,{R-7; 9} are recommended
as superior therapeutic choices in the treatment of endotoxic shock
(septic shock) when administered as an adjunct to treatment with
intravenous fluids and antibiotics.
Dogs: Methylprednisolone acetate injectable suspension is indicated in
the treatment of septic shock;{R-15; 16} however, the rapid-acting
corticosteroid formulations, such as [dexamethasone sodium phosphate]1 and prednisolone sodium succinate,{R-7; 9} are recommended
as superior therapeutic choices in the treatment of endotoxic shock
(septic shock) when administered as an adjunct to treatment with
intravenous fluids and antibiotics.
Cattle and pigs: Isoflupredone acetate injectable suspension is indicated
in the treatment of septic shock;{R-23} however, the rapidly acting
corticosteroid formulations, such as [dexamethasone sodium phosphate]1, are recommended as superior therapeutic choices in the
treatment of endotoxic shock (septic shock) when administered as an
adjunct to treatment with intravenous fluids and antibiotics.
Horses: Isoflupredone acetate injectable suspension is indicated in the
treatment of septic shock; {R-23} however, the rapid-acting corticosteroid formulations, such as [dexamethasone sodium phosphate]1
and prednisolone sodium succinate,{R-7; 9} are recommended as
superior therapeutic choices in the treatment of endotoxic shock
(septic shock) when administered as an adjunct to treatment with
intravenous fluids and antibiotics.
[Abortion, induction of]1—Cattle: Dexamethasone injection is used in
the induction of abortion. It is generally administered after the 100th
to 150th day of gestation, when prostaglandins administered alone are
no longer effective.{R-190; 191} Although it is usually administered in
conjunction with a prostaglandin, there is still a risk of fetal
mummification, retained placentas, metritis, or dystocia.{R-191} It
2004 The United States Pharmacopeial Convention, Inc.
should be noted that abortion can be associated with any C16methylated glucocorticoid (see the Side/Adverse Effects section).{R-213}
[Anemia, immune-mediated hemolytic (treatment)]1—Cats and dogs:
Dexamethasone, prednisolone, and prednisone are used in the treatment of autoimmune hemolytic anemia.{R-96; 100; 106} Primary
underlying causes should be ruled out to be certain therapy is
appropriate. Glucocorticoids may be used in conjunction with other
immunosuppressive drugs. In the treatment of some anemia cases,
medications may be used in conjunction with blood transfusion or
splenectomy.{R-96; 106}
[Hyperadrenocorticism (diagnosis)]1—
Cats: Dexamethasone injection and dexamethasone sodium phosphate
injection are used in the diagnosis of hyperadrenocorticism (Cushing’s syndrome).{R-140} Because of the lack of consistent clinical signs
in cats to support a diagnosis of hyperadrenocorticism and, therefore,
the small number of recognized cases available for testing, tests
are used for diagnosis based on studies performed with normal
cats.{R-140; 222} The screening test is generally performed with a dose
higher than that used in the low-dose test for dogs; the high dose is
more than 90% diagnostic for normal cats.{R-140} Differentiation of
adrenal disease versus pituitary-dependent hyperadrenocorticism
has been performed by some clinicians{R-221} with a higher dose
than that used for the high-dose dexamethasone test in dogs;
however, there is no substantive research evidence to show that the
two can be differentiated by this test in cats.{R-177}
Dogs: Dexamethasone injection and dexamethasone sodium phosphate
injection are used in the diagnosis of hyperadrenocorticism (Cushing’s syndrome).{R-58; 62-64} The low-dose dexamethasone test
typically is used for screening. The high-dose dexamethasone test
has been used for differentiation of pituitary- versus adrenal-origin
hyperadrenocorticism. The low-dose test is approximately 90%
accurate{R-60; 62} in screening for hyperadrenocorticism and
possibly 61% accurate in differentiation of pituitary- from adrenaldisease.{R-64} The high-dose dexamethasone test is 75 to 80%
accurate in differentiating the two forms of this disorder. {R-63; 64}
Horses: Dexamethasone injection is used in the diagnosis of pituitary
pars intermedia-dependent hyperadrenocorticism.{R-178; 179}
[Lupus erythematosus, systemic (treatment)]1—Dogs: Methylprednisolone, prednisolone, and prednisone are used in the treatment of
systemic lupus erythematosus.{R-98; 99}
[Lymphoma (treatment adjunct)]1—Cats and dogs: Prednisolone and
prednisone are used in the treatment of lymphoma.{R-83-89; 100; 109}
Although prednisone alone can cause some remission of
signs,{R-86; 87} tumor resistance develops quickly and remission is
short;{R-86} therefore, corticosteroids are more commonly used in
combination chemotherapy with other agents. One widely used
combination protocol includes prednisone, cyclophosphamide, and
vincristine (COP), although there are many published regimens.{R-86;
90}
Treatment with corticosteroids alone can decrease the chance of
remission with combination therapies instituted later;{R-83} however,
prednisone has been used as a single therapy when cost or other
factors warrant it.{R-109}
[Mast cell tumors (treatment)]1—Dogs: Prednisolone{R-100} and prednisone{R-107; 108} are used in the treatment of mast cell tumors,
although initial wide surgical excision, if possible, is generally the
primary treatment. In a group of dogs with relatively aggressive
tumors (grades II and III), prednisone was shown to be effective in
reducing tumor size in 20% of cases.{R-107}
All rights reserved
28 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
[Parturition, induction of]1—
Cattle: Dexamethasone and flumethasone have been used in the
induction of parturition;{R-110-113} however, only dexamethasone is
labeled for use in cattle in the U.S. Parturition may be induced in the
last few weeks of gestation to speed the onset of lactation or to
control timing of parturition and involves much less risk to the fetus
than earlier termination of pregnancy.{R-111; 113} Administration of
corticosteroids more than 1 month before expected gestation often
leads to poor neonatal survival,{R-114} but may be necessary in some
situations. Induction of parturition requires a knowledge of breeding
date and is generally accomplished with administration of a
glucocorticoid in conjunction with a prostaglandin in order to
produce a predictable response time.{R-110} In cattle, retained
placentas are a common sequela to steroid-induced labor even when
glucocorticoids are administered with prostaglandin (61% or more
retained). The administration of a longer-acting glucocorticoid, such
as triamcinolone, a week before induction may reduce the incidence
of retained placentas (in one study, reduced to 14% retained);{R-110;
112; 114}
however, in 40% of cows, the triamcinolone preadministration itself can induce parturition before the induction dose
administered 6 days later takes effect.
Sheep: Dexamethasone and flumethasone have been used in the
induction of parturition;{R-116; 117} however, these products are not
labeled for use in sheep in the U.S.
[Pemphigoid (treatment)]1; or
[Pemphigus (treatment)]1—Cats and dogs: Prednisolone{R-40; 41} and
prednisone{R-39; 42} have been used in the treatment of pemphigus
diseases in cats and dogs and pemphigoid in dogs. When corticosteroids are used alone, they have been reported to be successful in
controlling symptoms in approximately 40% of the cases treated. For
animals not responsive to treatment with prednisolone or prednisone
alone, other immunosuppressive medications or aurothioglucose (gold
salts) have been added to the treatment regimen.{R-39-42}
[Spinal cord trauma, acute (treatment)]1—Cats and dogs: Methylprednisolone sodium succinate has been shown to improve clinical
outcome in cats when administered within 1 hour of acute experimental spinal cord trauma.{R-25; 44; 45; 91; 173; 182} The strength of
evidence of efficacy of methylprednisolone sodium succinate in cats
leads clinicians to recommend use for this indication in dogs, also.
[Thrombocytopenia, immune-mediated (treatment)]1—Dogs: Prednisolone{R-94-96} and prednisone{R-100} are used in the treatment of
immune-mediated thrombocytopenia.{R-94-96} Other underlying
causes of thrombocytopenia, such as infection, drug reactions, or
neoplasia, should be ruled out to be certain therapy is appropriate.{R94; 95}
In cases that are initially refractory to prednisolone, other
immunosuppressive medications, such as vincristine or cyclophosphamide, may be added.{R-94}
ACCEPTANCE NOT ESTABLISHED
Note: Product labeling in the U.S. and Canada includes the use of
glucocorticoids{R-4; 5; 23; 24} as supportive therapy in the treatment of
various disorders, including fatigue, heat exhaustion, influenza,
metritis, milk fever, perioperative problems, pneumonia, pyelonephritis, retained placenta, shipping fever, stress, and traumatic gastritis.
Although glucocorticoids may be helpful in treating specific effects,
such as inflammation, associated with these disorders and are used in
selected cases, routine use is not recommended.
2004 The United States Pharmacopeial Convention, Inc.
Glomerular disease (treatment)1—Cats and dogs: Although the use of
prednisolone in the treatment of glomerular disease (nephrosis) is
mentioned on U.S. product labeling,{R-8} the efficacy and safety of this
use has not been established and is not recommended.{R-194} Immunecomplex or immune-mediated glomerulonephritis is believed to exist in
cats, dogs, and human beings but the use of glucocorticoids in the
treatment of these disorders in animals has not yet been demonstrated
to be beneficial.{R-174} There are no controlled studies with immunosuppressive doses in animals, but in one small retrospective study of
dogs, an anti-inflammatory dose of prednisolone was not beneficial for
glomerulonephritis and may have been detrimental.{R-175} The use of
corticosteroids in the treatment of immune-mediated glomerulonephritis is not recommended.
Mastitis (treatment)1—Cattle: Although some product labeling mentions
the use of dexamethasone as supportive therapy in the treatment of
mastitis,{R-4} the efficacy and safety have not been clearly established.
Dexamethasone is used as adjunctive therapy in the treatment of
selected cases of acute coliform mastitis{R-142; 143; 144} because it can
relieve some of the systemic signs due to endotoxin produced by
Escherichia coli bacteria and reduce the significant mammary gland
inflammation that is the hallmark of some acute cases.{R-143; 144}
Dexamethasone is considered adjunctive therapy only and should be
administered in conjunction with primary treatments, such as
intravenous fluids, antimicrobials, and an increased number of
milkings a day.{R-142} Glucocorticoid therapy cannot be used in
pregnant cows in middle- to late-gestation without risk of induction of
abortion or parturition.{R-110-114; 142}
[Abortion, induction of]1—
Dogs: Although the safety and efficacy have not been established, the
use of dexamethasone in the induction of abortion in dogs is
supported by one uncontrolled study.{R-118} Frequent oral dosing for
10 days resulted in abortion in all treated dogs;{R-118} however, there
is no other supporting information and clinical use is not reported to
be common.
Sheep: Although the safety and efficacy have not been established,
dexamethasone has been used in the induction of abortion. However,
early abortion at the 88th to 92nd day of gestation was induced in
only 2 of 5 sheep by the administration of dexamethasone alone in
one study.{R-172} Dexamethasone is not labeled for use in sheep in
the U.S. or Canada.
[Anemia, immune-mediated hemolytic (treatment)]1—Horses: Although
the safety and efficacy have not been established, dexamethasone has
been used in the treatment of immune-mediated hemolytic anemia in
horses, based on a case report of successful responses.{R-97}
[Chronic obstructive pulmonary disease (treatment)]1—Horses: Although
the safety and efficacy have not been clearly established, dexamethasone, isoflupredone, prednisolone, prednisone, and triamcinolone
have been used in the treatment of chronic obstructive pulmonary
disease.{R-32; 100; 199; 200} Research studies are limited and give
conflicting results on efficacy, perhaps due to variable severity of the
disease and problems with diagnosis and evaluation.{R-199; 200} Efforts
to decrease environmental irritants are very important in the control
of this disorder;{R-201} bronchodilators are also often part of the
therapeutic strategy.{R-32} The risk of side effects, such as adrenal
suppression and, possibly, laminitis, with chronic systemic administration of corticosteroids to horses should be considered.{R-202}
[Inflammation, neurologic (treatment)]1—All species: The safety and
extent of efficacy have not been established for the use of glucocor-
All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 29
ticoids in the treatment of many types of inflammation associated
with the nervous system in domestic species, therefore use and
dosing continues to be debated.{R-30; 43} The goal of glucocorticoid
administration is to decrease tissue edema, vasculitis, and inflammation and, for acute injuries, to prevent post-traumatic autodestruction of tissue. Although treatment of intervertebral disk disease
in dogs is a labeled indication for dexamethasone injection and
flumethasone injection,{R-4; 18} glucocorticoids are used also in
many other types of acute and chronic nervous system disorders.
Some evidence supports the efficacy of intravenous methylprednisolone, a rapidly acting glucocorticoid, in speeding the return of
neurologic function when administered within an hour after
experimental acute spinal cord trauma in cats.{R-44; 91; 92}
Dexamethasone has been shown to decrease significantly the edema
associated with induced brain tumors{R-219} but to have little effect
on edema associated with induced trauma to the brain;{R-220}
however, there is some evidence that methylprednisolone can
improve recovery from neurologic dysfunction associated with brain
trauma.{R-93} Dexamethasone has been shown to decrease tissue
edema in induced spinal cord trauma in laboratory situations, but
an improvement in clinical outcome of induced acute spinal cord
trauma in cats has not been as consistently demonstrated as it has
been for methylprednisolone.{R-44; 45}
Glucocorticoids typically are used as adjunctive therapy in acute,
subacute, and chronic neurological inflammation and do not preclude
the necessity for specific diagnosis and disorder-specific therapy.
Caution should be used when administering glucocorticoids to animals
that may have a neurologic disorder involving fungal or viral infection
or in situations in which the benefits have been seriously questioned,
such as acute closed-head injuries.{R-141}
[Inflammatory bowel disease (treatment)]1—Cats and dogs: Although the
safety and efficacy have not been established, methylprednisolone,
prednisolone, or prednisone have been used in the treatment of
inflammatory bowel disease.{R-198} No controlled studies are available.
Because the term inflammatory bowel disease encompasses a variety of
syndromes with differing severity and probably even differing underlying causes, response to medication can vary.{R-193} Therapies such
as diet control may be instituted in conjunction with a medication or a
combination of medications.{R-198}
[Respiratory distress syndrome (treatment)]1—Calves: Although the
safety and efficacy have not been established, the use of corticosteroids
before birth in the prophylaxis of respiratory distress syndrome in
premature calves is supported by a controlled study in which
medication was administered 30 hours before premature cesarean.{R217}
Dexamethasone and flumethasone have been shown to increase
pulmonary surfactant in various species;{R-217; 218} however, only
dexamethasone is labeled for use in food-producing animals in the U.S.
[Shock, cardiogenic (treatment adjunct)]1; or
[Shock, hemorrhagic (treatment adjunct)]1—All species: Although U.S.
and Canadian product labeling includes the use of glucocorticoids in
the treatment of shock, there are insufficient data to confirm the safety
and efficacy of this use in cardiogenic or hemorrhagic shock. Canadian
product labeling for dexamethasone injection includes use as an
adjunct in the treatment of shock in cats, dogs, and horses.{R-184} In
the U.S. and Canada, isoflupredone acetate injectable suspension
is labeled for the treatment of shock in cattle, horses, and
pigs;{R-23} flumethasone injection is labeled for the treatment of shock
in dogs.{R-18}
2004 The United States Pharmacopeial Convention, Inc.
The use of glucocorticoids in the treatment of cardiogenic and hemorrhagic shock continues in the face of conflicting research data.{R-53-56}
The primary treatment of shock is the administration of large volumes
of crystalloid solutions.{R-56} High doses of glucocorticoids may aid in
reversing some of the effects of shock when administered in conjunction with intravenous fluids.{R-54-56} The rapidly acting corticosteroid
formulations are labeled for use in a limited number of species but are
recommended as a superior therapeutic choice when administered in
conjunction with other supportive therapies.{R-213} These rapidly
acting medications include dexamethasone sodium phosphate and
prednisolone sodium succinate.
UNACCEPTED
Laminitis, acute (treatment)—Horses: Although product labeling for
dexamethasone{R-4} and prednisolone sodium succinate{R-7} includes
use in the treatment of acute laminitis, there is some concern that
glucocorticoids can predispose horses to laminitis and may exacerbate
established conditions; therefore, this use is no longer recommended in
most cases.
Snakebite (treatment)—Cattle, dogs, and horses: Although product labeling in the U.S. and Canada includes the use of dexamethasone,
isoflupredone acetate injectable suspension, methylprednisolone acetate, or prednisolone sodium succinate in the treatment of snakebite,
this indication is too general to be accurate.{R-212} The venom
transmitted in a poisonous snakebite will vary depending on the species
and condition of the snake.{R-180} Depending on clinical circumstances,
the use of glucocorticoids in the treatment of an animal that is the
victim of a snakebite may be appropriate or extremely inappropriate.
There are little data on the efficacy of glucocorticoids in the treatment of
snakebite in animals, but routine use is not recommended in human
snakebite victims, based on a lack of evidence of any advantage.{R-212}
There is a general concern that glucocorticoids may mask signs while
not improving outcome; however, they may be indicated if specific
sequelae that are responsive to glucocorticoids occur.
[Appetite, lack of (treatment)]—Cats: Although Canadian product
labeling includes the use of flumethasone injection in the stimulation
of appetite in cats,{R-185} clinical use does not suggest that debilitated
animals experience an increase in appetite with corticosteroid administration.{R-194} Other medications, such as cyproheptadine or a
benzodiazepine, are more accepted choices for this indication.{R-212}
1
Not included in Candian product labeling or product not commercially
available in Canada.
REGULATORY CONSIDERATIONS
U.S.—
Dexamethasone oral powder, dexamethasone injection, and isoflupredone acetate injectable suspension are labeled for use in foodproducing animals. See the Dosage Forms section for further
information on withdrawal times.
Canada—
Dexamethasone oral powder, dexamethasone injection, dexamethasone 21 phosphate, dexamethasone sodium phosphate, flumethasone injection, isoflupredone acetate injectable suspension, and
prednisolone acetate injectable suspension are labeled for use in foodproducing animals. See the Dosage Forms section for further
information on withdrawal times.
All rights reserved
30 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
CHEMISTRY
Source: The natural corticosteroids can be taken from animal adrenal
glands; however, they usually are synthesized.{R-31}
Dexamethasone—A synthetic analog of prednisolone.{R-6}
Flumethasone—A chemical modification of prednisolone.{R-18}
Methylprednisolone—A 6-methyl derivative of prednisolone.{R-14; 192}
Prednisolone—A synthetic dehydrogenated analogue of cortisone.{R-8}
Chemical name:
Dexamethasone—Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11 beta,16 alpha)-.{R-29}
Dexamethasone
sodium
phosphate—Pregna-1,4-diene-3,20-dione,
9-fluoro-11,17-dihydroxy-16-methyl-21-(phosphonooxy)-, disodium
salt, (11 beta,16 alpha)-.{R-29}
Hydrocortisone—Pregn-4-ene-3,20-dione, 11,17,21,trihydroxy-, (11
beta)-.{R-29}
Isoflupredone acetate—Pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-9fluoro-11,17-dihydroxy-, (11 beta)-.{R-29}
Methylprednisolone—Pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6methyl-, (6 alpha,11 beta)-.{R-29}
Methylprednisolone acetate—Pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-11,17-dihydroxy-6-methyl-, (6 alpha,11 beta)-.{R-29}
Methylprednisolone sodium succinate—Pregna-1,4-diene-3,20-dione,
21-(3-carboxy-1-oxopropoxy)-11,17-dihydroxy-6-methyl-, monosodium salt, (6 alpha,11 beta)-.{R-29}
Prednisolone—Pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-, (11
beta)-.{R-29}
Prednisolone acetate—Pregna-1,4-diene-3,20-dione, 21-(acetyloxy)11,17-dihydroxy-, (11 beta)-.{R-29}
Prednisolone sodium succinate—Pregna-1,4-diene-3,20-dione, 21-(3carboxyl-1-oxopropoxy)-11,17-dihydroxy-, monosodium salt, (11
beta)-.{R-29}
Prednisone—Pregna-1,4-diene-3,11,20-trione monohydrate, 17,21-dihydroxy-.{R-29}
Triamcinolone—Pregna-1,4-diene-3,20-dione,
9-fluoro-11,16,17,21tetrahydroxy-, (11 beta,16 alpha).{R-29}
Triamcinolone acetonide—Pregna-1,4-diene-3,20-dione, 9-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis-(oxy)]-, (11 beta,16 alpha)-.{R-29}
Molecular formula:
Dexamethasone—C22H29FO5.{R-29}
Dexamethasone sodium phosphate—C22H28FNa2O8P.{R-29}
Hydrocortisone—C21H30O5.{R-29}
Isoflupredone acetate—C23H29FO6.{R-29}
Methylprednisolone—C22H30O5.{R-29}
Methylprednisolone acetate—C24H32O6.{R-29}
Methylprednisolone sodium succinate—C26H33NaO8.{R-29}
Prednisolone—C21H28O5.{R-29}
Prednisolone acetate—C23H30O6.{R-29}
Prednisolone sodium succinate—C25H31NaO8.{R-29}
Prednisone—C21H26O5ÆH2O.{R-29}
Triamcinolone—C21H27FO6.{R-29}
Triamcinolone acetonide—C24H31FO6.{R-29}
Molecular weight:
Dexamethasone—392.46.{R-29}
Dexamethasone sodium phosphate—516.40.{R-29}
2004 The United States Pharmacopeial Convention, Inc.
Hydrocortisone—362.46.{R-29}
Isoflupredone acetate—420.47.{R-29}
Methylprednisolone—374.47.{R-29}
Methylprednisolone acetate—416.51.{R-29}
Methylprednisolone sodium succinate—496.53.{R-29}
Prednisolone—360.44.{R-29}
Prednisolone acetate—402.48.{R-29}
Prednisolone sodium succinate—482.50.{R-29}
Prednisone—376.44.{R-29}
Triamcinolone—394.43.{R-29}
Triamcinolone acetonide—434.50.{R-29}
Description:
Dexamethasone USP—White to practically white, odorless, crystalline
powder. Is stable in air. Melts at about 250 C, with some decomposition.{R-183}
Dexamethasone Sodium Phosphate USP—White or slightly yellow,
crystalline powder. Is odorless or has a slight odor of alcohol, and is
exceedingly hygroscopic.{R-183}
Flumethasone—A white or creamy white, odorless, crystalline powder.{R-18}
Hydrocortisone USP—White to practically white, odorless, crystalline
powder. Melts at about 215 C, with decomposition.{R-183}
Methylprednisolone USP—White to practically white, odorless, crystalline powder. Melts at about 240 C, with some decomposition.{R-183}
Methylprednisolone Acetate USP—White or practically white, odorless,
crystalline powder. Melts at about 225 C, with some decomposition.{R-183}
Methylprednisolone Sodium Succinate USP—White or nearly white,
odorless, hygroscopic, amorphous solid.{R-183}
Prednisolone USP—White to practically white, odorless, crystalline
powder. Melts at about 235 C, with some decomposition.{R-183}
Prednisolone Acetate USP—White to practically white, odorless, crystalline powder. Melts at about 235 C, with some decomposition.{R-183}
Prednisolone Sodium Succinate for Injection USP—Creamy white powder
with friable lumps, having a slight odor.{R-183}
Prednisone USP—White to practically white, odorless, crystalline
powder. Melts at about 230 C, with some decomposition.{R-183}
Triamcinolone USP—White or practically white, odorless, crystalline
powder.{R-183}
Triamcinolone Acetonide USP—White to cream-colored, crystalline
powder, having not more than a slight odor.{R-183}
Solubility:
Dexamethasone USP—Practically insoluble in water; sparingly soluble in
acetone, in alcohol, in dioxane, and in methanol; slightly soluble in
chloroform; very slightly soluble in ether.{R-183}
Dexamethasone Sodium Phosphate USP—Freely soluble in water;
slightly soluble in alcohol; very slightly soluble in dioxane; insoluble
in chloroform and in ether.{R-183}
Hydrocortisone USP—Very slightly soluble in water and in ether;
sparingly soluble in acetone and in alcohol; slightly soluble in
chloroform.{R-183}
Methylprednisolone USP—Practically insoluble in water; sparingly
soluble in alcohol, in dioxane, and in methanol; slightly soluble in
acetone and in chloroform; very slightly soluble in ether.{R-183}
Methylprednisolone Acetate USP—Practically insoluble in water; soluble
in dioxane; sparingly soluble in acetone, in alcohol, in chloroform, and
in methanol; slightly soluble in ether.{R-183}
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CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 31
Methylprednisolone Sodium Succinate USP—Very soluble in water and
in alcohol; very slightly soluble in acetone; insoluble in chloroform.{R183}
Prednisolone USP—Very slightly soluble in water; soluble in methanol
and in dioxane; sparingly soluble in acetone and in alcohol; slightly
soluble in chloroform.{R-183}
Prednisolone Acetate USP—Practically insoluble in water; slightly
soluble in acetone, in alcohol, and in chloroform.{R-183}
Prednisone USP—Very slightly soluble in water; slightly soluble in
alcohol, in chloroform, in dioxane, and in methanol.{R-183}
Triamcinolone USP—Very slightly soluble in water, in chloroform, and in
ether; slightly soluble in alcohol and in methanol.{R-183}
Triamcinolone Acetonide USP—Practically insoluble in water; sparingly
soluble in dehydrated alcohol, in chloroform, and in methanol.{R-183}
PHARMACOLOGY/PHARMACOKINETICS
Note: Unless otherwise noted, the pharmacokinetics included in this
section are based on intravenous administration of a single dose.
Mechanism of action/Effect: The primary role of endogenous corticosteroids is the maintenance of homeostasis. In order to carry out this
function, they affect nearly every cell in the body, altering the function
of multiple systems.{R-30} The glucocorticoids affect protein, carbohydrate, and lipid balance, while the mineralocorticoids affect water and
electrolyte balance.{R-35} The actions of glucocorticoids are brought
about by interaction with specific glucocorticoid receptors in and on
the cell. Nonspecific effects may also be brought about at high doses by
direct interaction with the cell membrane.{R-31} The effects are widespread but are, in some cases, specific to cell type. Therapeutic goals
usually take advantage of only a few of the effects produced by
glucocorticoids.
For specific indications
Adrenocortical insufficiency—Corticosteroids complex with receptors
specific to glucocorticoid or mineralocorticoid effects on the plasma
membrane and in the cytoplasm of target cells.{R-31} Some nonspecific
effects may also occur with cell membrane contact alone at high
hormone concentrations.{R-31} When receptor binding occurs, the
complex formed by the corticosteroid and its receptor moves into the
nucleus where it alters the expression of specific genes and thereby
changes the production of enzymes causing the reactions needed for
the maintenance of homeostasis and prevention of hypoadrenal shock.
Glucocorticoid effects include maintenance of fluid homeostasis,
maintenance of adrenergic receptor responsiveness, inhibition of
fibroblast proliferation, secretion of digestive enzymes and absorption
of fats, and hematopoietic and cardiovascular system function.
Although the activity is insignificant in glucocorticoids other than
hydrocortisone, prednisolone, and prednisone, mineralocorticoid
effects include increased reabsorption of chloride, sodium, and water
and increased excretion of calcium and potassium; extracellular fluid
volume is increased.{R-30; 33}
Inflammation—The exact mechanism of action for the glucocorticoids in
decreasing inflammation is not known{R-14} but they decrease or
prevent tissue responses to inflammatory processes,{R-30} thereby
reducing the symptoms of inflammation without affecting the underlying cause. They block the increase in permeability of capillaries that
occurs in inflammation, thereby reducing the transport of protein and
maintaining microcirculation.{R-31} Glucocorticoids contribute to cell
membrane stability; they reduce inflammation by reducing the
2004 The United States Pharmacopeial Convention, Inc.
response to kinins and toxins and by decreasing the formation of
histamine induced by cell injury.{R-31} They alter the distribution and
function of peripheral leukocytes, decreasing their numbers at the site
of inflammation.{R-14; 31} To accomplish this, they decrease the
vascular adherence of neutrophils and decrease diapedesis, thus
preventing neutrophils from reaching the site of inflammation,{R-36;
37}
and they also decrease macrophage response to migration
inhibiting factor.{R-30} In addition, glucocorticoids also decrease
production of cytokines and other mediators.{R-228}
Immunosuppression—In general, glucocorticoids are considered less
immunosuppressive than anti-inflammatory;{R-38} however, the spectrum of effects they produce can also be very effective in controlling the
effects of immune-mediated disease. Prevention of inflammatory
mediator release, inhibition of inflammatory cell migration to and
response in the site, reduced capillary permeability, and the prevention
of passage of immune complexes through endothelial and basement
membranes all provide beneficial effect in immune-mediated disease.{R38}
The functional capacity of monocytes, macrophages, and eosinophils is decreased via inhibition of the formation of interleukins, and
virus-induced interferon synthesis is inhibited.{R-31} The alteration of
the movement and circulation of leukocytes may alter the immune
response.{R-14; 31} Circulating neutrophilia and eosinopenia in many
species, as well as the lymphopenia and monocytosis seen in some
species in response to glucocorticoids, may affect immune response.
Cell-mediated immunity is more affected than humoral immunity and
T-cells more than B-cells by the presence of glucocorticoids.{R-31; 36;
193}
Antibody production generally is inhibited only with high doses or
with long-term administration.{R-31}
Ketosis—Cattle: When a glucocorticoid is administered, the concentration of glucose in the blood is increased through the synthesis of
glucose from amino acids (gluconeogenesis), a decrease in the
synthesis of protein from amino acids, and altered lipid metabolism,{R-30; 31} thereby satisfying the systemic demand for glucose and
helping to prevent the metabolism of fats and production of ketones.
Also, peripheral utilization of glucose is reduced and liver storage of
glycogen is increased.{R-35}
Spinal cord trauma, acute—Glucocorticoids may limit neural damage by
preserving microcirculation by vasodilation, scavenging for free
radicals, acting to control edema and inflammation, and blocking
lipid peroxidation.{R-43}
Induction of abortion and
Induction of parturition—
Cattle: The corticosteroids are believed to suppress progesterone
production by the placenta and adrenal gland and, when administered in the final days of pregnancy, mimic rising fetal cortisol to
stimulate the initiation of natural parturition. After approximately
150 days of gestation in cattle, it is postulated that the placenta
produces enough progesterone to maintain pregnancy even in the
absence of a corpus luteum up until about 250 days of gestation. The
luteolysis produced by administration of prostaglandin is not
sufficient to induce abortion during this period, but the combination
of dexamethasone and prostaglandin is very effective.{R-190; 191}
Although corticosteroids may induce abortion any time after about
180 days of gestation, the combination of corticosteroid and
prostaglandin is typically given to make abortion or early parturition
more predictable.{R-110-114}
Dogs: The production of cortisol by the fetus also is believed to be part
of the induction of parturition in dogs; therefore, the administration
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32 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
of exogenous glucocorticoids can be successful in inducing abortion
in dogs after 28 days of gestation.{R-118}
Other actions/effects:
Adrenal axis suppression—The administration of glucocorticoids for
purposes other than physiologic replacement therapy in adrenal
insufficiency will result in species-specific dose-dependent suppression
of the hypothalamic-pituitary-adrenal axis. In most species, high
serum concentrations of circulating endogenous and/or exogenous
glucocorticoids inhibit the production of adrenocorticotropic hormone
(ACTH) by the anterior pituitary gland, preventing the subsequent
stimulation of cortisol production by ACTH.{R-31} Because of various
other feedback loops, the administration of exogenous glucocorticoids
can suppress the synthesis and secretion of thyroid stimulating
hormone, follicle-stimulating hormone, prolactin and luteinizing
hormone, and growth hormone.{R-31; 33} The suppression of the
production of cortisol is species-dependent and also varies widely
depending on the glucocorticoid, the dose, and the duration of therapy.
Measurable suppression can last from one or two weeks to as long as
several months and prevention of hypoadrenal crisis may require
gradual withdrawal of medication. However, there are few reports of
hypoadrenal crisis in animals.{R-27} One source states that animals at
risk are generally considered to be those that were on greater than
physiological replacement dosing for more than 2 weeks, whose
treatment was discontinued in the last 6 weeks, and that are under
some form of physiologic stress, such as surgery.{R-27}
Bone effects—Glucocorticoids inhibit osteoblasts and stimulate osteoclasts, thereby inhibiting bone healing.{R-31}
Cardiovascular effects—Glucocorticoids have direct positive chronotropic
and inotropic actions on the heart.{R-31} They enhance vasoconstriction and decrease capillary permeability, including that induced by
inflammation.{R-31} Blood pressure is increased, most likely from
vasoconstriction and increases in blood volume. Beta-adrenergic
receptors are increased in number and affinity; their presence
potentiates the effects of beta-adrenergic agonists on bronchial smooth
muscle to the benefit of asthmatic patients.{R-31}
Central nervous system (CNS) effects—Glucocorticoids are essential for
normal adrenergic receptor sensitivity in the autonomic nervous
system.{R-30} CNS effects include mood and behavioral changes
(euphoria in human experience), maintenance of alpha rhythm,
diminished response to pyrogens, appetite stimulation, and lowering of
the seizure threshold.{R-30; 33}
Gastrointestinal effects—Glucocorticoids decrease the absorption of
calcium and iron from the gastrointestinal tract, aid in the absorption
of fat, increase secretion of acid, pepsin, and trypsin, and alter the
structure of mucin in human beings.{R-30}
Glucose, lipid, and protein metabolism—Glucocorticoids enhance lipolysis and mobilize fatty acids from adipose tissue; however, they also
stimulate appetite, which stimulates hyperinsulinemia and results in
lipogenesis.{R-31} Abnormal redistribution of fat can occur with longterm use. Glucocorticoids cause a decrease in synthesis of proteins and
an increase in degradation.{R-30; 31} With prolonged use, muscle
atrophy, thin skin, and delayed healing can result.{R-30}
Absorption:
Oral—In the dog, prednisolone and prednisone are absorbed rapidly and
reach significant serum concentrations in less that 30 minutes.{R-100}
2004 The United States Pharmacopeial Convention, Inc.
Parenteral—Esterification of a glucocorticoid affects its water and lipid
solubility and the rate at which it is absorbed from the injection site.{R30; 31}
Succinate and phosphate esters are the most water-soluble
esters and are rapidly absorbed from intramuscular, intravenous, or
subcutaneous administration.{R-30} Acetate and acetonide esters are
poorly water-soluble and result in slow and sustained absorption from
intramuscular depot injections.{R-30; 31}
Note: In the cow, 95% of an intramammary dose of 40 mg of
prednisolone is absorbed systemically within 3 hours;{R-73} less than
5% is recovered in the milk.{R-73}
Bioavailability—Dexamethasone:
Intramuscular administration—
Cattle: 67%, with a dose of 0.1 mg per kg of body weight (mg/kg).{R-70}
Horses: 67 to 72%, with a dose of 0.1 mg/kg.{R-70}
Oral—Horses: 61 ± 19%, with a total dose of 10 mg.{R-68}
Distribution: Volume of distribution—
Dexamethasone:
Cattle—Area: 1.1 to 1.2 liters per kg (L/kg).{R-70}
Dogs—Area:
1.85 ± 1.16 L/kg, with a 0.01 mg/kg dose.{R-60}
6.41 ± 2.75 L/kg, with a 0.1 mg/kg dose.{R-60}
1.11 to 1.29 L/kg, with a 1 mg/kg dose.{R-61}
Horses—
Area: 0.906 to 0.966 L/kg.{R-67}
Steady state: 1.73 ± 0.48 L/kg.{R-68}
Methylprednisolone: Dogs—
Area: 1.76 ± 0.55 L/kg.{R-66}
Steady state: 1.69 ± 0.53 L/kg.{R-66}
Prednisolone:
Cattle—Administered as the 21-sodium succinate ester: Area—2.19 ±
0.865 L/kg.{R-74}
Dogs—Administered as the sodium succinate ester:
Area—0.918 ± 0.107 L/kg.{R-65}
Steady state—0.494 L/kg.{R-102}
Horses—Administered as the 21-sodium succinate ester: Area—0.561
± 0.132 L/kg.{R-67}
Pigs—Apparent: 1.2 at 0.2 L/kg.{R-82}
Rabbits—Administered as the 21-sodium succinate ester: Steady
state—
1.44 L/kg, with a 0.15 mg/kg dose.{R-78}
2.14 L/kg, with a 3 mg/kg dose.{R-78}
Protein binding:
Dexamethasone—Rats: High (83%).{R-81}
Methylprednisolone—Rabbits: High (77%).{R-80}
Prednisolone—Dogs: Moderate to high (51 to 84%, dose-dependent).{R102}
Biotransformation: Hepatic metabolism is the main elimination pathway of corticosteroids in animals.{R-79} In addition, many glucocorticoids are administered in a form that must undergo hydrolysis or
hepatic biotransformation to become active. Prednisone and cortisone
are prodrugs that must be converted by the liver to prednisolone and
hydrocortisone, respectively, to have glucocorticoid activity.{R-34} The
glucocorticoid esters, such as prednisolone acetate, must be converted
to base form, in this case prednisolone, to be active.
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CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 33
Prednisone/prednisolone—In dogs, prednisone is rapidly converted by
the liver into prednisolone, and prednisolone is rapidly converted into
prednisone, although peak serum concentrations are consistently
twice as high for prednisolone as for prednisone regardless of which is
administered.{R-100} Hepatic metabolism of prednisone to active
prednisolone is considered rapid enough and the serum concentration
versus time curves similar enough for the two medications that the
effects of the administered prednisone compared to prednisolone{R-100}
should not be significantly different in dogs without severe hepatic
compromise.
Methylprednisolone/methylprednisone—In rabbits, methylprednisolone
is rapidly and reversibly converted to methylprednisone.{R-80} Plasma
concentration of methylprednisolone is generally greater than methylprednisone regardless of whether methylprednisolone or methylprednisone is administered;{R-80} however, methylprednisolone is
only 67 ± 15% available from methylprednisone in the rabbit.{R-80}
From ester to the active base—
Methylprednisolone acetate: Rapidly hydrolyzed in fresh blood in
vitro to methylprednisolone with a half-life of hydrolysis of about
20 minutes in human beings, 1.4 minutes in cats, and 14
minutes in cattle.{R-66; 120} However, in the dog only 46% of an
intramuscular dose of 4 mg/kg becomes available as methylprednisolone base.{R-66}
Methylprednisolone sodium succinate: Only 43% of an intravenous
dose becomes available as methylprednisolone base{R-66} in the dog.
Prednisolone acetate: Completely available as the prednisolone base
after intramuscular administration.{R-67}
Prednisolone 21-sodium succinate: Appears to be immediately hydrolyzed to prednisolone in the horse after intravenous administration.{R-67} Completely available as the prednisolone base after
intramuscular administration.{R-74}
Half-life:
Absorption—Intramuscular administration:
Dexamethasone—Cattle: 1.2 to 1.6 hours, with a dose of
0.1 mg/kg.{R-70}
Methylprednisolone acetate—Dogs: 69 hours, with a dose of 4 mg/
kg.{R-66}
Distribution—Intravenous administration:
Dexamethasone—
Cattle: 0.13 to 0.18 hour.{R-70}
Dogs: 0.13 to 0.5 hour.{R-60; 61}
Prednisone—
Dogs: 0.25 hour.{R-105}
Monkeys: 0.55 hour.{R-105}
Elimination—
Note: Because glucocorticoids act intracellularly, plasma half-life may
not correlate well with the duration of biological effect.
Intravenous administration:
Dexamethasone—
Cattle: 4.9 to 5.6 hours.{R-70}
Dogs:
3.2 hours, with a 0.01 mg/kg dose.{R-60}
6.9 hours, with a 0.1 mg/kg dose.{R-60}
2 to 2.3 hours, with a 1 mg/kg dose.{R-61; 70}
Horses: 0.88 hour;{R-67} 2.63 ± 1.19 hours.{R-68}
Hydrocortisone—Dogs: 0.91 ± 0.06 minutes.{R-103}
Methylprednisolone—
2004 The United States Pharmacopeial Convention, Inc.
Cattle: 1.43 ± 0.32 hours.{R-120}
Dogs: 1.35 ± 0.13 hours;{R-16} 1.67 to 2.64 hours.{R-66}
Horses: 2.87 ± 1.5 hours.{R-121}
Rabbits: 1.82 hours.{R-80}
Methylprednisone—Rabbits: 2.1 hours.{R-80}
Prednisolone—
Cattle: 3.61 ± 1.18 hours, administered as the sodium succinate
ester.{R-74}
Dogs:
1.3 hours, with a dose of 0.39 mg/kg.{R-16; 102}
0.25 to 0.88 hour, with a dose of 1.7 to 3.4 mg/kg, administered as
the sodium phosphate ester.{R-104}
2.77 ± 0.53 hours, with a dose of 8.8 mg/kg, administered as the
sodium succinate ester.{R-65}
Horses: 1.65 hours, administered as the 21-sodium succinate
ester.{R-67}
Pigs: 0.73 ± 0.15 hour.{R-82}
Prednisone—
Dogs: 1.4 hours.{R-105}
Monkeys: 1.3 hours.{R-105}
Triamcinolone—Dogs: 1.95 ± 0.12 hours.{R-103}
Intra-articular administration: Elimination of methylprednisolone after
methylprednisolone acetate administration:
Cattle—With a total dose of 200 mg:{R-120}
First phase—0.92 ± 0.44 hour.
Second phase—18.7 ± 6.7 hours.
Third phase—18.1 ± 3.4 days.
Horses—With a total dose of 110 mg:{R-121}
First phase—10 hours.
Second phase—4.79 days (range of 1.54 to 8.6 days).
Onset of action: Due to the nature of the glucocorticoids, comparative
measurement of action, such as anti-inflammatory effect, is difficult to
quantify in terms of a specific time of onset and duration. However,
knowledge of the relative speed of absorption may be used to make
therapeutic decisions when a rapid response is needed.
Parenteral—Intravenous administration is the most rapid route and
certain products have been developed specifically to allow for rapid
intravenous utilization, such as the sodium phosphate{R-11} and
sodium succinate{R-7} esters. However, these products will only act as
rapidly as their base glucocorticoids; methylprednisolone or prednisone
may provide the most rapid effect.
Intramuscular and subcutaneous administration also may be rapidly
absorbed and utilized but possible absorption delays tend to make these
routes less favored for emergency treatment.
Oral—Oral routes of administration can provide a fairly rapid onset of
action. Prednisone produces high serum concentrations and presumably early glucocorticoid effects within 30 minutes after administration to dogs.{R-100}
Concentrations:
Endogenous serum cortisol, baseline—
Cats: Ranges from 3 to 82.8 nanograms per mL (nanograms/mL)
(mean 17 ± 2.8).{R-140; 155}
Cattle: 3 to 15 nanograms/mL.{R-70; 74; 75; 120}
Dogs: 15.8 ± 8 nanograms/mL.{R-102}
Horses: 43 to 87 nanograms/mL.{R-67; 121; 151; 178}
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34 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
Sheep: 6.2 to 6.9 nanograms/mL.{R-76}
Note: In many species, endogenous serum cortisol has been described as
cyclicly influenced by photoperiod. In horses, serum cortisol has been
measured as lowest at 8 p.m. and highest at 8 a.m. with a significant
difference consistently measured between the high and low values.{R151}
In cats and dogs, there is no evidence that cortisol concentrations
vary in a circadian pattern.{R-155; 156; 208; 209}
Peak serum concentration—
Dexamethasone:
Intramuscular administration—Cattle: 42 to 44 nanograms/mL at
3.6 to 4.3 hours after a dose of 0.1 mg/kg.{R-70}
Intravenous—Horses: 20 to 35 nanograms/mL at 15 minutes after a
total dose of 5 mg per animal.{R-69}
Oral—Horses: 4.9 ± 0.17 nanograms/mL at 1.3 ± 0.5 hours, with a
total dose of 10 mg per animal.{R-68}
Prednisolone:
Intramuscular—
Cattle: 1.2 mcg/mL at 8 minutes after a dose of 0.6 mg/kg,
administered as the prednisolone 21-sodium succinate ester.{R-74}
Horses: 59 ± 13.5 nanograms/mL at 10 hours{R-67} after a dose of
0.6 mg/kg, administered as the prednisolone acetate ester.
Oral—Dogs: 242 nanograms/mL at 0.9 hours after a total dose of one
5-mg tablet per animal (0.53 to 0.29 mg/kg).{R-100}
Prednisone: Oral—Dogs: 205 nanograms of prednisolone per mL at 1.3
hours after a total dose of one 5-mg tablet per animal (0.53 to 0.29
mg/kg).{R-100}
Note: Peak serum prednisolone concentrations were always approximately twice as high as peak serum prednisone concentrations,
regardless of whether oral prednisolone or prednisone was administered;{R-100} however, the combined prednisone and prednisolone
areas under the serum concentration–versus–time curves were
similar for oral prednisone and prednisolone administration.{R-100}
Peak concentrations, other—Intra-articular administration:
Methylprednisolone acetate—
Cattle:
Serum methylprednisolone—7.8 ± 5.7 nanograms/mL at 4.5 ± 1.3
hours, with a total dose of 200 mg per animal (single joint
treated).{R-120}
Synovial methylprednisolone—4 mg/mL at 20 minutes, with a total
dose of 200 mg per animal (single joint treated).{R-120}
Horses:
Serum methylprednisolone—Less than 5 nanograms/mL for the first
24 hours after intra-articular administration, with a total dose of
110 mg.{R-121}
Synovial methylprednisolone—138 ± 83 mcg/mL at 2 hours and 174
± 175 mcg/mL at 10 hours, with a total dose of 110 mg.{R-121}
Note: Although variable and not well defined, synovial methylprednisolone concentrations are detectable for up to 39 days (range 4
to 39 days).{R-121}
Triamcinolone—Horses:
Serum triamcinolone—4.3 nanograms/mL at 4 hours, with a single
dose of 6 mg.{R-129}
Synovial triamcinolone—7.5 mcg/mL 1 day after injection, with a
single dose of 6 mg.{R-129}
Note: Synovial triamcinolone concentrations are detectable for up to
14 days.{R-129}
2004 The United States Pharmacopeial Convention, Inc.
Duration of action: Some sources have considered the duration of
anti-inflammatory effect of administered glucocorticoids to be similar
in length to the duration of suppression of endogenous hormone{R61}
and this is still used as a general indication of duration; however,
the limitations of these measurements should be considered. It has
been shown that some glucocorticoids, such as prednisone, can have
readily apparent effects without changing measurable adrenocortical
function.{R-134} In other situations, adrenocortical suppression may
continue even though there are no longer measurable serum levels{R-74} or clinical effects.{R-139} There are also species-specific and
animal-specific variations in duration of action and in potency in
treating a specific disorder.
The glucocorticoid bases, before their modification to form esters, have
been classified into groups for description of duration of action for
human beings, which may vary from duration in animals. This human
classification lists cortisone and hydrocortisone as short-acting bases
(8 to 12 hours).{R-34} Intermediate-acting bases (12 to 36 hours)
include methylprednisolone, prednisolone, prednisone, and triamcinolone.{R-34} Long-acting bases (36 to 72 hours) include dexamethasone and flumethasone.{R-31; 34} The formation of esters from these
bases can greatly alter solubility and rate of absorption, and, therefore,
duration of action.
Duration of suppression of endogenous cortisol concentrations:
Dexamethasone—
Cats:
Intravenous—Serum cortisol was suppressed below baseline concentration for 24 hours after a dose of 0.1 or 1 mg per kg of body
weight (mg/kg).{R-140}
Oral—32 hours below detectable concentrations after a dose of 0.1
mg/kg.{R-155}
Dogs: Intramuscular—2 to 4 hours of negligible cortisol concentration
and 24 to 48 hours until a return to baseline, with a dose of 1 mg/
kg.{R-61}
Horses:
Intramuscular—24 hours below detectable concentration and 4 to 7
days until a return to baseline after a dose of 0.05 mg/kg.{R-67; 145}
Intravenous—48 hours below baseline concentration after a dose of 0.2
mg/kg.{R-151} Suppression began 2 hours after administration.{R-151}
Oral—72 hours below baseline concentrations after a dose of 0.2 mg/
kg.{R-151} Suppression began 2 hours after administration.{R-151}
Pigeons: Intravenous—
Less than 24 hours below baseline concentration with a dose of 0.5
micrograms per kg of body weight (mcg/kg).{R-146}
52 hours below baseline concentration with a dose of 500 mcg/
kg.{R-146}
Methylprednisolone—Cats: Oral—Adrenocorticotropic hormone (ACTH)
response was suppressed on the day after administration of 2 mg/kg
every 12 hours for 1 week but had returned to normal 1 week after
treatment was discontinued.{R-139}
Methylprednisolone acetate—
Cattle: Intra-articular—6 weeks of below measurable or low concentrations and 11 weeks until a return to baseline after a dose of 200
mg of methylprednisolone acetate.{R-120}
Dogs: Intramuscular—3 to 4 weeks below baseline concentration after
administration of 2.5 mg/kg.{R-135} Adrenal response to adrenocorticotrophic hormone (ACTH) was suppressed for at least 5
weeks.{R-135}
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CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 35
Note: Even a subconjunctival injection of 10 mg/kg caused a
suppression of endogenous cortisol starting 2 days later and a
suppressed ACTH response for at least 9 days.{R-138}
Horses: Intra-articular—6 to 18 hours below baseline concentration
after an intra-articular injection of 120 mg as a total dose.{R-151}
Prednisolone—
Cattle: Intramuscular or intravenous—2 days below baseline concentration after a prednisolone sodium succinate dose of 0.6 mg/kg.{R74}
Horses: Intramuscular or intravenous—24 hours below baseline
concentration after a dose of 0.6 mg/kg.{R-67}
Pigeons: Intravenous—
Less than 24 hours below baseline concentration after a dose of
0.7 mcg/kg.{R-146}
48 hours below baseline concentration after a single dose of 3500
mcg/kg (3.5 mg/kg).{R-146}
Prednisolone acetate—
Cattle: Intramuscular—3 weeks below detectable concentrations and
6 weeks below baseline concentration after a prednisolone acetate
dose of 0.6 mg/kg; prednisolone was no longer detectable in the
blood after 6 days.{R-74}
Horses: Intramuscular—21 days below baseline concentration and
5 days at nondetectable or low concentrations after a dose of 0.6 mg/
kg.{R-67}
Prednisone—Dogs: Oral (4 weeks of therapy)—
Dose of 0.22 mg/kg every 24 hours: For 2 of 8 dogs tested, serum
cortisol was below the limits of the assay (1 mcg of cortisol per
decaliter of serum) after 4 weeks of therapy.{R-136} ACTH response
was suppressed beginning 1 week after treatment and remained
suppressed for most of the treatment period.{R-136}
Dose of 0.55 mg/kg every 24 hours: Below the limits of the assay (1
mcg of cortisol per decaliter of serum) after 1 week of therapy until at
least the end of therapy.{R-136} Suppression of ACTH response was
noted when first measured after 1 week of therapy and lasted at least
until the cessation of treatment.{R-136}
Dose of 0.55 mg/kg every 12 hours: Significantly reduced below
baseline after 14 days of therapy until a return to baseline 2 weeks
after the end of treatment.{R-137}
Dose of 1.1 mg/kg every 48 hours: Serum cortisol was not significantly
affected during the treatment period; however, suppression of ACTH
response was noted after 2 to 3 weeks of therapy.{R-136}
Triamcinolone—Horses:
Intra-articular—5 days below baseline concentration after a total dose
of 6 mg per animal (single joint treated).{R-129}
Intramuscular—8 days below detectable concentrations and 14 days
until a return to baseline concentration after a dose of 0.044
mg/kg.{R-145}
Elimination: Hepatic metabolism is the main elimination pathway of
corticosteroids in animals;{R-79} however, biliary excretion, renal
metabolism, and renal clearance contribute to a small degree in some
species.{R-79}
Dexamethasone—Total clearance:
Cattle—2.4 to 2.6 mL per minute per kg (mL/min/kg).{R-70}
Dogs—
5.41 ± 1.74 mL/min/kg, with a 0.01 mg/kg dose.{R-60}
9.67 ± 2.7 mL/min/kg, with a 0.1 mg/kg dose.{R-60}
6.4 to 6.57 mL/min/kg, with a 1 mg/kg dose.{R-61}
2004 The United States Pharmacopeial Convention, Inc.
Horses—
7.98 at 1.06 mL/min/kg, with a total dose of 10 mg per animal.{R-68}
12.4 to 12.9 mL/min/kg, with a dose of 0.05 mg/kg.{R-67}
Methylprednisolone—In the dog, 25 to 34% of an oral or intramuscular
dose of methylprednisolone acetate is eliminated in the urine and 27 to
52% in the feces.{R-101} Multiple metabolites are found in the urine
and feces.{R-101}
Total clearance:
Dogs—9 ± 1.2 mL/min/kg.{R-66}
Horses—14.7 mL/min/kg.{R-121}
Rabbits—8 mL/min/kg.{R-80}
Methylprednisone—Total clearance: Rabbits—30.4 mL/min/kg.{R-80}
Prednisolone—In the cow, 42 to 46% of an intravenous injection of
0.067 mg of prednisolone per kg of body weight is eventually
eliminated in the urine.{R-73} Less than 0.2% is distributed into the
milk and it has been assumed that the majority is eliminated in the
feces.{R-73}
Total clearance:
Cattle—7.5 ± 0.83 mL/min/kg (prednisolone administered as the
21-sodium succinate ester).{R-74}
Dogs—8.4 mL/min/kg; 3.96 ± 0.96 mL/min/kg (administered as the
sodium succinate ester).{R-65; 102}
Horses—3.92 ± 0.66 mL/min/kg (administered as the 21-sodium
succinate ester).{R-67}
Pigs—25.7 ± 2.1 mL/min/kg.{R-82}
Prednisone—Dogs: After an intravenous or oral dose of 1 mg/kg, 61 to
72% of the dose is excreted in the urine, but only 2% as unmetabolized
prednisone and 6% as prednisolone.{R-104; 105}
Triamcinolone—Dogs: Elimination is equally divided between feces and
urine after an intravenous dose of 2 mg/kg.{R-103} Only 20% of
injected radiolabeled triamcinolone is recovered as unchanged drug in
the urine, although 90% of the injected drug is recovered in 120
hours.{R-103}
PRECAUTIONS TO CONSIDER
SPECIES SENSITIVITY
Mice, rabbits, and rats: These species are considered steroid-sensitive
because the administration of glucocorticoids causes a rapid lymphopenia induced by lymphocytolysis rather than the redistribution of
circulating lymphocytes seen in other animal species, such as cattle,
dogs, goats, horses, and pigs.{R-36}
PREGNANCY/REPRODUCTION
All species: Corticosteroid administered systemically during the last
trimester of pregnancy may induce the first stage of parturition.{R-5; 6;
15; 18; 19}
If induced prematurely, labor may be followed by dystocia,
fetal death, retained placenta, and/or metritis.{R-5; 6; 15; 18; 19} The
likelihood of inducing abortion in ruminants is highest with the C16methylated products, such as dexamethasone or flumethasone.{R-213}
Risk of abortion is still present but to a lesser degree with administration of isoflupredone or prednisolone.{R-213}
Dogs: Offspring of dogs administered corticosteroids during pregnancy
have had congenital anomalies, such as cleft palate, deformed forelegs,
phocomelia (absence of the proximal part of a limb), or anasarca
(generalized, massive edema).{R-5; 6; 15; 19}
Rabbits and rodents: Corticosteroids administered during pregnancy have
caused cleft palate.{R-5; 6; 15; 19}
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36 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
LACTATION
Cattle:
Dexamethasone—Dexamethasone concentrations in milk have been
measured to be 0.3 to 0.5 times the plasma concentration in healthy
cows.{R-71; 72} Dexamethasone was measurable in the milk 15
minutes after intravenous administration and concentrations
declined at a rate similar to that in plasma. The half-life of 3 hours
for elimination from the milk compares to 4.5 hours measured for
plasma using an intravenous dose of 0.1 mg per kg of body weight
(mg/kg).{R-72}
Intramuscular administration of dexamethasone crystalline suspension or a combination of sodium phosphate and long-acting
phenylproprionate ester to ketotic cows at a dose of 0.06 mg per
kg of body weight (mg/kg) resulted in dexamethasone milk concentrations of up to 8.4 nanograms per mL twelve hours after
treatment.{R-105} Three days after administration, milk dexamethasone concentrations had dropped to 1 nanogram per mL.{R-205}
Flumethasone—Intramuscular administration of aqueous flumethasone at a dose of 0.014 mg/kg, to ketotic cows resulted in milk
concentrations of flumethasone of 0.7 to 1.2 nanograms per mL
twelve hours after treatment.{R-205}
Prednisolone—Less than 0.2% of an intravenous dose of 0.067 mg of
prednisolone per kg of body weight is distributed into the milk in
cows.{R-73}
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Anti-inflammatory drugs, nonsteroidal (NSAIDs)
(in any species, the concurrent administration of glucocorticoids with
nonsteroidal anti-inflammatory drugs may increase the risk of
gastrointestinal irritation or ulceration)
Aspirin
(in the rat, aspirin lowers the half-life and increases the clearance of
dexamethasone, probably by enhancing the hepatic metabolism;{R-81}
also, in any species, the concurrent administration of glucocorticoids
with nonsteroidal anti-inflammatory drugs may increase the risk of
gastrointestinal irritation or ulceration)
Norgestomet and estradiol valerate combination
(flumethasone{R-119} and possibly other corticosteroids can prevent or
delay the generally predictable estrus in response to norgestomet and
estradiol valerate in cattle)
Phenylbutazone
(in the rat, phenylbutazone suppresses the overall metabolism of
dexamethasone, including decreasing the absorption rate and bioavailability and lowering the renal and plasma clearance, thereby
increasing the half-life;{R-81} also, in any species the concurrent
administration of glucocorticoids with nonsteroidal anti-inflammatory
drugs may increase the risk of gastrointestinal irritation or ulceration)
Vaccines
(as in human beings, vaccination of animals that have been
given immunosuppressive doses of corticosteroids is not recom-
2004 The United States Pharmacopeial Convention, Inc.
mended;{R-194} short-term anti-inflammatory dosing of corticosteroids
is not considered to interfere significantly with antibody response to
vaccination,{R-203; 204} although there is not a preponderance of
research in this area)
HUMAN DRUG INTERACTIONS AND/OR RELATED
PROBLEMS{R-2}
In addition to the above drug interactions reported in animals, the
following drug interactions have been reported in humans, and are
included in the human monograph Corticosteroids—Glucocorticoid
Effects (Systemic) in USP DI Volume I; these drug interactions are
intended for informational purposes only and may or may not be
applicable to the use of corticosteroids in the treatment of animals:
Acetaminophen
(induction of hepatic enzymes by corticosteroids may increase the
formation of a hepatotoxic acetaminophen metabolite, thereby
increasing the risk of hepatotoxicity, when they are used concurrently with chronic or high-dose acetaminophen therapy)
Aminoglutethimide
(aminoglutethimide suppresses adrenal function so that glucocorticoid supplementation may be required; however, aminoglutethimide
accelerates the metabolism of dexamethasone so that dexamethasone half-life may be reduced twofold; hydrocortisone is recommended instead because its metabolism is not known to be altered by
aminoglutethimide and because its mineralocorticoid activity may
also be required)
Amphotericin B, parenteral, or
Carbonic anhydrase inhibitors
(concurrent use with corticosteroids may result in severe hypokalemia and should be undertaken with caution; serum potassium
concentrations and cardiac function should be monitored during
concurrent use)
(the use of hydrocortisone to control adverse reactions to amphotericin B has resulted in cases of cardiac enlargement and congestive
heart failure)
(concurrent use of corticosteroids with acetazolamide sodium may
increase the risk of hypernatremia and/or edema because cortico
steroids cause sodium and fluid retention; the risk with corticosteroids may depend on the patient’s sodium requirement as
determined by the condition being treated)
(the possibility should be considered that concurrent chronic use of
both carbonic anhydrase inhibitors and corticosteroids may increase
the risk of hypocalcemia and osteoporosis because carbonic anhydrase inhibitors also increase calcium excretion)
Anabolic steroids or
Androgens
(concurrent use with glucocorticoids may increase the risk of
edema; also, concurrent use may promote the development of severe
acne)
Antacids
(concurrent chronic use with prednisone or dexamethasone may
decrease absorption of these glucocorticoids; efficacy may be
decreased sufficiently to require dosage adjustment in patients
receiving small doses, but probably not in those receiving large
doses, of the corticosteroid)
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CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 37
Anticholinergics, especially atropine and related compounds
(concurrent long-term use with glucocorticoids may increase intraocular pressure)
Anticoagulants, coumarin- or indandione-derivative, or
Heparin or
Streptokinase or
Urokinase
(effects of coumarin or indandione derivatives are usually decreased
[but may be increased in some patients] when these medications are
used concurrently with glucocorticoids; dosage adjustments based on
prothrombin time determinations may be necessary during and after
glucocorticoid therapy)
(the potential occurrence of gastrointestinal ulceration or hemorrhage during glucocorticoid therapy, and the effects of glucocorticoids on vascular integrity, may cause increased risk to patients
receiving anticoagulant or thrombolytic therapy)
Antidepressants, tricyclic
(these medications do not relieve, and may exacerbate, corticosteroid-induced mental disturbances; they should not be used for
treatment of these adverse effects)
Antidiabetic agents, oral, or
Insulin
(glucocorticoids may increase blood glucose concentration; dosage
adjustment of one or both agents may be necessary during
concurrent use; dosage readjustment of the hypoglycemic agent
may also be required when glucocorticoid therapy is discontinued)
Anti-inflammatory drugs, nonsteroidal (NSAIDs)
(risk of gastrointestinal ulceration or hemorrhage may be increased
when these substances are used concurrently with glucocorticoids;
however, concurrent use of NSAIDs in the treatment of arthritis may
provide additive therapeutic benefit and permit glucocorticoid dosage
reduction)
Antithyroid agents or
Thyroid hormone
(changes in the thyroid status of the patient that may occur as a
result of administration, changes in dosage, or discontinuation of
thyroid hormones or antithyroid agents may necessitate adjustment
of corticosteroid dosage because metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients; dosage adjustment should be based on results of
thyroid function tests)
Asparaginase
(glucocorticoids, especially prednisone, may increase the hyperglycemic effect of asparaginase and the risk of neuropathy and
disturbances in erythropoiesis; the toxicity appears to be less
pronounced when asparaginase is administered following, rather
than before or with, these medications)
Cyclosporine
(seizures have been observed in patients receiving cyclosporine and
high doses of methylprednisolone)
Digitalis glycosides
(concurrent use with glucocorticoids may increase the possibility of
arrhythmias or digitalis toxicity associated with hypokalemia)
Diuretic
(natriuretic and diuretic effects of these medications may be
decreased by sodium- and fluid-retaining actions of corticosteroids,
and vice versa)
(concurrent use of potassium-depleting diuretics with corticosteroids
2004 The United States Pharmacopeial Convention, Inc.
may result in severe hypokalemia; monitoring of serum potassium
concentration and cardiac function is recommended)
(effects of potassium-sparing diuretics and/or corticosteroids on
serum potassium concentration may be decreased during concurrent
use; monitoring of serum potassium concentration is recommended)
Ephedrine or
Phenobarbital or
Phenytoin or
Rifampin
(concurrent use may increase the metabolic clearance of corticosteroids; corticosteroid dosage adjustment may be required during and
following concurrent use)
Estrogens
(estrogens may alter the metabolism and protein binding of
glucocorticoids, leading to decreased clearance, increased elimination half-life, and increased therapeutic and toxic effects of the
glucocorticoid; glucocorticoid dosage adjustment may be required
during and following concurrent use)
Folic acid
(requirements may be increased in patients receiving long-term
corticosteroid therapy)
Hepatic enzyme-inducing agents
(concurrent use may decrease the corticosteroid effect because of
increased corticosteroid metabolism resulting from induction of
hepatic microsomal enzymes)
Immunosuppressant agents, other
(concurrent use with immunosuppressant doses of glucocorticoids
may increase the risk of infection and possibly the development of
lymphomas or other lymphoproliferative disorders; these neoplasms
may be associated with Epstein-Barr virus infections; a few studies in
organ transplant patients receiving immunosuppressant therapy
indicate that progression of the neoplasm may be reversed after
immunosuppressant dosage is decreased or therapy is discontinued)
Isoniazid
(glucocorticoids, especially prednisolone, may increase hepatic
metabolism and/or excretion of isoniazid, leading to decreased
plasma concentration and effectiveness of isoniazid, especially in
patients who are rapid acetylators; isoniazid dosage adjustment may
be required during and following concurrent use)
Mexiletine
(concurrent use with glucocorticoids may accelerate mexiletine
metabolism, leading to decreased mexiletine plasma concentration)
Mitotane
(mitotane suppresses adrenocortical function; glucocorticoid supplementation is usually required during mitotane administration, but
higher doses than those generally used for replacement therapy may
be required because mitotane alters glucocorticoid metabolism)
Neuromuscular blocking agents, nondepolarizing
(hypokalemia induced by glucocorticoids may enhance the blockade
of nondepolarizing neuromuscular blocking agents, possibly leading
to increased or prolonged respiratory depression or paralysis [apnea];
serum potassium determinations may be necessary prior to administration of these agents)
Potassium supplements
(effects of these medications and/or corticosteroids on serum
potassium concentration may be decreased when these medications
are used concurrently; monitoring of serum potassium concentration
is recommended)
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38 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
Salicylates
(although concurrent use with glucocorticoids in the treatment of
arthritis may provide additive therapeutic benefit and permit
glucocorticoid dosage reduction, glucocorticoids may increase salicylate excretion and reduce salicylate plasma concentrations so that
the salicylate dosage requirement may be increased; salicylism may
occur when glucocorticoid dosage is subsequently decreased or
discontinued, especially in patients receiving large [antirheumatic]
doses of salicylates; also, the risk of gastrointestinal ulceration or
hemorrhage may be increased during concurrent use)
Sodium-containing medications or foods
(concurrent use with pharmacologic doses of glucocorticoids may
result in edema and increased blood pressure, possibly to hypertensive levels)
(although patients receiving replacement doses of glucocorticoids
may require sodium supplementation, adjustment of dietary sodium
intake may be required when a medication having a high sodium
content is also administered concurrently)
Somatrem or
Somatropin
(inhibition of the growth response to somatrem or somatropin may
occur with chronic therapeutic use of glucocorticoids above certain
doses)
Troleandomycin
(troleandomycin may decrease metabolism of methylprednisolone
and possibly other glucocorticoids, leading to increased plasma
concentration, elimination half-life, and therapeutic and toxic effects;
glucocorticoid dosage adjustment may be required during and
following concurrent use)
Vaccines, live virus, or other immunizations
(administration of live virus vaccines to patients receiving pharmacologic [immunosuppressant] doses of glucocorticoids may potentiate
replication of the vaccine virus, thereby increasing the risk of the
patient developing the viral disease, and/or decrease the patient’s
antibody response to the vaccine and is not recommended; the
patient’s immunologic status should be evaluated prior to administration of a live virus vaccine; also, immunization with oral
poliovirus vaccine should be postponed in persons in close contact
with the patient, especially family members)
(other immunizations are not recommended in patients receiving
pharmacologic [immunosuppressant] doses of glucocorticoids because of the increased risk of neurological complications and the
possibility of decreased or absent antibody response)
(immunizations may be administered to patients receiving glucocorticoids via routes or in quantities that are not likely to cause
immunosuppression, for example, those receiving local injections,
short-term [less than 2 weeks] therapy, or physiologic doses)
LABORATORY VALUE ALTERATIONS
The following have been selected on the basis of their potential clinical
significance (possible effect in parentheses where appropriate)—not
necessarily inclusive (» = major clinical significance):
With diagnostic tests
Skin tests, intradermal
(dogs have significantly reduced responses to intradermally injected
histamine phosphate solution for at least 6 days after a single
intramuscular injection of 2.2 mg of prednisone per kg of body
weight or 0.22 mg of triamcinolone per kg of body weight{R-134})
2004 The United States Pharmacopeial Convention, Inc.
With physiology/laboratory test values
Adrenal function as assessed by ACTH stimulation or measurement of
plasma or urinary free cortisol
(may be decreased with chronic glucocorticoid treatment{R-31})
Alanine aminotransferase (ALT [SGPT]){R-5; 19; 148} and
Alkaline phosphatase (ALP){R-5; 19; 147; 148} and
Gamma-glutamyltransferase (GGT){R-147; 148}
(values may be increased in dogs, horses, and possibly other species)
Amylase, serum and
Lipase, serum
(in dogs, amylase may be increased or decreased; lipase may be
increased without clinical pancreatitis{R-161})
Eosinophil count
(in dogs and other species, eosinopenia may occur{R-152; 153; 161})
Globulins, alpha-2/haptoglobin
(although the significance is not known, alpha-2-globulin measured
in the serum will increase in dogs{R-152} and sheep; the increase may
be primarily the haptoglobin component{R-154})
Glucose
(hyperglycemia may occur)
Lymphocyte count
(in dogs and rodents, count may be decreased;{R-36; 153; 161} in cattle
and cats, it is less likely to be altered{R-36})
Monocyte count
(in dogs, count may be increased;{R-156; 161} in other species, it is less
likely to be altered{R-36})
Neutrophil count
(in cattle, dogs, goats, lambs, and other species, count may be
increased{R-36; 156; 161})
Testosterone, serum
(in bulls and rams, dexamethasone can decrease serum testosterone
levels{R-169; 170})
Triiodothyronine (T3) and
Thyroxine (T4), total and free and
Thyrotropin stimulation test (TSH) and
Thyrotropin-releasing hormone test (TRH)
(in dogs, with anti-inflammatory dosing [oral prednisone, 0.55 mg/
kg every 12 hours], baseline serum T3 is reduced while T4 is
unaffected and the thyroid becomes hyper-responsive to TSH after 2
to 4 weeks;{R-130} with immunosuppressive dosing [oral prednisolone, 1.1 mg/kg every 12 hours], T3, T4, and fT4 are decreased as
early as 24 hours after initiation of treatment, but response to TSH
and TRH tests is increased, allowing the latter two tests to be used to
differentiate primary hypothyroidism from changes due to prednisolone administration;{R-131} in horses, 5 days of treatment with
dexamethasone [intramuscular, 0.04 mg/kg every 24 hours] can
significantly blunt TSH response so that normal horses do not show
the twice baseline T4 concentration response considered normal{R133}
)
HUMAN LABORATORY VALUE ALTERATIONS{R-2}
In addition to the above laboratory value alterations reported in animals,
the following laboratory value alterations have been reported in
humans, and are included in the human monograph Corticosteroids—Glucocorticoid Effects (Systemic) in USP DI Volume I; these drug
interactions are intended for informational purposes only and may or
may not be applicable to the use of corticosteroids in the treatment of
animals:
All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 39
With results of dexamethasone suppression tests
Due to other medications
Benzodiazepines (high doses) or
Cyproheptadine (high doses) or
Glucocorticoid therapy, long-term or
Indomethacin
(may cause false-negative results in test for endogenous depression)
Ephedrine or
Estrogens (high doses) or
Hepatic enzyme–inducing agents
(may cause false-positive results in tests for Cushing’s disease or
endogenous depression)
Due to medical problems or conditions
Adrenal hyperfunction (Cushing’s syndrome) or
Carcinoma, disseminated, with concurrent serious infection or
Cardiac failure or
Dehydration or
Diabetes mellitus, unstable or
Fever or
Hypertension or
Malnutrition leading to extreme weight loss, recent or
Pregnancy or
Renal failure or
Temporal lobe disease
(may cause false-positive results in test for endogenous depression)
Adrenal insufficiency or
Hypopituitarism
(may cause false-negative results in test for endogenous depression)
With other diagnostic test results
Brain imaging using sodium pertechnetate Tc 99m, technetium Tc
99m gluceptate, or technetium Tc 99m pentetate
(uptake of these diagnostic aids into cerebral tumors may be
decreased in patients receiving large doses of glucocorticoids because
of glucocorticoid-induced reduction of peritumor edema)
Gonadorelin test for hypothalamic-pituitary-gonadal axis function
(glucocorticoids may alter the results of the gonadorelin test by
affecting pituitary secretion of gonadotropins through a complicated
feedback mechanism)
Nitroblue-tetrazolium test
(false-negative test results may occur)
Protirelin test for thyroid function
(physiologic doses of corticosteroids have no effect, but pharmacologic doses may reduce the thyroid-stimulating hormone response to
protirelin; however, withdrawal of corticosteroids in patients with
known hypopituitarism is generally not recommended)
Skeletal imaging using technetium Tc 99m medronate, technetium Tc
99m oxidronate, or technetium Tc 99m pyrophosphate
(long-term use of glucocorticoids may induce bone calcium depletion, thus causing decreased bone uptake of these diagnostic aids)
Skin tests, including tuberculin and histoplasmin skin tests and patch
tests for allergy
(reactions may be suppressed, especially with daily administration of
large doses of corticosteroids)
Thyroid 123I or 131I uptake
(may be decreased)
With physiology/laboratory test values
Calcium, serum
(concentrations may be decreased)
2004 The United States Pharmacopeial Convention, Inc.
Glucose, blood and urine
(concentrations may be increased because of intrinsic hyperglycemic
activity)
Hypothalmic-pituitary-adrenal (HPA) axis function as assessed by:
Adrenocorticotropic hormone (ACTH, corticotropin) or
Cortisol, blood or
Cortisol, urine or
17-Hydroxycorticosteroids, urine (17-OHCS) or
17-Ketosteroids, urine (17-KS)
(concentrations may be decreased with pharmacologic doses of
glucocorticoids)
Lipid (fatty acid), serum
(concentrations may be increased)
Platelet count
(may be increased or decreased)
Polymorphonuclear leukocyte count
(may be increased)
Potassium, serum
(concentrations may be decreased because of increased potassium
excretion, especially with agents having significant
mineralocorticoid activity)
Sodium, blood
(concentrations may be increased because of sodium retention,
especially with glucocorticoids having significant mineralocorticoid
activity)
Uric acid, serum
(concentrations may be increased in patients with acute leukemia;
may be decreased in other patients because of weak uricosuric
effect)
White blood cell count
(may be decreased)
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
given in parentheses where appropriate)—not necessarily inclusive (»
= major clinical significance).
Except under special circumstances, this medication should not be
used when the following medical problems exist:
For intra-articular injection
» Fracture, intra-articular
(healing may be retarded)
» Infection, periarticular
(intrasynovial, intratendinous, or other injections for local effect
should not be performed when acute infections are present{R-15;16})
For all routes of administration
Corneal ulcers{R-14}
(in corneal ulceration that is not due to underlying disorders
responsive to glucocorticoids, the ability to fight infection may be
suppressed and healing delayed with administration of either
ophthalmic or systemic corticosteroids; ophthalmic corticosteroids
are generally considered contraindicated if corneal ulceration exists;
systemic corticosteroids are thought by many to pose a much lower
risk of exacerbating a corneal ulcer, although no corroborating
evidence to confirm this could be found{R-223})
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40 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
» Gastrointestinal ulcers{R-14; 15; 16}
(may be exacerbated by glucocorticoid administration)
Hyperadrenocorticism (Cushing’s syndrome){R-5; 6; 14; 15; 16}
(with the exception of dexamethasone suppression tests, the administration of glucocorticoids to hyperadrenal animals is counterproductive)
» Infections, bacterial, uncontrolled or
» Infections, viral{R-14} or
» Mycosis, systemic{R-164; 165} or
» Tuberculosis{R-14; 15; 16; 22}
(may be exacerbated; the ability of the immune system to combat
infections may be compromised with pharmacologic doses of glucocorticoids, particularly with systemic mycoses, mycobacterial infections, or infections that are refractory to therapy)
Risk-benefit should be considered when the following medical
problems exist:
For all routes of administration
Abdominal surgery, extensive
Bone fractures, severe or
Tissue damage, extensive, other
(corticosteroids can delay tissue healing and should be used with
caution in patients with massive bone fractures or extensive
abdominal surgery; if corticosteroids are used due to life-threatening
events, a short- to intermediate-acting medication should be administered for the shortest period possible{R-213})
Congestive heart failure{R-5; 6; 14; 15; 16} or
Hypertension{R-14; 15; 16}
(may be exacerbated; glucocorticoids have direct chronotropic and
ionotropic actions on the heart and also enhance vasoconstriction
and decrease capillary permeability, thereby increasing blood
pressure{R-31})
Diabetes mellitus{R-5; 6; 14; 15; 16}
(glucocorticoids may increase insulin requirement{R-14})
Renal function impairment{R-5; 6; 14; 15; 16}
(agents with mineralocorticoid effects may increase fluid retention
and edema)
Thrombophlebitis{R-14; 15; 16}
(may increase risk of thrombophlebitis)
PATIENT MONITORING
The following may be especially important in patient monitoring (other
tests may be warranted in some patients, depending on condition; » =
major clinical significance):
Adrenal reserve
(signs of iatrogenic adrenal insufficiency should be monitored after
long-term glucocorticoid therapy and the adrenocorticotropic hormone [ACTH] stimulation test may be performed during or after
administration)
SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their
potential clinical significance (possible signs and, for humans, symptoms in parentheses where appropriate)—not necessarily inclusive:
THOSE INDICATING NEED FOR MEDICAL ATTENTION
Incidence unknown
2004 The United States Pharmacopeial Convention, Inc.
All species
Allergic reactions, specifically anaphylactoid reactions;{R-20}
anorexia—uncommon;{R-5; 14; 22} bone resorption or inhibition
of bone growth;{R-30; 33} collagen synthesis inhibition;{R-30; 33}
decreased growth rate;{R-171} delayed bone and wound healing;{R-19} diarrhea;{R-5; 14; 22} suppression of endogenous steroid
production;{R-6} fever, reduced;{R-19} gastrointestinal irritation/
ulceration/perforation;{R-166; 167} hematopoietic changes; hypotension, acute—may occur with rapid parenteral administration of
formulations containing polyethylene glycol or propylene glycol as a
vehicle;{R-127} hypertension;{R-31} negative nitrogen balance;{R19}
panting;{R-31} potassium loss, sodium retention, and fluid
retention{R-214}—may occur with corticosteroids having some
mineralocorticoid effects, such as hydrocortisone, isoflupredone,
prednisolone, or prednisone; recrudescence of latent infections{R159}
or decreased resistance to infectious agents;{R-19; 159; 160;
164; 165}
suppressed inflammation;{R-19} weight gain or weight
{R-5; 6; 14; 18}
loss
Note: Administration of corticosteroids always has the potential for
causing a suppression of endogenous production of steroids.{R-6} The
likelihood and degree of suppression increases with length of therapy.
Gastrointestinal irritation/ulceration/perforation are considered most
likely with high doses or long-term administration of corticosteroids.
Colonic perforation has been noted as a sequela to neurosurgery, in
particular, surgery for intervertebral disk herniation, and the high
doses of corticosteroids typically administered before and after
surgery.{R-166} Gastrointestinal perforation and other serious gastrointestinal problems have been considered uncommon side effects of
short-term corticosteroid therapy, but certain factors, such as surgery
or the administration of high doses, may increase the incidence.{R-166}
Hematopoietic changes vary from species to species. Mature circulating
neutrophilia occurs in many species, including cattle, dogs, goats, and
lambs, but in the early response this is considered primarily a
redistribution, rather than an increase in production.{R-36} Lymphopenia occurs in dogs and rodents; however, in dogs this occurs by
redistribution and in mice, rabbits, and rats, it occurs from direct
cytotoxicity.{R-36} In cats and cattle, lymphopenia is not a predictable
finding.{R-36} Although decreased monocyte counts occur in human
patients with corticosteroid administration, monocytosis occurs in
dogs and monocyte count responses are not otherwise significant in
other species.{R-36}
Increased protein degradation and conversion of proteins to carbohydrates lead to a negative nitrogen balance or catabolic state with
administration of corticosteroids.{R-19}
Reduced fever and suppressed inflammation become side effects when they
are undesirable, as in cases where signs of infection are suppressed and
more serious infection is allowed to occur before diagnosis.
Glucocorticoids alter the immune system through a variety of effects
on cells and cell mediators.{R-38} Recrudescence of latent infections{R-159}
or decreased resistance to infectious agents can occur, although the
specific situations in which they will occur is not always easily
predicted. One study investigated the effects of immunosuppressive or
anti-inflammatory dosages of prednisolone administered with doxycycline to dogs experimentally infected with Rickettsia rickettsii.{R-207}
They found no significant change in outcome in this disease model,
other than an increased duration of rickettsemia with immunosuppressive, but not anti-inflammatory, dosing. There was a mild decrease
in diagnostic antibody titers but comparison of acute and convalescent
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CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 41
titers was not affected.{R-207} Immunosuppressive therapy can obviously affect defenses against pathogens, but even with the administration of lower doses the beneficial effects must be weighed against the
cell inhibitory effects in the face of infection.
Cats
Diarrhea;{R-5; 19} vomiting{R-5; 19}
Note: Although cats are reported to be more resistant to the effects of
corticosteroids than dogs{R-156} and there are few documented side/
adverse effects, many of the effects listed for dogs and all species are
considered potential feline problems with sufficient dose and duration
of administration.
Cattle
Decreased milk production, temporary;{R-215; 216} hypokalemia
syndrome;{R-214} sperm defects;{R-169} termination of pregnancy{R-110-114; 190; 191}
Note: Hypokalemia has been noted in cattle prone to anorexia or ketosis
when treated with repeated doses of isoflupredone,{R-214} a corticosteroid with some mineralocorticoid effect. It is not yet known what
dairy management factors may also contribute to this effect.
A significant rise in visible sperm defects occurs after intramuscular
administration of 20 mg of dexamethasone a day as a total dose
(approximately 0.04 mg/kg) for 7 days;{R-169} the effects appear to
be reversed within 6 weeks of the end of treatment.
Termination of pregnancy will occur with administration of C16methylated corticosteroids, including dexamethasone and flumethasone, beginning in mid-gestation to end of gestation.
Dogs
Adrenocortical atrophy;{R-136} alopecia;{R-38} calcinosis cutis;{R38}
diabetes mellitus;{R-158} diarrhea;{R-5; 14; 19; 22} ecchymosis;{R14}
hematopoietic changes, including neutrophilia, lymphopenia,
and eosinopenia;{R-38} hepatopathy (hepatomegaly);{R-20; 148} hyperadrenocorticism (Cushing’s syndrome) (decreased hair growth,
hepatomegaly, lethargy, muscle weakness and atrophy,{R-30; 38}
pendulous abdomen, polyuria/polydipsia, skin atrophy{R-30; 33;
38}
)—generally with prolonged use and/or high dosage; hyperglycemia{R-38} from gluconeogenesis and possibly insulin resistance;{R-157} hyperlipidemia, fasting;{R-136} increased appetite;
inelasticity of skin;{R-38} osteoporosis, increased incidence
of—primarily in older dogs;{R-19} polydipsia/polyuria;{R-5; 14; 148}
termination of pregnancy;{R-118} thyroid hormone metabolism
alterations;{R-132} urinary tract infection—up to 40% of dogs on
chronic corticosteroid therapy for 6 months to 5 years;{R-163}
vomiting{R-5; 14; 19}
Note: After 2 weeks of oral prednisolone given at a dose of 0.55 mg per
kg of body weight a day, dogs showed evidence of adrenocortical
atrophy, fasting hyperlipidemia, focal hepatocellular fatty changes, and
skin atrophy.{R-136}
The circumstances predisposing to the appearance of diabetes mellitus
in dogs with iatrogenic or spontaneous hyperadrenocorticism are
unclear; it is not known whether animals must have subclinical
diabetes for the clinical disorder to occur or if glucocorticoids may
potentially damage or alter beta cell function through induction of
hyperglycemia. An additional factor may be the production of insulin
resistance in tissues. Diabetes mellitus has been reported in a dog
treated with methylprednisolone pulse therapy.{R-158}
Hepatopathy or liver changes associated with glucocorticoid administration have been noted in some cases as early as the day after
initiation of treatment,{R-148} but the degree and pattern of the
2004 The United States Pharmacopeial Convention, Inc.
response varies.{R-152} Hepatocytes become swollen and vacuolated{R-148; 149; 152} and this initially may be due to hepatocellular
accumulation of glycogen,{R-148; 149} of water, or of some combination of components. Laboratory value alterations associated with
glucocorticoid administration include increased serum gammaglutamyltransferase (SGGT; 23-fold increase in one study{R-148}),
serum alkaline phosphatase (ALP; 64-fold in one study{R-148}),
alanine aminotransferase (ALT [SGPT]; 10-fold in one study{R-148})
and normal to increased sulfobromophthalein sodium excretion test
(BSP);{R-38; 147-150} however, alterations in enzymes are not always
proportional to degree of histologic change in hepatic tissue.{R-152}
Severe hepatocellular changes may be present before enzymes are
significantly elevated.{R-152} Although the predominance of ALP
compared to the elevation of other enzymes is considered a marker of
cholestasis,{R-147; 148} there is no evidence of cholestasis in dogs with
steroid hepatopathy. The increased serum ALP activity has been
shown to be the result of enzyme induction.{R-148} Steroid hepatopathy is considered reversible in many dogs when corticosteroid
therapy is ended; however, the return to normal may be prolonged in
some animals.{R-150}
Chronic administration (‡ 35 days) of glucocorticoids in doses as low
as those required for anti-inflammatory effects in dogs significantly
changes the peripheral metabolism of thyroid hormones T4 and T3 by
changing their binding to carrier proteins, altering their distribution,
and by reducing T3 production from T4.{R-132} Glucocorticoids also
affect thyroid metabolism by affecting the hypothalamic-pituitarythyroid axis.{R-132}
Urinary tract infections are as likely to occur in dogs receiving longterm alternate-day anti-inflammatory therapy as in those treated
daily.{R-163}
Abnormal amylase and lipase values can occur in dogs in response to
glucocorticoids without clinical pancreatitis.{R-161} A definite connection between long-term corticosteroid administration and induction of clinical pancreatitis has not been shown, although mild
pancreatic inflammation has been demonstrated.{R-101} The risk of
pancreatitis may be increased by concurrent administration of a
glucocorticoid with azathioprine.{R-127}
Horses
Hepatopathy—rare;{R-150} laminitis—has been reported in association with dexamethasone, methylprednisolone, and triamcinolone
administration; {R-5; 22; 77; 150} lethargy—with doses higher than
labeled doses;{R-6} long, shaggy haircoat (hirsutism){R-38}
With intra-articular injections
Arthritis, septic;{R-128} increased inflammation (postinjection
flare-up){R-15; 16}
Rabbits
Hepatopathy{R-20}
Sheep
Appetite, decreased;{R-76} thyroid hormone metabolism alterations—decreased plasma thyroxine;{R-168} shedding of or slowed
growth of wool—the decrease in wool growth and the amount of
shedding is dose-related{R-76; 168}
THOSE OCCURRING PRINCIPALLY AFTER MEDICATION
IS DISCONTINUED, INDICATING NEED FOR MEDICAL
ATTENTION
All species
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42 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
Hypoadrenocorticism, acute{R-38} (lethargy, malaise, collapse, death)
Note: Rapid withdrawal of administered corticosteroids can lead to
acute hypoadrenocorticism in animals with insufficient production of
corticosteroids; however, because reports of this effect are rare, it is
unknown how much risk occurs for most animals; animals
undergoing sudden physiologic stress are believed to be most at
risk of adrenal crisis.{R-6; 27; 136}
HUMAN SIDE/ADVERSE EFFECTS{R-2}
In addition to the above side/adverse effects reported in animals, the
following side/adverse effects have been reported in humans, and are
included in the human monograph Corticosteroids—Glucocorticoid
Effects (Systemic) in USP DI Volume I; these side/adverse effects are
intended for informational purposes only and may or may not be
applicable to the use of corticosteroids in the treatment of animals:
Incidence more frequent
Gastrointestinal irritation; increased appetite; indigestion;
nervousness or restlessness; trouble in sleeping; weight gain
Incidence less frequent or rare
Burning, numbness, pain, or tingling at or near injection site;
changes in skin color or hypopigmentation; congestive heart
failure—in susceptible individuals; diabetes mellitus; dizziness or
lightheadedness; flushing of face or cheeks; generalized allergic
reaction; headache; hiccups; increased joint pain—following
intra-articular injection; increased sweating; infection at injection site; local allergic reaction; psychic disturbances such as
delirium, disorientation, euphoria, hallucinations, manicdepressive episodes, mental depression, or paranoia; sudden
blindness; vertigo
Note: Flushing of face or cheeks may persist for 24 to 48 hours.
Hypopigmentation is more likely at the injection site.
Increased joint pain may occur within a few hours postinjection and
persist for up to 48 hours.
Psychic disturbances are more likely in patients with chronic
debilitating illnesses that predispose them to psychic disturbances
and in patients receiving higher daily dosages. Psychic disturbances
may be related to dose rather than duration of therapy; symptoms
may appear within a few days to 2 weeks after initiation of therapy
and are usually associated with doses equivalent to 40 mg or more
of prednisone per day. Additionally, euphoria or fear of relapse may
lead to psychological dependence or abuse of corticosteroids.
Sudden blindness following injection into sites in the head or neck
area, such as nasal turbinates or scalp, is due to possible entry of
drug crystals into ocular blood vessels.
For triamcinolone
Loss of appetite
With intravenous administration
Anaphylaxis, generalized; cardiac arrythmias; flushing of face
or cheeks; seizures
Note: Rapid intravenous administration of high doses of corticosteroids has
been reported to cause convulsions, angioedema and/or anaphylactic reactions, and sudden death associated with cardiac arrhythmias.
Monitoring of the electrocardiogram (ECG) is recommended. Equipment, medications, and trained personnel necessary for treating
these complications should be immediately available.
Those occurring principally during long-term use indicating need for
medical attention
2004 The United States Pharmacopeial Convention, Inc.
Acne; adrenal suppression; avascular necrosis; cataracts, posterior subcapsular; Cushing’s syndrome effects, including
filling or rounding out of face, hirsutism, hypertension,
menstrual irregularities, muscle weakness, or striae; cutaneous
or subcutaneous tissue atrophy—with frequent repository injections; ecchymosis; fluid and sodium retention; glaucoma with
possible damage to optic nerves; growth suppression in children; hypokalemic syndrome; impaired wound healing; increased intracranial pressure; ocular infection, secondary,
fungal or viral; osteoporosis or bone fractures—includes vertebral compression and long bone pathologic fractures; pancreatitis;
peptic ulceration or intestinal perforation; scarring at injection
site; steroid myopathy; tendon rupture; thin, fragile skin
Those occurring principally after medication is discontinued, indicating a corticosteroid withdrawal syndrome
Withdrawal syndrome (abdominal or back pain, dizziness, fainting,
frequent or continuing unexplained headaches, low-grade fever,
muscle or joint pain, nausea, prolonged loss of appetite, rapid weight
loss, reappearance of disease symptoms, shortness of breath, unusual
tiredness or weakness, vomiting)
Note: Too-rapid withdrawal of therapy, especially after prolonged use,
may cause acute, possibly life-threatening, adrenal insufficiency and/
or a withdrawal syndrome not related to HPA axis suppression.
Note: The risk of adverse effects with pharmacologic doses of corticosteroids generally increases with the duration of therapy and frequency
of administration and, to a lesser extent, with dosage.
Chronic administration of physiologic replacement doses of corticosteroids rarely causes adverse effects.
Administration of glucocorticoids via local injection reduces the risk of
systemic effects. The risk of both systemic and local adverse effects is
still present to a degree, however, and increases with the frequency of
injections.
Pharmacologic doses of glucocorticoids lower resistance to infection;
the patient may be predisposed to systemic infections during, and for a
time following, therapy. Increased susceptibility to infection may occur
with short-term high-dose use (pulse therapy) as well as with more
prolonged use. Also, symptoms of onset or progression of infections
may be masked.
OVERDOSE
For more information in cases of overdose or unintentional ingestion,
contact the American Society for the Prevention of Cruelty to
Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation)
and/or the drug manufacturer.
Corticosteroids are synthesized hormones intended to act in a similar
fashion to endogenous hormones; therefore, toxicity tends to occur in
the midst of a variety of natural responses to therapy that the clinician
may expect during treatment, particularly with higher doses. An
overdose tends to be defined as the point at which adverse effects
outweigh beneficial effects rather than a specific mg per kg of body
weight dose known to cause a toxic reaction. The point at which the
array of effects induced by hormones becomes an overdose varies
among individual animals and among species. A single high dose may
be intolerable or even fatal if an animal develops a severe effect, such
as a perforated bowel, while another animal repeatedly given the same
dose tolerates and benefits from the therapy with only minor side
effects. Because side effects often occur and severe effects are not
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CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 43
clearly predictable, some might define a toxicity situation as one in
which an animal is on more medication than is minimally necessary to
control disease and develops serious side effects.
CLINICAL EFFECTS OF OVERDOSE
The following effects have been selected on the basis of their potential
clinical significance (possible signs in parentheses where appropriate)—not necessarily inclusive:
Note: The acute effects listed below may be associated with a shortterm (1 to 4 days) high-dose administration.
Acute effects
All species
Diarrhea; muscle weakness;{R-30} polyuria/polydipsia;{R-1, 5, 14, 148}
sodium and fluid retention and potassium loss—associated with
medications that have mineralocorticoid effects{R-6}
Chronic effects
All species
Hyperadrenocorticism (encompassing some or all of the side effects
that can occur with pharmacologic glucocorticoid administration; see
the Side/Adverse Effects section); vulnerability to hypoadrenal
crisis—with cessation of therapy
TREATMENT OF OVERDOSE
Discontinuation of therapy. Usually, a gradual withdrawal to avoid
adrenal crisis is the primary treatment. When long-term treatment is
essential to an animal, modification of dosing, such as alternate-day
therapy, may be instituted to minimize adverse effects.
Supportive treatment, such as medication to treat infection or gastrointestinal disorders, also may be necessary.
CLIENT CONSULTATION
In providing consultation, consider emphasizing the following selected
information:
Following dosage and length-of-treatment recommendations
Encouraging clients to communicate with the veterinarian about
disease management, particularly in cases that require long-term
therapy; noting the decrease in disease symptoms and the incidence
of side effects in patients
Risks of sudden withdrawal of medication after moderate- to long-term
therapy
VETERINARY DOSING INFORMATION
Because the glucocorticoids affect every cell in the body in often
beneficial but potentially negative ways, it is important to administer
these medications to produce the maximum positive effect necessary
with the least side effects produced. The choice of dose of corticosteroid
in the treatment of disorders in animals is inherently an empirical
process. The clinician must individualize the dosage regimen using
recommended guidelines for treatment of the disorder, the animal’s
signalment and concurrent medical conditions, the animal’s response
to medication, and other factors. The primary guideline is always the
smallest dose for the shortest amount of time necessary to gain
effective control of signs. However, for some difficult-to-control
disorders, such as autoimmune diseases, high initial doses may be
required until signs are controlled.
2004 The United States Pharmacopeial Convention, Inc.
Physiologic or replacement dosing is administered to hypoadrenal animals
for maintenance.
Pharmacologic therapy is the administration of corticosteroids at doses
higher than natural levels of corticosteroids to produce a desired
therapeutic effect—
Anti-inflammatory dosing: Often the lowest pharmacologic doses are
necessary to control inflammation and signs of allergies.
Immunosuppressive dosing: Glucocorticoids are primarily anti-inflammatory medications and much higher doses are often required to
control signs of immune-mediated disorders.
Emergency, shock, or intensive short-term dosing: High-dose, shortterm therapy is initiated to control hypoadrenal crisis, acute lifethreatening inflammation, acute central nervous system (CNS)
trauma, certain forms of CNS edema, and septic shock.{R-30}
Alternate-day therapy: Changing the dosing interval from every 24 hours
to every 48 hours once signs of disease are controlled has been called
alternate-day therapy. It has been recommended to minimize adrenocortical suppression and other side/adverse effects of prolonged
administration of glucocorticoids.{R-30; 136} For alternate-day dosing
to be successful, the administration of glucocorticoids with a duration
of action of 12 to 36 hours, such as prednisolone, prednisone, or
methylprednisolone, is necessary.{R-30; 136} Originally, in order to
change from daily to alternate-day dosing, it was recommended that
the total dose given in a 48-hour period remain the same. For example,
a dog given 20 mg of prednisolone a day would be gradually changed
to 40 mg every other day. However, clinicians often combine the
transition to a 48-hour dosing interval with tapering the dose in the
treatment of some disorders. In the example given, the original 20-mg
dose administered every 24 hours would be administered every
48 hours. The veterinarian chooses what type of transition to the
longer dosing interval and/or lower dose is likely to be most successful,
based on clinical history and, later, the response to initial changes in
dosage. The goal of alternate-day dosing is to achieve a period within
the 48-hour dosing interval when suppression of the adrenal axis is
relieved.{R-30} Alternate-day therapy can reduce adrenocortical suppression and decrease the effects of hyperadrenocorticism,{R-30; 136}
but it will not completely prevent the eventual development of adverse
effects.{R-136} Among other things, the susceptibility to urinary tract
infections may not be decreased.{R-163} Also, alternate-day therapy
may not work well for conditions requiring high doses because
exacerbations can occur during the second day. However, this regimen
should be considered whenever dosing is required for more than 2
weeks.{R-30; 136} To begin alternate-day therapy, the animal must first
be on therapy administered every 24 hours until good clinical results
are achieved.
Tapering dose: In order to decrease adrenocortical suppression, tapering
the dose to the minimum required to control signs is an important
strategy while treatment is ongoing. Tapering the dose is also
important when discontinuing treatment.
It is unknown how much risk of iatrogenic secondary hypoadrenocorticism there is for an animal without a subsequent episode of
stress.{R-136} Reports of iatrogenic acute adrenocortical insufficiency
are rare in animals.{R-27} The possible suppression of adrenal function
should be considered whenever glucocorticoid administration is
discontinued and, if necessary, the dose should be tapered off to allow
resumption of normal endogenous cortisol concentrations and avoid
hypoadrenal crisis.{R-19} Many practitioners assume that therapy for
more than 2 weeks requires a tapering of dose for withdrawal in
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44 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
dogs;{R-31; 136} however, the duration of adrenal recovery is highly
variable among individual animals.{R-127} Animals that have been
considered most at risk are those that are given greater than
physiological replacement dosing for more than 2 weeks and that
subsequently undergo sudden physiologic stress in the 6 weeks after
therapy is discontinued.{R-27}
Glucocorticoid product formulations
The glucocorticoids are all structural relatives of endogenous cortisol,
produce similar effects, and in many situations requiring a glucocorticoid, they might be considered interchangeable when dose-adjusted
for potency; however, because of the wide variation among medications in onset of action, duration of action, the amount of mineralocorticoid effect, and potency, there are preferred glucocorticoids for
specific clinical situations. Similar animals may respond differently to
the same dose of medication; therefore, the clinical response also helps
define the dosage regimen.
The potency and duration of action depend on the structure of the
glucocorticoid chosen for therapy.
Bases—These are the glucocorticoids in their free alcohol or base form.
Each has a slightly different structure affecting its glucocorticoid and
mineralocorticoid activity and its duration of action. The bases have
traditionally been divided into short, intermediate, and long duration:{R-34} a) short-acting—cortisone, hydrocortisone, b) intermediate-acting—prednisone, prednisolone, methylprednisolone, and
triamcinolone, c) long-acting—dexamethasone and flumethasone.
Esters or salts—Esterification of a glucocorticoid affects its water and
lipid solubility and the rate at which it is absorbed from the injection
site:{R-30; 31}
Acetate, diacetate, and tebutate esters—Slow and sustained absorption from intramuscular depot injections.{R-30; 31} These are
poorly water-soluble.
Acetonide esters—Slow and sustained absorption from intramuscular or subcutaneous depot injections.{R-30; 31} These are poorly
water-soluble.
Succinate and phosphate esters—Rapid action from intravenous or
intramuscular administration. These are the most water-soluble
esters and are rapidly absorbed; their duration of action is similar to
their corresponding base.{R-30}
The relative anti-inflammatory potencies of the glucocorticoid bases have
been described based on four different irritant response tests in rats,
Cortisol
(hydrocortisone)
Cortisone
Prednisolone
Prednisone
Methylprednisolone
Triamcinolone{R-31}
Isoflupredone
Betamethasone
Dexamethasone
Flumethasone
Relative antiinflammatory
potency
Relative
sodiumretaining
potency*
Approximate
duration of action
(adrenal suppression)
(hours)
1
1
<12
0.8
4
4
5
3–5
17
25–30
25–30
30
0.8
0.8
0.8
0–0.5
0
0*
0
0
0
<12
12–36
12–36
12–36
24–48
–
>48
>48
>48
*
Repeated high doses of some glucocorticoids with previously unreported
mineralocorticoid effect may exacerbate electrolyte disturbances in susceptible
animals.{R-214} One example is clinical hypokalemia reported in some ketotic,
postparturient cattle treated with multiple high doses of isoflupredone, in
combination with other medications.{R-214}
2004 The United States Pharmacopeial Convention, Inc.
with varying results.{R-38; 188} The relevance of these potencies to dose
and efficacy in particular clinical situations can vary.
FOR INTRASYNOVIAL ADMINISTRATION
Product labeling recommends intrasynovial injection when it can help
reduce or avoid systemic administration of corticosteroids or when
systemic corticosteroids are contraindicated.{R-15; 16} Strict asepsis
should be followed to minimize the risk of septic arthritis. Exercise
should be restricted and repeated injections should be avoided{R-121126}
to reduce the risk of side effects.
DIET/NUTRITION
When long-term glucocorticoid therapy is used, a protein-rich, potassium
chloride–supplemented diet has been recommended to counteract
nitrogen and potassium loss.{R-18}
DEXAMETHASONE
SUMMARY OF DIFFERENCES
Laboratory value alterations: Dexamethasone can decrease serum
testosterone in bulls and rams.{R-169; 170}
Lactation: Dexamethasone concentrations in milk have been measured
in cattle.{R-71; 72}
Pharmacology/pharmacokinetics: Dexamethasone sodium phosphate is
well-suited for rapid utilization when administered intravenously.{R-11}
Side/adverse effects: Dexamethasone has been associated with temporary
sperm defects in cattle.{R-169}
Veterinary dosing information: In rats, dexamethasone has approximately 25 to 30 times the anti-inflammatory potency of cortisol and
six to seven times the potency of prednisolone.{R-38} Dexamethasone
has an insignificant amount of mineralocorticoid effect.{R-38}
ORAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
DEXAMETHASONE ORAL POWDER
Usual dose:
Inflammation, including musculoskeletal inflammation—Cattle and
horses: Oral, 0.04 to 0.15 mg per kg of body weight a day.{R-212}
Ketosis—Cattle: Oral, [0.01 to 0.04 mg per kg of body weight a day (5 to
20 mg total dose)].{R-5}
Note: Product labeling lists a dose of 0.01 to 0.02 mg per kg of body
weight a day for cattle.
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):{R-5}
10 mg per 15 grams of powder (Rx) [Azium Powder].
Canada—
Veterinary-labeled product(s):{R-3}
10 mg per 15 grams of powder (Rx) [Azium Powder; Dexone; generic].
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CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 45
Withdrawal times:
U.S. and Canada—Although dexamethasone oral powder is labeled for
use in cattle, product labeling does not list an established meat or
milk withdrawal time{R-3; 5} and the U.S. government has not
established a safe level for dexamethasone in animal products for
human consumption. However, if dexamethasone is administered to
cattle at a dose of 0.04 to 0.07 mg per kg of body weight (20 to 30
mg total dose), there is some evidence to suggest that a withdrawal
time of 96 hours for milk is necessary to avoid residues that would be
considered potentially harmful by some national and international
authorities.{R-21}
Currently, there are not enough data to estimate withdrawal times for
meat for most dexamethasone formulations available in the U.S. and
Canada. However, there is some evidence that a significant
withdrawal is necessary. For this formulation, it is possible that if a
dose of 0.06 mg per kg of body weight is administered to cattle, at
least 4 days are necessary to clear muscle tissue of residues. Some
data suggest longer withdrawals may be necessary to clear
dexamethasone residues from other tissues. Pigs may clear all
tissues of residues within 1 day of administration.{R-21}
Information is not available for residue depletion or human food safety
if a dose higher than 0.07 mg per kg of body weight is administered
to food-producing animals.
Note: Product labeling lists a total dose of 5 to 10 mg per animal (0.01
to 0.02 mg per kg of body weight) a day for cattle.{R-3; 5}
These products are not labeled for use in horses intended for food or
in preruminating calves.{R-5; 22}
Packaging and storage: Store between 2 and 30 C (36 and 86 F),
unless otherwise specified by the manufacturer.{R-19} Protect from
light.{R-19}
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-2}
0.25 mg (250 mcg) (Rx) [Decadron; generic].
0.5 mg (500 mcg) (Rx) [Decadron; Hexadrol; generic].
0.75 mg (750 mcg) (Rx) [Decadron; Hexadrol; generic].
1 mg (Rx) [Generic].
1.5 mg (Rx) [Decadron; Hexadrol; generic].
2 mg (Rx) [generic].
4 mg (Rx) [Decadron; Hexadrol; generic].
6 mg (Rx) [Decadron; generic].
Canada—
Veterinary-labeled product(s):{R-12; 13}
0.25 mg (250 mcg) (OTC) [Dextab].
Human-labeled product(s):{R-2}
0.5 mg (500 mcg) (Rx) [Dexasone; generic].
0.75 mg (750 mcg) (Rx) [Dexasone; generic].
4 mg (Rx) [Dexasone; generic].
Packaging and storage: Store below 40 C (104 F), preferably
between 15 and 30 C (59 and 86 F), unless otherwise specified by
the manufacturer. Store in a well-closed container.
USP requirements: Preserve in well-closed containers. Contain the
labeled amount, within ±10%. Meet the requirements for Identification, Dissolution (70% in 45 minutes in dilute hydrochloric acid
[1 in 100] in Apparatus 1 at 100 rpm), and Uniformity of dosage
units.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
USP requirements: Not in USP.{R-183}
DEXAMETHASONE TABLETS USP
Usual dose:
[Dermatoses];
[Inflammation, general]; or
[Inflammation, musculoskeletal]—Cats and dogs: Oral, 0.07 to
0.15 mg per kg of body weight a day for five to ten days or as
appropriate for the disease condition.{R-212}
Note: [Induction of abortion]1 —Dogs: Although the safety and efficacy
have not been established for use in the induction of abortion, an
oral dose of 0.2 mg per kg of body weight every twelve hours for five
days, followed by a tapering dose of 0.16 mg per kg of body weight
every twelve hours on day six, 0.08 mg per kg of body weight every
twelve hours on day seven, and 0.02 mg per kg of body weight every
twelve hours on day eight has been used.{R-118}
For dogs more than 40 days into gestation, expulsion of fetuses is
likely to occur, but for dogs between days 28 and 35 of gestation
when medication is begun, a simple discharge is more often
observed.{R-118} In 60% of dogs treated, lethargy and depression
may be noted during the abortion period.{R-118}
Strength(s) usually available:
Note: Human products have been listed for this dosage form based on
relevance to veterinary practice.
2004 The United States Pharmacopeial Convention, Inc.
PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
DEXAMETHASONE INJECTION USP
Usual dose:
Allergic disorders—
Cats and dogs: Intramuscular or intravenous, 0.07 to 0.15 mg per kg
of body weight a day.{R-212} This dose may be repeated every
twenty-four hours for three to five days{R-4} or as necessary for the
disease condition.
Cattle and horses: Intramuscular or intravenous, [0.04 to 0.15 mg
per kg of body weight a day].{R-212}
Note: Product labeling lists a total dose of 5 to 20 mg per animal
(0.01 to 0.04 mg per kg of body weight) a day for cattle.{R-4; 6}
Dermatoses—Cats and dogs: Intramuscular or intravenous, 0.07 to 0.15
mg per kg of body weight a day.{R-212} This dose may be repeated
every twenty-four hours for three to five days{R-4} or as necessary for
the disease condition.
Disk disease, intervertebral—Dogs: Intravenous, 0.07 to 0.15 mg per kg
of body weight a day.{R-212}
Note: Because of a lack of research data on an effective dose of
glucocorticoids in the treatment of disk disease in dogs, an anti-
All rights reserved
46 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
inflammatory dose is listed above, based on clinical judgment. This is
not the dose or dosage form recommended for neurologic dysfunction
or paralysis due to disk disease (see acute spinal trauma under
Methylprednisolone Sodium Succinate For Injection USP).
Inflammation, including musculoskeletal and [ocular]1 inflammation—
Cats and dogs: Intramuscular or intravenous, 0.07 to 0.15 mg per kg of
body weight a day.{R-212} This dose may be repeated every twentyfour hours for three to five days{R-4} or as necessary for the disease
condition.
Cattle: Intramuscular or intravenous, 0.04 to 0.15 mg per kg of body
weight a day.{R-212}
Note: Product labeling lists a total dose of 5 to 20 mg per animal (0.01
to 0.04 mg per kg of body weight) a day for cattle.{R-4; 6}
Horses: Intramuscular or intravenous, 0.04 to 0.15 mg per kg of body
weight a day.
Ketosis—Cattle: Intramuscular or intravenous, 0.01 to 0.04 mg per kg of
body weight (5 to 20 mg total dose) a day.{R-4; 6}
[Abortion, induction of]1—Cattle: Intramuscular, 0.05 mg per kg of body
weight (approximately 25 mg as a total dose), administered after the
100th day of gestation, usually in conjunction with a prostaglandin.{R190; 191}
The risk of fetal mummification, retained placenta, metritis, or
dystocia should be considered.{R-191}
[Hyperadrenocorticism (diagnosis)]1—
Cats:
Low-dose dexamethasone suppression test: After a baseline blood
cortisol sample is taken, an intravenous bolus of 0.1 mg per kg of
body weight is administered as a single dose.{R-140; 177} Blood
cortisol samples are taken at four and eight hours postinjection.{R64}
Normal adrenocortical suppression is typically defined as
< 1.4 mcg of cortisol per decaliter at eight hours.{R-140}
Note: The above test dose is based on a study establishing suppression
of endogenous cortisol in normal cats in response to dexamethasone administration.{R-140}
Although insufficient data are available to confirm the accuracy of
the high-dose dexamethasone suppression test in cats, some clinicians
have used the following regimen: After a baseline blood cortisol
sample is taken, an intravenous bolus of 1 mg per kg of body weight
is administered as a single dose.{R-140; 177} Blood cortisol samples
are taken at four and eight hours postinjection.{R-64} Plasma
cortisol < 50% of baseline concentration at four or eight hours
postinjection or plasma cortisol < 1.4 mcg/decaliter at four or eight
hours may be an indication of pituitary-dependent hyperadrenocorticism;{R-177} however, specific values may vary depending on
the laboratory. A lack of cortisol suppression sufficient to meet the
criteria is presumed to indicate an adrenal tumor.
Dogs:
Low-dose dexamethasone suppression test—After a baseline blood
cortisol sample is taken, an intravenous bolus of 0.01 mg per kg of
body weight is administered as a single dose.{R-58-60} Blood cortisol
samples are taken at four and eight hours postinjection.{R-64}
Normal adrenocortical suppression is typically defined as < 1.4
mcg of cortisol per decaliter at eight hours.{R-58; 62-64} For dogs
that show evidence of hyperadrenocorticism by a cortisol concentration of ‡ 1.4 mcg/decaliter at eight hours, a plasma cortisol <
50% of baseline concentration at four or eight hours postinjection
or plasma cortisol < 1.4 mcg/decaliter at four hours is a strong
indication of pituitary-dependent hyperadrenocorticism;{R-64}
however, specific values may vary depending on the laboratory.
2004 The United States Pharmacopeial Convention, Inc.
High-dose dexamethasone suppression test—After a baseline blood
cortisol sample is taken, an intravenous bolus of 0.1 mg per kg of
body weight is administered as a single dose.{R-64} Blood cortisol
samples are taken at four and eight hours postinjection.{R-64}
Plasma cortisol < 50% of baseline concentration at four or eight
hours postinjection or plasma cortisol < 1.4 mcg per decaliter at
four or eight hours is a strong indication of pituitary-dependent
hyperadrenocorticism;{R-64} however, specific values may vary
depending on the laboratory. A lack of cortisol suppression sufficient
to meet the criteria is presumed to indicate an adrenal tumor.
Note: The above test recommendations are based on controlled studies
in dogs.
Horses: Dexamethasone suppression test—After a baseline blood
cortisol sample is taken, an intramuscular injection of 0.04 mg per
kg of body weight is administered.{R-179} A blood cortisol sample is
taken nineteen to twenty-four hours postinjection.{R-177; 179}
Normal adrenocortical suppression is typically defined as less than
1 mcg of cortisol per decaliter at twenty to twenty-four hours.{R-179}
Note: The above test dose is based on a controlled study in horses.
[Parturition induction]1—
Cattle: Intramuscular, 0.05 mg per kg of body weight (approximately 25
mg total dose per animal), given as a single dose in the last week to two
weeks of gestation{R-110; 112; 190; 191} and administered concurrently
with an intramuscular dose of a prostaglandin (PGF2alpha), such as
cloprostenol at a total dose of 0.5 mg per animal.{R-110; 112}
Note: It has been suggested that the likelihood of accurate prediction of
the time of parturition may be increased and the risk of some side
effects, such as retained placenta, may be decreased by pretreatment
administration of a relatively long-acting corticosteroid approximately one week before induction.{R-110; 112} Triamcinolone at an
intramuscular dose of 0.016 mg per kg of body weight has been used
for pretreatment in the induction of parturition;{R-110} however,
there is some risk that the pretreatment itself will induce early
parturition before induction.
Sheep: Intramuscular, 0.15 mg per kg of body weight (10 mg total
dose) a day for one to five days, administered in the last week of
gestation.{R-116; 172}
Note: [Edema associated with brain tumors (see Inflammation, neurologic in the Indications section of this monograph)]1—Although the
safety and efficacy have not been established in the treatment of
edema associated with brain tumors, in a controlled study an
intramuscular dose of 3 mg per kg a day in divided doses has caused
significant reduction of edema associated with induced tumors in
dogs.{R-219} However, it should be emphasized that corticosteroids
have not been shown to be effective in trauma-induced cerebral
edema,{R-220} although they may be of benefit in reducing tissue
damage mediated by mechanisms other than cerebral edema.{R-223}
[Anemia, immune-mediated hemolytic]1—Horses: Although the
safety and efficacy have not been established in the treatment of
immune-mediated hemolytic anemia, an intravenous or intramuscular dose of 0.3 to 1 mg per kg of body weight every twelve to
twenty-four hours has been suggested. Once control of hemolysis is
achieved, treatment is often switched to a corticosteroid more
suitable for alternate-day therapy.
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):{R-4; 6}
All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 47
2 mg per mL (Rx) [Azium Solution; Dexaject; Dexasone; Dexazone 2
mg; generic].
Canada—
Veterinary-labeled product(s):{R-181; 184}
2 mg per mL (Rx) [Rafter Dex].
Withdrawal times:
U.S. and Canada—Although dexamethasone injection is labeled for use
in cattle, product labeling does not list an established meat or milk
withdrawal time{R-4; 181} and the U.S. government has not established
a safe level for dexamethasone in animal products for human
consumption. However, if dexamethasone is administered to cattle at
a dose of 0.04 to 0.07 mg per kg of body weight (20 to 30 mg total dose),
there is some evidence to suggest that a withdrawal time of 96 hours for
milk is necessary to avoid residues that would be considered potentially
harmful by some national and international authorities.{R-21}
Currently, there are not enough data to estimate withdrawal times for
meat for most dexamethasone formulations available in the U.S. and
Canada. However, there is some evidence that a significant withdrawal
is necessary. For this formulation, it is possible that if a dose of 0.06 mg
per kg of body weight is administered to cattle, at least 4 to 8 days are
necessary to clear muscle tissue of residues. The rate at which this
formulation clears other tissues is unknown, but other formulations
available in Europe have shown that at least 3 weeks for liver and
kidney tissues and up to 6 weeks for the injection site are necessary for
residues to fall within generally accepted standards. In the same
situation for pigs, residues may fall more rapidly in liver and kidney
tissues.{R-21} Information is not available for residue depletion or
human food safety if a dose higher than 0.07 mg per kg of body weight
is administered to food-producing animals.
Note: Product labeling lists a total dose of 5 to 20 mg per animal (0.01
to 0.04 mg per kg of body weight) a day for cattle.{R-4; 6; 13}
These products are not labeled for use in horses intended for food or
in preruminating calves to be processed for veal.{R-4}
Packaging and storage: Store between 2 and 30 C (36 and 86 F),
unless otherwise specified by manufacturer.{R-4} Protect from freezing.
USP requirements: Preserve in light-resistant single-dose or multipledose containers, preferably of Type I glass. A sterile solution of Dexamethasone in Water for Injection. Label it to indicate that it is for
veterinary use only. Contains the labeled amount, within ±10%. Meets
the requirements for Identification, Bacterial endotoxins, Sterility, pH
(4.0–5.5), and Particulate matter, and for Injections.{R-183}
DEXAMETHASONE 21 PHOSPHATE INJECTION
Usual dose:
[Inflammation, musculoskeletal]—Cattle and horses: Intramuscular or
intravenous, 0.04 to 0.15 mg per kg of body weight as an initial dose,
followed by the same dose every twenty-four hours, as necessary for
the disease condition.{R-212}
[Ketosis]—Cattle: Intramuscular or intravenous, 0.02 to 0.04 mg per kg
of body weight as an initial dose, followed by the same dose every
twenty-four hours, as necessary for the disease condition.{R-1}
Strength(s) available:{R-13}
U.S.—
Veterinary-labeled product(s):
Not commercially available.
2004 The United States Pharmacopeial Convention, Inc.
Canada—
Veterinary-labeled product(s):
5 mg per mL (OTC) [generic].
Withdrawal times:
U.S. and Canada—Dexamethasone 21 phosphate injection is not
labeled for use in animals in the U.S.; therefore, withdrawal times
have not been established, and the U.S. government has not
established a safe level for dexamethasone in animal products for
human consumption. Although dexamethasone 21 phosphate
injection is labeled for use in cattle in Canada, product labeling does
not list an established meat or milk withdrawal time.{R-1} However, if
dexamethasone is administered to cattle at a dose of 0.04 to 0.07 mg
per kg of body weight (20 to 30 mg total dose), there is some
evidence to suggest that a withdrawal time of 96 hours for milk is
necessary to avoid residues that would be considered potentially
harmful by some national and international authorities.{R-21}
Currently, there are not enough data to estimate withdrawal times
for meat for most dexamethasone formulations available in the U.S.
and Canada. However, there is some evidence that a significant
withdrawal is necessary. For this formulation, it is possible that if a
dose of 0.06 mg per kg of body weight is administered to cattle, at
least 4 to 8 days are necessary to clear muscle tissue of residues. The
rate at which this formulation clears other tissues is unknown, but
other formulations available in Europe have shown that at least 3
weeks for liver and kidney tissues and up to 6 weeks for the injection
site are necessary for residues to fall within generally accepted
standards. In the same situation for pigs, residues may fall more
rapidly in liver and kidney tissues.{R-21} Information is not available
for residue depletion or human food safety if a dose higher than 0.07
mg per kg of body weight is administered to food-producing animals.
Note: Canadian product labeling lists a total dose of 0.02 to 0.04 mg
per kg of body weight (about 10 to 20 mg per animal) for cattle.{R-1}
Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by the
manufacturer. Protect from freezing.{R-1}
USP requirements: Not in USP.{R-183}
DEXAMETHASONE SODIUM PHOSPHATE INJECTION
USP
Note: The dosing and strengths of the dosage forms available are expressed
in terms of dexamethasone base (not the sodium phosphate salt).
4 grams of dexamethasone sodium phosphate equals 3.04 grams of
dexamethasone base.
Usual dose:
Inflammation—
Dogs: Intravenous, 0.07 to 0.15 mg (base) per kg of body weight a day.
Horses: Intravenous, 0.01 to 0.15 mg (base) per kg of body weight a day.
[Cats]: Intravenous, 0.07 to 0.15 mg (base) per kg of body weight a
day. The dose may be repeated daily if necessary.
[Cattle]: Intramuscular or intravenous, 0.04 to 0.15 mg (base) per kg
of body weight a day.
[Hyperadrenocorticism (diagnosis)]1—Cats and dogs: See Dexamethasone
Injection.
[Ketosis]—Cattle: Intramuscular or intravenous, 0.01 to 0.04 mg (base)
per kg of body weight (5 to 20 mg total dose) a day.{R-176}
All rights reserved
48 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
[Septic shock]1 —Cats, cattle, dogs, horses and pigs: Intravenous, 0.5 to 5
mg (base) per kg of body weight.{R-212}
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):{R-11}
3.33 mg per mL (base; equivalent to 4 mg per mL sodium
phosphate salt) (Rx) [Dexaject SP; generic].
Canada—
Veterinary-labeled product(s):{R-176}
1.67 mg (base; equivalent to 2 mg sodium phosphate salt) per mL
(OTC) [Dexamethasone 2; generic].
4.16 mg (base; equivalent to 5 mg sodium phosphate salt) per mL
(OTC) [Dexamethasone 5; Uni-Dex].
Withdrawal times:
U.S. and Canada—Dexamethasone sodium phosphate injection is not
labeled for use in food-producing animals in the U.S.; therefore,
withdrawal times have not been established{R-11} and the U.S.
government has not established a safe level for dexamethasone in
animal products for human consumption. Although dexamethasone
sodium phosphate is labeled for use in cattle in Canada, product
labeling does not list an established meat or milk withdrawal time.{R176}
However, if dexamethasone is administered to cattle at a dose of
0.04 to 0.07 mg per kg of body weight (20 to 30 mg total dose), there is
some evidence to suggest that a withdrawal time of 96 hours for milk is
necessary to avoid residues that would be considered potentially
harmful by some national and international authorities.{R-21}
Currently, there are not enough data to estimate withdrawal times for
meat for most dexamethasone formulations available in the U.S. and
Canada. However, there is some evidence that a significant withdrawal
is necessary. For this formulation, it is possible that if a dose of 0.06 mg
per kg of body weight is administered to cattle, at least 4 days are
necessary to clear muscle tissue of residues. Some data suggest longer
withdrawals may be necessary to clear dexamethasone residues from
other tissues. Pigs may clear all tissues of residues within 1 day of
administration.{R-21} Information is not available for residue depletion
or human food safety if a dose higher than 0.07 mg per kg of body
weight is administered to food-producing animals.
Note: Canadian product labeling lists a total dose of 5 to 20 mg per
animal (0.01 to 0.04 mg per kg of body weight) a day for cattle.{R-176}
These products are not labeled for use in horses intended for
food.{R-176}
Packaging and storage: Store between 15 and 30 C (59 and 86 F),{R11}
unless otherwise specified by the manufacturer. Protect from light.
Protect from freezing.
USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I glass, protected from light. A sterile solution
of Dexamethasone Sodium Phosphate in Water for Injection. Contains
an amount of dexamethasone sodium phosphate equivalent to the labeled amount of dexamethasone phosphate, within –10% to +15%,
present as the disodium salt. Meets the requirements for Identification,
Bacterial endotoxins, and pH (7.0–8.5), and for Injections.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in the U.S.
2004 The United States Pharmacopeial Convention, Inc.
FLUMETHASONE
SUMMARY OF DIFFERENCES
Veterinary dosing information: Flumethasone has approximately 30
times the anti-inflammatory activity of cortisol and six to seven times
the potency of prednisolone. Flumethasone has an insignificant
amount of mineralocorticoid effect.
PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
FLUMETHASONE INJECTION
Usual dose:
Note: The following doses are those included on product labeling for
flumethasone; however, some members of the USP Veterinary Medicine Advisory Panel prefer the use of higher doses like those
recommended for dexamethasone, a similarly potent glucocorticoid.
Allergic disorders—
Dogs: Intramuscular, intravenous, or subcutaneous, 0.0625 to 0.25
mg a day per animal, as a single dose. If necessary, the dose may be
repeated.{R-18; 185}
Horses1: Intramuscular or intravenous, 1.25 to 2.5 mg per animal, as
a single dose. If necessary, the dose may be repeated.{R-18}
[Cats]1: Intramuscular, intravenous, or subcutaneous, 0.03125 to
0.125 mg a day per animal, as a single dose. If necessary, the dose
may be repeated.{R-18; 185}
Dermatoses—
Cats: Intramuscular, intravenous, or subcutaneous, 0.03125 to 0.125
mg a day per animal, as a single dose. If necessary, the dose may be
repeated.{R-18; 185}
Dogs: Intramuscular, intravenous, or subcutaneous, 0.0625 to 0.25
mg a day per animal, as a single dose. If necessary, the dose may be
repeated.{R-18; 185}
Disk disease, intervertebral—Dogs: Intramuscular, intravenous, or subcutaneous, 0.0625 to 0.25 mg a day per animal, as a single dose. If
necessary, the dose may be repeated.{R-18; 185}
Inflammation, including musculoskeletal inflammation—
Dogs: Intramuscular, intravenous, or subcutaneous, 0.0625 to 0.25
mg a day per animal, as a single dose. If necessary, the dose may be
repeated.{R-18; 185}
Horses: Intramuscular or intravenous, 1.25 to 2.5 mg per animal, as a
single dose. If necessary, the dose may be repeated.{R-18}
[Cats]: Intramuscular, intravenous, or subcutaneous, 0.03125 to
0.125 mg a day per animal, as a single dose. If necessary, the dose
may be repeated.{R-185}
[Cattle]: Canadian product labeling lists an intramuscular or intravenous dose of 1.25 to 5 mg a day per animal as a single dose.{R-185} If
necessary, the dose may be repeated.{R-185}
Inflammation, musculoskeletal (joint)1—
Dogs: Intra-articular, 0.166 to 1 mg per animal, as a single dose.{R-18}
Horses: Intra-articular, 1.25 to 2.5 mg per animal, as a single dose.{R-18}
[Ketosis]—Cattle: Canadian product labeling lists an intramuscular or
intravenous dose of 1.25 to 5 mg a day per animal as a single
dose.{R-185} If necessary, the dose may be repeated.{R-185}
Note: The use of a microsyringe or standard tuberculin syringe may be
helpful in accurately administering small amounts of flumethasone.{R-18}
All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 49
Strength(s) usually available:{R-13}
U.S.—{R-18}
Veterinary-labeled product(s):
0.5 mg per mL (Rx) [Flucort].
Canada—{R-185}
Veterinary-labeled product(s):
0.5 mg per mL (OTC) [Flucort].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-2}
10 mg (Rx) [Cortef].
20 mg (Rx) [Cortef].
Withdrawal times:
U.S.—This product is not labeled for use in food-producing animals in the
U.S.; therefore there are no established withdrawal times.
Canada—{R-185}
Withdrawal time
Species
Meat (days)
Cattle
4
Packaging and storage: Store below 40 C (104 F), preferably
between 15 and 30 C (59 and 86 F), unless otherwise specified by
the manufacturer. Protect from freezing.
{R-183}
USP requirements: Not in USP.
1
Not included in Canadian product labeling or product not commercially
available in Canada.
HYDROCORTISONE
SUMMARY OF DIFFERENCES
Indications: Hydrocortisone is indicated in the treatment of adrenocortical insufficiency.
Veterinary dosing information: Hydrocortisone or cortisol is the unit to
which the anti-inflammatory and mineralocorticoid potencies of other
corticosteroids are compared.
ORAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
Human products have been listed for this dosage form based on
relevance to veterinary practice.
HYDROCORTISONE TABLETS USP
Usual dose:—[Adrenocortical insufficiency]1—Cats and dogs: Oral, 1 to
2 mg per kg of body weight a day as an initial dose. Maintenance dose
is determined based on patient response.
Note: Generally, other mineralocorticoids and glucocorticoids are
preferred over hydrocortisone{R-223} in the treatment of adrenocortical insufficiency.
Strength(s) usually available:
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-2}
5 mg (Rx) [Cortef].
10 mg (Rx) [Cortef; Hydrocortone; generic].
20 mg (Rx) [Cortef; Hydrocortone; generic].
2004 The United States Pharmacopeial Convention, Inc.
Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F). Store in a well-closed container.
USP requirements: Preserve in well-closed containers. Contain the
labeled amount, within ±10%. Meet the requirements for Identification, Dissolution (70% in 30 minutes in water, in Apparatus 2 at 50
rpm), and Uniformity of dosage units.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
ISOFLUPREDONE
SUMMARY OF DIFFERENCES
Veterinary dosing information: Isoflupredone has approximately 17
times the anti-inflammatory potency of cortisol and four times the
potency of prednisolone.
PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
ISOFLUPREDONE ACETATE INJECTABLE SUSPENSION
Usual dose:
Allergic disorders;
Inflammation, musculoskeletal; or
Inflammation, ocular—
Cattle: Intramuscular, 10 to 20 mg as a total single dose per
animal.{R-23; 24} The dose may be repeated in twelve to twentyfour hours.{R-23; 24}
Horses: Intramuscular, 5 to 20 mg as a total single dose per
animal.{R-23; 24} The dose may be repeated in twelve to twentyfour hours, as necessary.
Pigs: Intramuscular, 0.036 mg per kg of body weight.{R-23; 24}
Inflammation, musculoskeletal (joint)—Horses: Intrasynovial, 5 to 20 mg
or more, as a total single dose per animal, depending on the size of
the cavity.{R-23; 24}
Ketosis—Cattle: Intramuscular, 10 to 20 mg as a total single dose per
animal.{R-23} The dose may be repeated in twelve to twenty-four
hours.{R-23; 24} The high end of the dose is recommended as an initial
dose, rather than repeating smaller doses.{R-23; 24}
Note: Repeating large doses of isoflupredone outside of label directions
may lead to hypokalemia in some cattle.{R-214}
Note: [Chronic obstructive pulmonary disease]1 —Horses Although the
safety and efficacy have not been established in the treatment of
chronic obstructive pulmonary disease in horses, a total intramuscular
dose of 10 to 14 mg (approximately 0.02 to 0.03 mg per kg of body
weight), administered every twenty-four hours for five days, may be
effective in the relief of signs.{R-26; 32} The dose may then be tapered off
over a period of 10 to 20 days.{R-26}
All rights reserved
50 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):{R-24}
2 mg per mL (Rx) [Predef 2X].
Canada—
Veterinary-labeled product(s):{R-23}
2 mg per mL (Rx) [Predef 2X].
METHYLPREDNISOLONE TABLETS USP
Withdrawal times:
U.S.—{R-24}
Withdrawal time
Species
Meat (days)
Cattle, pigs
7
Note: This product is not labeled for use in preruminating calves
intended to be processed for veal.{R-24}
Canada—{R-23}
Withdrawal time
Species
Meat (days)
Milk (hours)
Cattle
Pigs
5
5
72
Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by the
manufacturer. Protect from freezing.
Incompatibilities: Isoflupredone should not be added to intravenous
infusion solutions.{R-23}
USP requirements: Not in USP.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
METHYLPREDNISOLONE
SUMMARY OF DIFFERENCES
Pharmacology/pharmacokinetics: Methylprednisolone sodium succinate
is well-suited for rapid utilization when administered intravenously.
Methylprednisolone acetate is well-suited for extended absorption
when administered intramuscularly.
Veterinary dosing information: In mice, methylprednisolone has
approximately five to six times the anti-inflammatory potency of
cortisol and 1.5 times the potency of prednisolone.{R-16; 38} It has
approximately one half the sodium-retaining effect of cortisol in
mice.{R-38}
Usual dose:
Adrenocortical insufficiency, acute1—Cats and dogs: Oral, 0.1 to 0.25 mg
per kg of body weight a day.{R-193; 206; 211}
Allergic disorders1;
Dermatoses1; or
Inflammation, including ocular and musculoskeletal inflammation1—Cats and dogs: Oral, 0.05 to 0.45 mg per kg of body weight
every twelve hours.{R-14}
Asthma1—Cats: Oral, 0.05 to 0.45 mg per kg of body weight every
twelve hours.{R-14}
Colitis, ulcerative1—Dogs: Oral, 0.05 to 0.45 mg per kg of body weight
every twelve hours.{R-14}
Note: A response is expected in 2 to 7 days, at which time the dose is
reduced gradually. For acute disorders, the dose is tapered and
discontinued. For chronic disorders, the minimal necessary dose for
long-term maintenance is found.{R-14}
[Disk disease, intervertebral]1—Dogs: Oral, 0.05 to 0.45 mg per kg of
body weight every twelve hours.
Note: Because of a lack of research data on an effective dose of
glucocorticoids in the treatment of disk disease in dogs, an antiinflammatory dose is listed above, based on clinical judgement. This
is not the dose or dosage form recommended for neurologic
dysfunction or paralysis due to disk disease (see acute spinal
trauma under Methylprednisolone Sodium Succinate For Injection
USP).
[Lupus erythematosus]1—Dogs: Oral, 2 to 4 mg per kg of body weight a
day as an initial dose, which may be administered in divided doses.
With a good response to treatment two weeks after initiation of
therapy, the dose could be halved and four weeks after initiation the
dosing interval may be doubled.{R-98; 99}
Note: The above dose is based on retrospective studies and case reports.
Strength(s) usually available:{R-13}
U.S.—{R-14; 192}
Veterinary-labeled product(s):
2 mg (Rx) [generic].
4 mg (Rx) [Medrol].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by the
manufacturer. Store in a tight container.
USP requirements: Preserve in tight containers. Contain the labeled
amount, within ± 7.5%. Meet the requirements for Identification,
Dissolution (70% in 30 minutes in water in Apparatus 2 at 50 rpm),
and Uniformity of dosage units.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
ORAL DOSAGE FORMS
PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
2004 The United States Pharmacopeial Convention, Inc.
All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 51
METHYLPREDNISOLONE ACETATE INJECTABLE
SUSPENSION USP
METHYLPREDNISOLONE SODIUM SUCCINATE FOR
INJECTION USP
Usual dose:
Allergic disorders; or
Dermatoses—
Cats: Intramuscular, 10 to 20 mg as a total dose administered at an
interval from one week{R-15} to six months apart.{R-31} The average
total dose administered is 10 mg.{R-15}
Dogs: Intramuscular, 2 to 120 mg as a single total dose{R-15} (1.1 mg
per kg of body weight{R-31}). The average total dose administered is
20 mg.{R-15}
Asthma—Cats: Intramuscular, 10 to 20 mg as a total dose administered
at an interval from one week to six months apart.{R-15}
Inflammation, including musculoskeletal inflammation—
Cats: Intramuscular, 10 to 20 mg as a total dose, administered at an
interval from one week{R-15} to six months apart.{R-31} The average
total dose administered is 10 mg.{R-15}
Dogs: Intramuscular, 2 to 120 mg as a single total dose{R-15} (1.1 mg
per kg of body weight{R-31}). The average total dose administered is
20 mg.{R-15}
Horses: Intramuscular, 200 mg as a single total dose.{R-15}
Inflammation, musculoskeletal (joint)—
Dogs: Intrasynovial, 20 mg as a single total dose for large synovial
spaces.{R-15} The dose is decreased as the size of the joint space
decreases.{R-15}
Horses: Intrasynovial, 40 to 240 mg as a single total dose.{R-15} The
average dose is 120 mg.{R-15} The dose is decreased as the size of the
joint space decreases.{R-15}
Note: Human products have been listed for this dosage form based on
relevance to veterinary practice.
The dosing and strengths of the dosage forms available are expressed
in terms of methylprednisolone base (not the sodium succinate salt).
Usual dose: [Spinal cord trauma, acute]1—Cats and dogs: Intravenous, 15 to 30 mg (base) per kg of body weight, administered in a
solution of 5% dextrose in water over one to several minutes. This
dose has been effective when administered as an initial dose immediately after injury followed by a dose of 15 mg (base) per kg every
eight hours and a tapered dose every eight hours over the week
following the injury.{R-44}
Note: The above dosing regimens are based on efficacy studies in cats
with induced spinal trauma.
Some suggest that administering glucocorticoids for longer than six
to eight hours after the spinal trauma occurs is nonproductive or
even counterproductive.{R-223}
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):{R-15}
20 mg per mL (Rx) [Depo-Medrol].
40 mg per mL (Rx) [Depo-Medrol].
Canada—
Veterinary-labeled product(s):{R-16; 17}
20 mg per mL (OTC) [Depo-Medrol].
40 mg per mL (OTC) [Depo-Medrol; Methysone 40; Unimed;
Vetacortyl].
Withdrawal times:
U.S. and Canada—Methylprednisolone acetate injectable suspension is not labeled for use in horses intended for food
production.{R-16; 17}
Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by the
manufacturer. Protect from freezing.
USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I glass. A sterile suspension of Methylprednisolone Acetate in a suitable aqueous medium. Contains the
labeled amount, within ±10%. Meets the requirements for Identification, Uniformity of dosage units, pH (3.0–7.0), and Particle size
(not less than 99% are less than 20 micrometers in length [measured on longest axis] and not less than 75% are less than 10
micrometers in length, using 400x magnification), and for Injections.{R-183}
2004 The United States Pharmacopeial Convention, Inc.
Size(s) usually available:
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-2; 186}
40 mg (base) (Rx) [Solu-Medrol; generic].
125 mg (base) (Rx) [Solu-Medrol; generic].
500 mg (base) (Rx) [A-methaPred; Solu-Medrol; generic].
1 gram (base) (Rx) [A-methaPred; Solu-Medrol; generic].
2 grams (base) (Rx) [Solu-Medrol].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-2}
40 mg (base) (Rx) [Solu-Medrol].
125 mg (base) (Rx) [Solu-Medrol].
500 mg (base) (Rx) [Solu-Medrol].
1 gram (base) (Rx) [Solu-Medrol].
Packaging and storage: Store below 40 C (104 F), preferably
between 15 and 30 C (59 and 86 F), unless otherwise specified by
the manufacturer. Store in a tight container. Protect from freezing.
Preparation of dosage form: See instructions on manufacturer
labeling.
Stability: Reconstituted solution should be used within 48 hours.{R-186}
USP requirements: Preserve in Containers for Sterile Solids. A sterile
mixture of Methylprednisolone Sodium Succinate with suitable buffers.
May be prepared from Methylprednisolone Sodium Succinate or from
Methylprednisolone Hemisuccinate with the aid of Sodium Hydroxide
or Sodium Carbonate. Contains an amount of methylprednisolone
sodium succinate equivalent to the labeled amount of methylprednisolone, within ±10%, in the volume of constituted solution designated
on the label. Meets the requirements for Constituted solution, Identification, Bacterial endotoxins, pH (7.0–8.0, in a solution containing
about 50 mg of methylprednisolone sodium succinate per mL), Loss
on drying (not more than 2.0%), Particulate matter, and Free
All rights reserved
52 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
methylprednisolone (not more than 6.6% of labeled amount of methylprednisolone), and for Sterility tests, Uniformity of dosage units, and
Labeling under Injections.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
PREDNISOLONE
SUMMARY OF DIFFERENCES
Pharmacology/pharmacokinetics: Prednisolone sodium succinate{R-7}
has been developed specifically to allow for rapid onset of action,
when administered intravenously.
Veterinary dosing information: Prednisolone has approximately four
times the anti-inflammatory potency of cortisol and its potency equals
that of prednisone.{R-16; 38} It has approximately 0.8 times the
sodium-retaining effect of cortisol.{R-38}
ORAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
PREDNISOLONE TABLETS USP
Usual dose:
Adrenocortical insufficiency, acute1 —
Dogs and [cats]: Oral, 0.2 mg per kg of body weight a day.{R-100; 195;
196}
This is the average dose administered to control signs, although
clinicians may start with a higher initial dose of 0.3 to 0.4 mg per kg
of body weight a day.{R-195} The dose is used in combination with
mineralocorticoid replacement or alone in the treatment of secondary hypoadrenocorticism.{R-195}
[Horses]: Oral, 0.1 to 0.5 mg per kg of body weight a day.{R-210; 211}
Allergic disorders1; or
Dermatoses1—Dogs and [cats]: Oral, 0.5 to 1 mg per kg of body weight
every twelve to twenty-four hours as an initial dose.{R-8} Once clinical
effect is achieved, the dose should be gradually reduced to reach the
lowest dose that is effective. Additionally, alternate-day therapy should
be employed to reduce side effects.{R-8; 100; 193}
Inflammation, including ocular and musculoskeletal inflammation1—
Dogs: Oral, 0.5 to 1 mg per kg of body weight every twenty-four hours as
an initial dose.{R-8} Once clinical effect is achieved, the dose should be
gradually reduced to reach the lowest dose that is effective. Additionally, alternate-day therapy should be employed to reduce side
effects.
[Cats]: Oral, 2.2 mg per kg of body weight every twenty-four hours as
an initial dose.{R-28; 31; 100; 189} Once clinical effect is achieved, the
dose should be reduced gradually to reach the lowest dose that is
effective. Additionally, alternate-day therapy should be employed to
reduce side effects.
Ulcerative colitis1—Dogs: Oral, 0.5 to 1 mg per kg of body weight every
twelve to twenty-four hours as an initial dose.{R-8} Once clinical
effect is achieved, the dose should be reduced gradually to reach the
lowest dose that is effective. Additionally, alternate-day therapy
should be employed to reduce side effects.
2004 The United States Pharmacopeial Convention, Inc.
[Anemia, autoimmune, hemolytic]1—Cats and dogs: Oral, 1 to 3 mg per
kg of body weight every twelve to twenty-four hours.{R-39-41; 94; 98;
99}
Treatment is continued until the disease is controlled and, when
clinically possible, changed to an alternate-day dose. A gradual
decrease in dose to a maintenance therapy of 0.5 to 1 mg per kg of
body weight every forty-eight hours is recommended.{R-38}
[Asthma]1—Cats: Oral, 2.2 mg per kg of body weight every twelve to
twenty-four hours as an initial dose.{R-28; 31; 100; 189} Once clinical
effect is achieved, the dose should be gradually reduced to reach the
lowest dose that is effective. Additionally, alternate-day therapy
should be employed to reduce side effects.
[Disk disease, intervertebral]1—Dogs: Oral, 0.5 to 1 mg per kg of body
weight every twenty-four hours as an initial dose. Once clinical effect
is achieved, the dose should be reduced gradually to reach the lowest
dose that is effective. Additionally, alternate-day therapy should be
employed to reduce side effects.
Note: Because of a lack of research data on an effective dose of
glucocorticoids in the treatment of disk disease in dogs, an antiinflammatory dose is listed above, based on clinical judgment. This is
not the dose or dosage form recommended for neurologic dysfunction
or paralysis due to disk disease (see acute spinal trauma under
Methylprednisolone Sodium Succinate For Injection USP).
[Lupus erythematosus]1—Dogs: Oral, 2 to 4 mg per kg of body weight a
day as an initial dose, which may be administered in divided doses.
With a good response to treatment two weeks after initiation of
therapy, the dose could be halved, and four weeks after initiation the
dosing interval may be doubled.{R-98; 99}
Note: The above dose is based on retrospective studies and case reports.
[Lymphoma]1—Cats and dogs: Oral 2.2 mg per kg of body weight a day,
administered in combination with chemotherapeutic medications
effective in the treatment of lymphoma.{R-83-86; 100; 108} It is very
uncommon for prednisolone to be administered as a sole agent
because combination chemotherapy is often much more effective,
and use of prednisolone alone is thought to make lymphoma less
responsive to subsequent chemotherapy. The particular combination
therapeutic regimen should be chosen based on initial evaluation of
the animal and cancer staging, followed by subsequent evaluations.
[Mast cell tumors]1—Dogs: Oral, 1 mg per kg of body weight every
twenty-four hours.{R-100; 107}
[Pemphigoid]1; or
[Pemphigus]1—Dogs: Oral, 2 to 3 mg per kg of body weight every twelve
hours.{R-39-41} After symptoms have been controlled, a maintenance
dose of 1 to 2 mg per kg of body weight, administered every fortyeight hours, has been successful in continuing remission of signs in
many animals that responded well to initial treatment with
corticosteroids alone.{R-39-41}
Note: The above dose is based on dose-response trials and case reports.
[Pemphigus]1—Cats: Oral, 2 to 3 mg per kg of body weight every twelve
hours.{R-39-41} After symptoms have been controlled, a maintenance
dose of 2 mg per kg of body weight, administered every forty-eight
hours, has been successful in continuing remission of signs in many
animals that responded well to initial treatment with corticosteroids
alone.{R-39-41}
Note: The above dose is based on dose-response trials and case reports.
[Thrombocytopenia, immune-mediated]1—Dogs: Oral, 2 mg per kg of
body weight every twelve hours for seven to fourteen days.{R-94}
Note: In some cases that are refractory to treatment, other immunosuppressants, such as azathioprine or cyclophosphamide, are added to
All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 53
this regimen;{R-94} however, it is controversial whether the combined
therapy improves survival.
The above dose is based on retrospective studies.
Note: [Chronic obstructive pulmonary disease]1—Horses: Although the
safety and efficacy have not been established, an initial dose of 0.5 to 1
mg per kg of body weight every twelve to twenty-four hours has been
recommended for use in the treatment of chronic obstructive pulmonary disease.{R-26; 32} The dose should be tapered and, when feasible,
discontinued.{R-26}
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):{R-8; 187}
5 mg (Rx) [PrednisTab].
20 mg (Rx) [PrednisTab].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by the
manufacturer. Store in a well-closed container.
USP requirements: Preserve in well-closed containers. Contain the
labeled amount, within ±10%. Meet the requirements for Identification, Dissolution (70% in 30 minutes in water in Apparatus 2 at 50
rpm), and Uniformity of dosage units.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
PREDNISOLONE ACETATE INJECTABLE SUSPENSION
USP
Usual dose:
[Dermatoses]—Dogs: Intramuscular, 10 to 30 mg as a total dose per
animal.{R-10}
[Inflammation, musculoskeletal]—
Dogs: Intramuscular, 10 to 30 mg as a total dose per animal.{R-10}
Horses: Intramuscular, 100 to 200 mg as a total dose per animal.{R-10}
[Ketosis]—Cattle: Intramuscular, 100 to 200 mg as a total dose per
animal.{R-10}
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Canada—
Veterinary-labeled product(s):{R-10}
10 mg per mL (OTC) [generic].
50 mg per mL [Uni-Pred 50; generic].
Withdrawal times:
U.S.—This product is not labeled for use in food-producing animals in
the U.S.; therefore, there are no established withdrawal times.
2004 The United States Pharmacopeial Convention, Inc.
Canada—{R-10}
Withdrawal time
Species
Meat (days)
Milk (hours)
Cattle
5
72
Packaging and storage: store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by the
manufacturer. Store in a well-closed container. Protect from freezing.
Auxiliary labeling: Shake well before using.{R-10}
USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I glass. A sterile suspension of Prednisolone
Acetate in a suitable aqueous medium. Contains the labeled amount,
within ±10%. Meets the requirements for Identification and pH (5.0–
7.5), and for Injections.{R-183}
PREDNISOLONE SODIUM SUCCINATE FOR INJECTION
USP
Usual dose:
Adrenocortical insufficiency, acute—Cats and dogs: Intramuscular or
intravenous, 1 to 2 mg per kg of body weight as an initial dose,{R-193}
followed by equal maintenance doses at one-, three-, six-, or ten-hour
intervals.{R-7; 9} The intravenous dose should be administered
slowly.{R-7}
Allergic disorders; or
Inflammation, including ocular and musculoskeletal inflammation
Cats: Intramuscular, 1 mg per kg of body weight.{R-9} The dose may be
repeated in twelve to twenty-four hours and continued for three to
five days, if necessary.{R-7}
Dogs: Intramuscular, 0.5 to 1 mg per kg of body weight.{R-9; 193} The
dose is repeated in twelve to twenty-four hours and continued for
three to five days.{R-7}
Horses: Intramuscular or intravenous, 0.25 to 1 mg per kg of body
weight.{R-9} If administered intravenously, the dose should be given
slowly over thirty seconds to one minute.{R-7} The dose should be
repeated at twelve, twenty-four, or forty-eight hours, depending on
clinical response.{R-9}
Dermatoses—
Cats: Intramuscular, 1 mg per kg of body weight.{R-9} The dose may be
repeated in twelve to twenty-four hours and continued for three to
five days, if necessary.{R-7}
Dogs: Intramuscular, 0.5 to 1 mg per kg of body weight.{R-9; 193} The
dose is repeated in twelve to twenty-four hours and continued for
three to five days.{R-7}
Septic shock—
Cats, dogs, and horses: Intravenous, 15 to 30 mg per kg of body weight
as an initial dose,{R-193} to be repeated in 4 to 6 hours.{R-54-56} The
intravenous dose should be administered slowly.{R-9}
Note: This treatment regimen should be administered with aggressive
fluid therapy.
Note: [Immunosuppression]1—Cats and dogs: Although the safety and
efficacy have not been established, an intramuscular or intravenous dose
of 2 to 4 mg per kg of body weight a day for three or more days as needed
to control the condition{R-9} has been used for immunosuppression. The
All rights reserved
54 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
dose is then tapered to 2 to 4 mg per kg of body weight every forty-eight
hours.{R-189}
Strength(s) usually available:{R-13}
(When mixed according to manufacturer’s instructions)—
U.S.:
Veterinary-labeled product(s)—{R-7}
10 mg per mL (Rx) [Solu-Delta-Cortef].
50 mg per mL (Rx) [Solu-Delta-Cortef].
Canada:
Veterinary-labeled product(s)—{R-9}
10 mg per mL (Rx) [Solu-Delta-Cortef; generic].
50 mg per mL (Rx) [Solu-Delta-Cortef].
Packaging and storage: Store below 40 C (104 F), preferably
between 15 and 30 C (59 and 86 F) in a well-closed container,
unless otherwise specified by the manufacturer. Protect from freezing.
Stability: Reconstituted product should be used immediately and should
not be stored;{R-7} any unused reconstituted product should be discarded.{R-7} If the solution becomes cloudy after reconstitution, it
should not be used intravenously.{R-7}
Incompatibilities: Prednisolone sodium succinate should not be added
to calcium infusion solutions.{R-7}
USP requirements: Preserve in Containers for Sterile Solids. It is sterile
prednisolone sodium succinate prepared from Prednisolone Hemisuccinate with the aid of Sodium Hydroxide or Sodium Carbonate. Contains suitable buffers. Contains an amount of prednisolone sodium
succinate equivalent to the labeled amount of prednisolone, within
±10%. Meets the requirements for Constituted solution, Identification,
Bacterial endotoxins, pH (6.7–8.0, determined in the solution constituted as directed in the labeling), Loss on drying (not more than 2.0%),
and Particulate matter, and for Sterility tests, Uniformity of dosage
units, and Labeling under Injections.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
PREDNISONE
SUMMARY OF DIFFERENCES
Pharmacology/pharmacokinetics: Prednisone requires conversion by the
liver to the active compound prednisolone. Hepatic metabolism of
prednisone to prednisolone is considered rapid enough and the serum
concentration versus time curves similar enough for the two medications that the effects of the administered prednisone are not significantly less than those of prednisolone{R-100} in dogs without severe
hepatic compromise.
Veterinary dosing information: In mice, prednisone has approximately
four times the anti-inflammatory potency of cortisol and equals that of
prednisolone.{R-16; 38} It has approximately 0.8 times the sodiumretaining effect of cortisol in mice.{R-38}
ORAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
2004 The United States Pharmacopeial Convention, Inc.
Dosing for prednisone is considered comparable to prednisolone in
animals without severe liver disease.
PREDNISONE TABLETS USP
Usual dose:
[Adrenocortical insufficiency]1—
Cats and dogs: Oral, 0.2 mg per kg of body weight a day.{R-100; 195; 196}
This is the average dose administered to control signs, although
clinicians may start with a higher initial dose of 0.3 to 0.4 mg per kg
of body weight a day.{R-195} The dose is used in combination with
mineralocorticoid replacement therapy or alone in the treatment of
secondary hypoadrenocorticism.{R-195}
Horses: Oral, 0.1 to 0.5 mg per kg of body weight a day.{R-100; 210; 211}
[Allergic disorders];
[Dermatoses]; or
[Inflammation], including ocular1 and musculoskeletal inflammation—
Cats: Oral, 2.2 mg per kg of body weight every twelve to twenty-four
hours as an initial dose.{R-31; 189} Once clinical effect is achieved, the
dose should be tapered to reach an effective alternate-day dose
administered every forty-eight hours.
Dogs: Oral, 0.5 to 1 mg per kg of body weight every twelve to twentyfour hours as an initial dose.{R-31; 189} Once clinical effect is
achieved, the dose should be tapered to reach an effective alternateday dose administered every forty-eight hours.
[Anemia, autoimmune, hemolytic]1—Cats and dogs: Oral, 1 to 3 mg per
kg of body weight every twelve to twenty-four hours.{R-39-41; 94; 98; 99}
Treatment is continued until the disease is controlled and, when
clinically possible, then changed to an alternate-day dose. A gradual
decrease in dose to a maintenance therapy of 0.5 to 1 mg per kg of
body weight every forty-eight hours is recommended.{R-38}
[Asthma]1—Cats: Oral, 2.2 mg per kg of body weight every twelve to
twenty-four hours as an initial dose.{R-28; 31; 189} Once clinical effect is
achieved, the dose should be tapered to reach an effective alternate-day
dose administered every forty-eight hours.
[Disk disease, intervertebral]1—Dogs: Oral, 0.5 to 1 mg per kg of body
weight every twelve to twenty-four hours as an initial dose.{R-31; 189}
Once clinical effect is achieved, the dose should be tapered to reach an
effective alternate-day dose administered every forty-eight hours.
Note: Because of a lack of research data on an effective dose of
glucocorticoids in the treatment of disk disease in dogs, an antiinflammatory dose is listed above, based on clinical judgment. This
is not the dose or dosage form recommended for neurologic
dysfunction or paralysis due to disk disease (see acute spinal
trauma under Methylprednisolone Sodium Succinate For Injection
USP).
[Lupus erythematosus]1—Dogs: Oral, 1 to 1.5 mg per kg of body weight
every twelve hours or 2 to 3 mg every twenty-four hours for two
weeks.{R-98; 99} With a good response to treatment two weeks after
initiation, the dose should be halved, and four weeks after initiation
the dosing interval should be doubled to forty-eight hours and the
response monitored.
Note: The above dose is based on retrospective studies and case reports.
[Lymphoma]1—Cats and dogs: Oral, 2.2 mg per kg of body weight a day,
administered in combination with chemotherapeutic medications
effective in the treatment of lymphoma.{R-83-86; 100; 108} It is very
uncommon for prednisone to be administered as a sole agent because
All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 55
combination chemotherapy is often much more effective and use of
prednisone alone is thought to make lymphoma less responsive to
subsequent chemotherapy. The particular combination therapeutic
regimen is chosen based on the animal’s initial evaluation and cancer
staging followed by subsequent evaluations.
[Mast cell tumors]1—Dogs: Oral, 1 mg per kg of body weight every
twenty-four hours.{R-107}
[Pemphigoid]1—Dogs: Oral, 2 to 3 mg per kg of body weight every
twelve hours.{R-39-41; 100} After symptoms have been controlled, a
maintenance dose of 1 to 2 mg per kg of body weight, administered
every forty-eight hours, has been successful in continuing remission of
signs in many animals that responded well to initial treatment with
corticosteroids alone.{R-39-41}
Note: The above dose is based on dose-response trials and case reports.
[Pemphigus]1—Cats and dogs: Oral, 2 to 3 mg per kg of body weight
every twelve hours.{R-39-41} After symptoms have been controlled, a
maintenance dose of 2 mg per kg of body weight for cats and 1 to 2 mg
per kg of body weight for dogs, administered every forty-eight hours,
has been successful in continuing remission of signs in many animals
that responded well to initial treatment with corticosteroids alone.{R39-41}
Note: The above dose is based on case reports and dose-response trials.
[Thrombocytopenia, immune-mediated]1—Dogs: Oral, 2 mg per kg of
body weight every twelve hours for seven to fourteen days.{R-94;
100}
Note: The above dose is based on retrospective studies. In some cases that
are refractory to treatment, more potent immunosuppressants, such as
azathioprine or cyclophosphamide, are added to this regimen.{R-94}
[Ulcerative colitis]1—Dogs: Oral, 0.5 to 1 mg per kg of body weight every
twelve to twenty-four hours as an initial dose.{R-8} Once clinical effect
is achieved, the dose should be tapered to reach an effective alternateday dose administered every forty-eight hours.
Note: [Chronic obstructive pulmonary disease]1—Horses: Although the
safety and efficacy have not been established, a initial dose of 0.5 to
1 mg per kg of body weight every twelve to twenty-four hours has
been recommended for use in the treatment of chronic obstructive
pulmonary disease.{R-26; 32} The dose should be tapered and, when
feasible, discontinued.{R-26}
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Canada—
Veterinary-labeled product(s):{R-28}
5 mg (Rx) [Predsone-5].
Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F), unless otherwise specified by the
manufacturer. Store in a well-closed container.
USP requirements: Preserve in well-closed containers. Contain the
labeled amount, within ±10%. Meet the requirements for Identification, Dissolution (80% in 30 minutes in water in Apparatus 2 at 50
rpm), and Uniformity of dosage units.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
2004 The United States Pharmacopeial Convention, Inc.
TRIAMCINOLONE
SUMMARY OF DIFFERENCES
Veterinary dosing information: Triamcinolone has approximately five
times the anti-inflammatory potency of cortisol and 1.25 times the
potency of prednisolone. It has no significant mineralocorticoid effect.
ORAL DOSAGE FORMS
TRIAMCINOLONE TABLETS USP
Usual dose:
Allergic disorders1;
Dermatoses1; or
Inflammation1, including musculoskeletal inflammation—Cats and dogs:
Oral, 0.5 to 1 mg per kg of body weight every twenty-four hours as an
initial dose, then taper to 0.5 to 1 mg per kg of body weight every
forty-eight hours.{R-189} With acute, short-term conditions, as soon as
clinical signs are controlled, the dose should be gradually reduced and
then discontinued.{R-20} In the case of chronic conditions, after a
satisfactory clinical response the dose should be reduced until the
minimum effective maintenance dose is reached.
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):{R-20}
0.5 mg (Rx) [Cortalone; Triamtabs].
1.5 mg (Rx) [Cortalone; Triamtabs].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Packaging and storage: Store below 40 C (104 F), preferably between 15 and 30 C (59 and 86 F) in a well-closed container, unless
otherwise specified by the manufacturer.
USP requirements: Preserve in well-closed containers. Contain the
labeled amount, within ±10%. Meet the requirements for Identification, Dissolution (75% in 45 minutes in 0.01 N hydrochloric
acid in Apparatus 1 at 100 rpm), and Uniformity of dosage
units.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
TRIAMCINOLONE ACETONIDE INJECTABLE SUSPENSION USP
Usual dose:
Allergic disorders1; or
Dermatoses1—Cats and dogs: Intramuscular or subcutaneous, 0.11 to
0.22 mg per kg of body weight as a single dose.{R-22} If symptoms
recur, the dose may be repeated after seven to fifteen days.{R-22}
All rights reserved
56 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
Note: For dermatitis, 0.22 mg per kg as a single dose is recommended.{R-22}
For injections directly into the lesion, a total dose of 1.2 to 1.8 mg as
a single dose is used.{R-22} It is recommended that the dose at any
one site should not exceed 0.6 mg and should be made well into the
cutis. Injections are circumscribed around the lesion using a tuberculin syringe with a small bore needle (23 to 25 gauge). When multiple
lesions are treated, the total dose should not exceed 6 mg.{R-22}
Inflammation1, including musculoskeletal inflammation—
Cats and dogs: Intramuscular or subcutaneous, 0.11 to 0.22 mg per kg
of body weight as a single dose.{R-22} If symptoms recur, the dose
may be repeated after seven to fifteen days.{R-22}
Horses: Intramuscular or subcutaneous, 0.022 to 0.044 mg per kg of
body weight as a single dose.{R-22}
Inflammation, musculoskeletal (joint)—
Cats and dogs: Intra-articular or intrasynovial, a total dose of 1 to 3 mg
as a single dose.{R-22} The dose may be repeated after three to four
days, if necessary.{R-22}
Horses: Intra-articular or intrasynovial, 6 to 18 mg as a total single
dose.{R-22} The dose may be repeated after three to four days, if
necessary.{R-22}
Note: If marked increases in pain, local swelling, restriction of joint
motion, and fever are noted, septic arthritis should be considered. If
sepsis is present, antimicrobial therapy should be instituted immediately.{R-22}
[Parturition induction]1—Pretreatment dose: Cattle—Intramuscular,
0.016 mg per kg of body weight,{R-110} given one week before
induction of parturition with dexamethasone.
Note: Forty percent of cows given this pretreatment may calve before
the parturition induction dose that is administered 6 days later.{R110}
Note: [Chronic obstructive pulmonary disease]—Horses: Although the
safety and efficacy have not been established in the treatment of
chronic obstructive pulmonary disease in horses, a single intramuscular dose of 0.09 mg per kg of body weight may be effective in the
relief of signs for up to four weeks.{R-199}
Strength(s) usually available:{R-13}
U.S.—
Veterinary-labeled product(s):{R-22}
2 mg per mL (Rx) [Vetalog].
6 mg per mL (Rx) [Vetalog].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Withdrawal times:
U.S.—Triamcinolone acetonide suspension is not labeled for use in horses
intended for food.{R-22}
Packaging and storage: Store below 40 C (104 F), preferably
between 15 and 30 C (59 and 86 F), unless otherwise specified by
the manufacturer. Protect from freezing.{R-22}
USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I glass, protected from light. A sterile suspension of Triamcinolone Acetonide in a suitable aqueous medium.
2004 The United States Pharmacopeial Convention, Inc.
Contains the labeled amount, within –10% to +15%. Meets the
requirements for Identification, Bacterial endotoxins, and pH
(5.0–7.5), and for Injections.{R-183}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
Developed: 7/15/98
Interim revision: 11/10/99; 2/6/04
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All rights reserved
CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic 59
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2004 The United States Pharmacopeial Convention, Inc.
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2550, 2557, 2563, 2570, 2585.
All rights reserved
60 CORTICOSTEROIDS—GLUCOCORTICOID EFFECTS Veterinary—Systemic
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194. Panel consensus, 11/10/97.
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196. Panel comment, Rec 12/29/97.
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2004 The United States Pharmacopeial Convention, Inc.
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207. Breitschwerdt EB, Davidson MG, Hegarty BC, et al. Prednisolone at antiinflammatory or immunosuppressive dosages in conjunction with doxycycline does not potentiate the severity of Rickettsia rickettsii infection in dogs.
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223. Panel comment, Rec 4/14/98.
All rights reserved
DERACOXIB Veterinary—Systemic 61
DERACOXIB Veterinary—Systemic
A commonly used brand name for a veterinary-labeled product is
Deramaxx.
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
Not commercially available in Canada.
CATEGORY:
Analgesic; anti-inflammatory (nonsteroidal).
INDICATIONS
ACCEPTED
Inflammation, musculoskeletal (treatment)1; or
Pain, musculoskeletal (treatment)1—Dogs: Deracoxib is indicated for the
control of pain and inflammation associated with osteoarthritis.{R-1}
Inflammation, postoperative (treatment)1; or
Pain, postoperative (treatment)1—Dogs, at least 1.8 kilograms (4 pounds)
of body weight: Deracoxib is indicated for the control of postoperative
pain and inflammation associated with orthopedic surgery.{R-1}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
REGULATORY CONSIDERATIONS
U.S.—
Deracoxib is labeled for use only by or on the order of a licensed
veterinarian.{R-1}
CHEMISTRY
Chemical group: Diaryl substituted pyrazole.{R-1}
Chemical name: 4-[5-(3-difluoro-4-methoxyphenyl)-(difluoromethyl)1H-pyrazole-1-yl] benzenesulfonamide.{R-1}
Molecular formula: C17H14F3N3O3S.{R-1}
Molecular weight: 397.38.{R-1}
PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/Effect: Anti-inflammatory—Deracoxib is a
nonsteroidal anti-inflammatory drug (NSAID) of the coxib class.{R-1} It
is a cyclooxygenase inhibitor and decreases the production of prostaglandin E1 (PGE1) and 6-keto prostaglandin F1 (6-keto PGF1).{R-1}
Cyclooxygenase 1 (COX-1), present in most cells and tissues, is believed
to produce cytoprotective prostaglandins active in maintaining normal
gastrointestinal and renal function in mammals while COX-2 produces
prostaglandins involved in inflammation.{R-1}
In lipopolysacharride-stimulated human whole blood, deracoxib was
shown to inhibit COX-2-mediated PGE2 production. Studies using
cloned canine cyclooxygenase have shown that concentrations
expected in vivo with administration of 2 to 4 mg per kg of body
weight a day do not inhibit COX-1 in vitro.{R-1; 6} However, it is not
known how well this in vitro data relates to effects in vivo{R-1}; there is
still much to be learned about the mechanisms of action for the
NSAIDs.
2004 The United States Pharmacopeial Convention, Inc.
Absorption: Oral bioavailability (F)—Dogs: With a single oral dose of
2.35 mg per kg of body weight (mg/kg), bioavailability is greater than
90%.{R-1}
Distribution: Volume of distribution—Dogs: Approximately 1.5 liters
per kg.{R-1}
Protein binding: Dogs—Greater than 90% at in vitro plasma concentrations of 0.1 to 10 micrograms per milliliter.{R-1}
Biotransformation: Deracoxib undergoes hepatic metabolism, producing four major metabolites.{R-1}
Half-life: Terminal elimination—Dogs: Intravenous administration—
With a dose of 2 to 3 mg/kg: 3 hours.{R-1}
With a dose of 20 mg/kg: 19 hours.{R-1}
Note: Nonlinear elimination kinetics can be seen in dogs administered
more than 8 mg/kg a day,{R-1} causing deracoxib plasma concentration to rise higher than would be expected if proportional to the
increasing dose.{R-3} Competitive inhibition of COX-1 can occur when
doses higher than recommended are administered, leading to increased
risk of toxicity.{R-1; 3}
Time to peak serum concentration: Dogs—With an oral dose of 2.35
mg/kg: 2 hours.{R-1}
Elimination: Deracoxib is eliminated primarily in the feces as parent
drug and metabolites. Only metabolites are distributed into the urine.
There is great intersubject variability in drug metabolite profiles in
feces and urine.{R-1}
Clearance—Dogs:
With an intravenous dose of 2 mg/kg—Approximately 5 milliliters per
minute per kilogram (mL/min/kg).{R-1}
With an intravenous dose of 20 mg/kg—Approximately 1.7 mL/min/
kg.{R-1}
PRECAUTIONS TO CONSIDER
CROSS-SENSITIVITY
There is a possibility that animals hypersensitive to sulfonamide
medications could also be hypersensitive to deracoxib; however, there
is no clinical evidence available to confirm it.{R-1}
SPECIES SENSITIVITY
Cats: The use of deracoxib in cats is not recommended until more
information about safety is available.{R-7}
REPRODUCTION/PREGNANCY/LACTATION
Dogs: The safety of administering deracoxib to dogs during breeding,
pregnancy, or lactation has not been studied.{R-1}
PEDIATRICS
Dogs: The safety of administering deracoxib to dogs younger than 4
months of age has not been studied.{R-1}
All rights reserved
62 DERACOXIB Veterinary—Systemic
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications,
depending on the amount present, may also interact with this
medication.
Anti-inflammatory drugs, nonsteroidal (NSAID) or
Corticosteroids
(administration of more than one NSAID or of a corticosteroid
concurrently with a NSAID may greatly increase the risk of adverse
effects){R-1; 2}
Nephrotoxic medications
(concurrent adminstration of NSAIDs with other medications associated with renal toxicity should be considered carefully before
implementation){R-1}
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
given in parentheses where appropriate)—not necessarily inclusive
(»= major clinical significance).
Except under special circumstances, this medication should not be
used when the following medical problems exist:
Cardiovascular disease{R-1} or
Hepatic dysfunction{R-1} or
Renal dysfunction{R-1}
(because NSAIDs have been associated with renal toxicity in certain
circumstances, risk to patients with cardiovascular, hepatic, or renal
compromise may be increased; also, deracoxib is metabolized by the
liver)
Dehydration{R-1}
(dehydration can increase the risk of renal toxicity)
Gastrointestinal ulceration
(many NSAIDs are known to increase the risk of gastrointestinal
disease, particularly ulceration;{R-1} therefore, the presence of lesions
before treatment may put an animal at risk of exacerbation or
perforation)
Hypersensitivity to deracoxib{R-1}
(previous development of adverse effects from deracoxib may be an
indication of increased risk of future sensitivity)
PATIENT MONITORING
The following may be especially important in patient monitoring (other
tests may be warranted in some patients, depending on condition; »
=major clinical significance):
Blood chemistry and
Complete blood count (CBC) and
Urinalysis
(bloodwork and urinalysis pretreatment and periodically during
treatment is recommended){R-1}
Physical exam
(a physical exam and history before treatment is recommended){R-1}
SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their
potential clinical significance (possible signs and, for humans, symptoms in parentheses where appropriate)—not necessarily inclusive:
2004 The United States Pharmacopeial Convention, Inc.
Note: The side effects most commonly associated with nonsteroidal antiinflammatory drugs are gastrointestinal. However, in a field study of
the treatment of osteoarthritis pain and inflammation, the incidence of
observed clinical adverse reactions, including diarrhea and vomiting,
in dogs treated with the labeled dose of deracoxib (1 to 2 mg/kg a day
for 43 days; 105 dogs) was similar to that of dogs administered placebo
(104 dogs). There were no significant differences in complete blood
count, serum chemistry, or buccal mucosal bleeding time results
between deracoxib- and placebo-treated animals.{R-1}
In a field study comparing the treatment of postoperative pain and
inflammation with deracoxib (3 to 4 mg/kg a day from a day before
surgery to 6 days after surgery) in a group of 105 dogs to treatment
with placebo in another group of 102 dogs, the following abnormal
health findings were recorded:
Incidence more frequent
Dogs
Diarrhea—reported in 6% of dogs treated with deracoxib for
postoperative pain and 7% of placebo-treated dogs;{R-1} incision site
lesion (drainage, oozing)—10% of dogs treated with deracoxib and 6%
of placebo-treated dogs;{R-1} vomiting—reported in 10% of dogs
treated with deracoxib and 6% of placebo-treated dogs{R-1}
Incidence less frequent
Dogs
Hematochezia—4% of dogs treated with deracoxib; hematuria—2%
of dogs treated with deracoxib; otitis externa—2% of dogs treated
with deracoxib; skin lesions, nonincisional—2% of dogs treated
with deracoxib{R-1}
Incidence rare—<1% of animals treated with deracoxib
Dogs
Conjunctivitis—2% of dogs treated with placebo; hepatomegaly;
phlebitis; positive joint culture; splenomegaly
OVERDOSE
For more information in cases of overdose or unintentional ingestion,
contact the American Society for the Prevention of Cruelty to
Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation)
and/or the drug manufacturer.
CLINICAL EFFECTS OF OVERDOSE
The following effects have been selected on the basis of their potential
clinical significance (possible signs in parentheses where appropriate)—not necessarily inclusive:
Note: Nonlinear elimination kinetics can be seen in dogs administered
more than 8 mg per kg of body weight (mg/kg) a day,{R-1} causing
deracoxib plasma concentration to rise higher than would be expected
if proportional to the increasing dose.{R-3} Competitive inhibition of
COX-1 can occur when doses higher than recommended are administered, leading to increased risk of toxicity.{R-1; 3}
Dogs
With a dose of 6 to 10 mg/kg a day for 6 months, the following were
reported during the treatment period:{R-1}
Elevated blood urea nitrogen (BUN); hyposthenuria; polyuria;
renal changes
Note: Elevated blood urea nitrogen (BUN, mean 30, 35.3, and 48.2 mg
per decaliter for dogs given 6, 8, or 10 mg/kg a day, respectively)
was recorded at the end of six months in all dogs administered
All rights reserved
DERACOXIB Veterinary—Systemic 63
deracoxib in this dosage range. Two of ten dogs given 6 mg/kg a day
developed hyposthenuria and polyuria. All dogs had serum creatinine, serum electrolyte, and urine sediment within normal range. In
some dogs, renal histopathology revealed a dose-dependent focal
renal tubular degeneration/regeneration and, in a few dogs given the
highest doses, focal renal papillary necrosis was seen.{R-1; 4}
With a dose of 16.92 mg/kg a day for 7 days, the following were reported
in the one dog treated:{R-1}
Decreased appetite; diarrhea; increased water intake; vomiting
Note: Signs resolved within 3 days of ending treatment.
With a dose of 10 to 100 mg/kg a day for 14 days, the following were
reported during the treatment period:{R-1}
Gastrointestinal irritation or ulceration (decreased body weight,
melena, vomiting)
Note: In this study, the number and severity of gastrointestinal lesions
seen in dogs increased with increasing dose. With the lowest dose,
moderate diffuse congestion of gut associated lymphoid tissue and
erosions or ulcers were observed in the jejunum while no change in
body weight was recorded.{R-1} Most dogs that received a dose ‡25
mg/kg developed melena, sporadic vomiting, and a reduction in body
weight.{R-3} With the dose of 100 mg/kg, ulcers in the stomach and
erosions or ulcerations in the small intestine were observed in every
dog.{R-1; 3}
CLIENT CONSULTATION
A sheet entitled DeramaxxTM Chewable Tablets: Information for Dog Owners
is provided by the United States manufacturer for clients administering
oral deracoxib to their dogs.{R-2}
In providing consultation, consider emphasizing the following selected
information:
Keeping water readily available during the treatment period to avoid
dehydration
Never exceeding the prescribed daily amount without veterinary
consultation; contacting a veterinarian if more than the daily dose is
consumed{R-2}
Familiarizing clients with signs that an adverse reaction may be
occurring, including vomiting, change in bowel movements, change
in drinking habits, change in urination habits, or a decrease in
appetite.{R-2} Instructing them to discontinue medication and
contact their veterinarian if a reaction is suspected
Not administering nonsteroidal anti-inflammatory drugs labeled for
human use to animals without guidance from a veterinarian; human
dosages may be toxic or fatal for animals
VETERINARY DOSING INFORMATION
ORAL ADMINISTRATION
Postprandial administration of deracoxib is recommended because
bioavailability is highest when it is given with food; however,
bioavailability is sufficient even if it must be given to a fasted dog.{R1; 2}
FOR PERIOPERATIVE ADMINISTRATION
Because nonsteroidal anti-inflammatory drugs (NSAIDs) can produce
renal complications in animals prone to them, intravenous fluid
2004 The United States Pharmacopeial Convention, Inc.
therapy during surgery may be an appropriate precaution in some
animals at risk for renal disease.{R-1}
ORAL DOSAGE FORMS
DERACOXIB TABLETS
Usual dose:
Inflammation, musculoskeletal1; or
Pain, musculoskeletal1—Dogs: Oral, 1 to 2 mg per kg of body weight
every twenty-four hours.{R-1}
Inflammation, postoperative1; or
Pain, postoperative1—Dogs, at least 1.8 kg (4 pounds) of body weight:
Oral, 3 to 4 mg per kg of body weight every twenty-four hours, for up
to seven days.{R-1}
Note: In clinical trials that demonstrated efficacy in treatment of
postoperative pain and inflammation in dogs, deracoxib was administered the evening before surgery and then once a day for six
days.{R-1}
Product labeling states that deracoxib is effective when a dog has
been fasted, although it is preferably administered with food.{R-1}
Strength(s) usually available:
U.S.—{R-1}
Veterinary-labeled product(s):
25 mg (Rx) [Deramaxx (chewable with flavoring; scored)].
100 mg (Rx) [Deramaxx (chewable with flavoring; scored)].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Caution: Keep out of the reach of children.{R-1}
Packaging and storage: Store between 15 and 30 C (59 and 86
F),{R-1} unless otherwise specified by manufacturer.
USP requirements: Not in USP.{R-5}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
Developed: 2/6/04
REFERENCES
1. Deramaxx Chewable Tablets package insert (Novartis—US), Rev 11/02, Rec 9/
5/03.
2. Deramaxx chewable tablets: information for dog owners (Novartis—US), Rev
10/02. Available at www.deramaxx.com. Accessed August 29, 2003.
3. Deramaxx (deracoxib) chewable tablets freedom of information summary
(NADA # 141-203 [perioperative]). Sponsor: Novartis Animal Health US.
Approval Date: 8/21/02.
4. Deramaxx (deracoxib) chewable tablets freedom of information summary
(Supplemental NADA # 141-203 [osteoarthritis]). Sponsor: Novartis Animal
Health US. Approval Date: 2/11/03.
5. The United States pharmacopeia. The national formulary. USP 26th revision
(January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United
States Pharmacopeial Convention, Inc., 2002.
6. Gierse JK, Staten NR, Casperson GF, et al. Cloning, expression, and selective
inhibition of canine cyclooxygenase-1 and cyclooxygenase-2. Vet Therapeutics
2002; 3(3): 270-80.
7. Committee comment, Rec 10/22/03.
All rights reserved
64 ETODOLAC Veterinary—Systemic
ETODOLAC Veterinary—Systemic
A commonly used brand name for a veterinary-labeled product is Etogesic.
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
Not commercially available in Canada.
CATEGORY:
Anti-inflammatory (nonsteroidal); analgesic; antipyretic.
INDICATIONS
ACCEPTED
Inflammation, musculoskeletal (treatment)1; or
Pain, musculoskeletal (treatment)1—Dogs: Etodolac tablets are indicated
in the management of inflammation and pain associated with
osteoarthritis.{R-1}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
REGULATORY CONSIDERATIONS
U.S.—
Etodolac is labeled for use only by or on the order of a licensed
veterinarian.{R-1}
Another study reported a 7-fold selectivity of etodolac for COX-2 over
COX-1 using a canine whole blood assay.{R-18}
The roles of COX-1 and COX-2 in normal physiological function and in
production of inflammation are not yet completely defined. Based on
early evidence that their effects may overlap, some authors have
stated that, at certain dosages, a finely balanced partial inhibition of
both COX-1 and COX-2 may be preferred to maximize the inhibition
of inflammation and protection of gastrointestinal mucosa; more
research is necessary.{R-19} It may be that COX inhibition by etodolac
is not the predominant mechanism in its production of antiinflammatory effects.{R-12} Etodolac also inhibits macrophage chemotaxis in vivo and in vitro.{R-1}
Chirality: Etodolac exists in two enantiomeric forms.{R-9} Differences in
pharmacokinetics and pharmacodynamics between the two enantiomers have not been defined in animals.
Absorption:
Dogs—Oral administration:
Rapidly and nearly completely
absorbed.{R-1; 8} Administration with food does not affect bioavailability but does lower and delay the peak serum concentration.{R-10}
Horses—Bioavailability (oral dose of 20 mg/kg): 77% (range, 43 to
100%).{R-16}
Rats—Oral administration: Nearly completely absorbed.{R-8}
CHEMISTRY
Chemical group: Pyranocarboxylic acid.{R-1}
Chemical name: Pyrano[3,4-b]indole-1-acetic
1,3,4,9-tetrahydro-(±)-.{R-2}
Molecular formula: C17H21NO3.
Distribution: Volume of distribution (steady state)—Horses: 0.29 ±
0.09 Liter per kg.{R-16}
acid,
1,8-diethyl-
{R-1; 2}
Molecular weight: 287.37.{R-17}
Other characteristics: N-octanol:water partition coefficient of 11.4 at
pH 7.4.{R-1}
Description: White crystalline solid.{R-1; 17}
pKa: 4.65.{R-1}
Solubility: Insoluble in water; soluble in alcohols, in chloroform, in
dimethyl sulfoxide, and in aqueous polyethylene glycol.{R-1}
PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/effect: Anti-inflammatory—
Inhibition of cyclooxygenase (COX) occurs with etodolac administration.{R-1} COX-1, present in most cells and tissues, is believed to
produce cytoprotective prostaglandins active in maintaining normal
gastrointestinal and renal function in mammals while COX-2
produces prostaglandins involved in inflammation.{R-1} Although
in vitro studies of human enzymes show etodolac selectively
inhibiting COX-2 over COX-1, one in vitro experiment using canine
cells demonstrated a fairly equal inhibition of COX-1 and COX-2.{R-5}
2004 The United States Pharmacopeial Convention, Inc.
Protein binding: Dogs, human beings, and rats—Highly protein-bound
(>95%).{R-8}
Half-life: Elimination—
Dogs:
Adult—Intravenous administration: 9.7 ± 0.97 hours.{R-8}
5 months of age (beagles)—Oral dose of 12 to 17 mg/kg: Terminal
half-life—
Fasted: 7.66 ± 2.05 hours.{R-1}
Fed: 11.98 ± 5.52 hours.{R-1}
Horses:
Intravenous administration—2.85 hours (harmonic mean).{R-16}
Oral dose of 20 mg/kg— 2.72 hours (harmonic mean).{R-16}
Human beings: 7 hours.{R-8}
Rats: 16.6 ± 1.0 hours.{R-8}
Peak concentration:
Dogs, 5 months of age (beagles)—Oral dose of 12 to 17 mg/kg:
Fasted—Peak plasma concentration of 22.0 ± 6.42 microgram per mL
(mcg/mL) at 1.69 ± 0.69 hours after administration.{R-1}
Fed—Peak plasma concentration of 16.9 ± 8.84 mcg/mL at 1.08 ±
0.46 hours after administration.{R-1}
Horses—Oral dose of 20 mg/kg: 32.6 ± 11.0 mcg/mL at 1.03 ± 0.27
hours.{R-16}
Elimination:
Dogs—Primarily eliminated by hepatic metabolism and excretion into the
feces (91%).{R-8} Etodolac is thought to undergo extensive enteroheAll rights reserved
ETODOLAC Veterinary—Systemic 65
patic metabolism.{R-1; 8} Only about 6 to 10% of the dose is excreted
into the urine;{R-1; 7; 8} one-third as free etodolac, one-third as a
glucuronide metabolite, and the remainder as polar metabolites.{R-8}
Rats—Primarily eliminated by hepatic metabolism and excretion into the
feces (81%).{R-8} Etodolac is thought to undergo extensive enterohepatic metabolism.{R-8} Only about 11 to 15% of the dose is excreted
into the urine, primarily as free etodolac with some polar metabolites
present.{R-1; 7; 8}
Horses—Three hydroxylated metabolites of etodolac have been identified
in the urine of horses after oral administration.{R-6}
Systemic clearance: 4.14 ± 0.88 mL/min/kg.{R-16}
Human beings and mice—About 65 and 53% of the dose is excreted into
the urine in human beings and mice, respectively.{R-7}
PRECAUTIONS TO CONSIDER
CROSS-SENSITIVITY
Animals sensitive to one of the nonsteroidal anti-inflammatory drugs
(NSAIDs) may be sensitive to any of the other NSAIDs also.
PREGNANCY/REPRODUCTION
The safety of etodolac in breeding, pregnant or lactating dogs has not
been studied.{R-1}
Fertility—A reduction in the number of fertilized eggs implanted was
demonstrated in reproduction studies in rats receiving 8 mg/kg a day,
but no impairment of fertility was demonstrated in male or female rats
receiving up to 16 mg/kg a day.{R-13}
Pregnancy—Isolated alterations of limb development, including polydactyly, oligodactyly, syndactyly, and unossified phalanges, occurred
in offspring of rats receiving 2 to 14 mg/kg a day. Also, oligodactyly
and synostosis of metatarsals occurred in offspring of rabbits receiving
2 to 14 mg/kg a day. However, the frequency and dosage group
distribution in initial and repeated studies did not establish a clear
drug- or dose-response relationship.{R-13}
NSAID administration during late pregnancy can cause prolonged
gestation and dystocia. Delayed and prolonged parturition was associated with decreased rat pup survival in studies with etodolac.{R-13}
LACTATION
It is not known whether etodolac is distributed into milk.
PEDIATRICS
The safety of etodolac in dogs less than 1 year of age has not been
studied.{R-1}
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications,
depending on the amount present, may also interact with this
medication.
Angiotensin converting enzyme inhibitors (ACE inhibitors) or
Furosemide
(because ACE inhibitors and furosemide act through the effects of
vasodilatory prostaglandins on renal function, NSAIDS may decrease
2004 The United States Pharmacopeial Convention, Inc.
their effectiveness; there is not yet any evidence that this is clinically
significant, but monitoring is recommended)
Anti-inflammatory medications,{R-1} such as
Aspirin
Corticosteroids
Other nonsteroidal anti-inflammatory drugs
(concurrent use of two or more NSAIDs or an NSAID and a
corticosteroid is not recommended; concurrent therapy may increase
the risk of gastrointestinal toxicity, including ulceration or hemorrhage, without providing additional symptomatic relief)
(concurrent administration of two or more NSAIDs may alter the
pharmacokinetic profile of at least one of the medications, which may
alter the therapeutic effect and/or increase the risk of adverse effects;
specifically, in human beings, aspirin decreases protein binding of
ketoprofen and etodolac [but does not alter etodolac clearance])
Medications that are moderately to highly protein bound, other{R-1}
(the potential exists for concurrent administration of significantly
protein-bound medications with etodolac to cause displacement of
one or the other drug from protein binding, causing higher or lower
than predicted free-drug concentrations for each; it is recommended
that the medications be monitored; specifically, aspirin and phenylbutazone decrease protein binding of etodolac in in vitro and human
studies)
HUMAN DRUG INTERACTIONS:{R-13}
In addition to the above drug interactions reported in animals, the
following drug interactions have been reported in humans, and are
included in the human monograph Anti-inflammatory Drugs, Nonsteroidal (Systemic) in USP DI Volume I; these drug interactions are
intended for informational purposes only and may or may not be
applicable to the use of etodolac in the treatment of animals:
Note: All of the following interactions have not been documented with
every NSAID. However, they have been reported with several and
should be considered potential precautions to the use of any NSAID,
especially with chronic administration.
Anticoagulants, coumarin- or indandione-derivative or
Heparin or
Thrombolytic agents
(inhibition of platelet aggregation by NSAIDs, and the possibility of
NSAID-induced gastrointestinal ulceration or bleeding, may be
hazardous to patients receiving anticoagulant or thrombolytic
therapy)
Antidiabetic agents, oral or
Insulin
(NSAIDs may increase the hypoglycemic effect of these medications
because prostaglandins are directly involved in regulatory mechanisms of glucose metabolism and possibly because of displacement of
the oral antidiabetics from serum proteins; dosage adjustments of the
antidiabetic agent may be necessary)
Diuretics
(NSAIDs may decrease the diuretic, natriuretic, and antihypertensive
effects of diuretics, probably by inhibiting renal prostaglandin
synthesis)
(concurrent use of an NSAID and a diuretic may increase the risk of
renal failure secondary to a decrease in renal blood flow caused by
inhibition of renal prostaglandin synthesis)
All rights reserved
66 ETODOLAC Veterinary—Systemic
Bone marrow depressants
(leukopenic and/or thrombocytopenic effects of these medications
may be increased with concurrent or recent therapy if an
NSAID causes the same effects; dosage adjustment of the bone
marrow depresssant; if necessary, should be based on blood
counts)
Cyclosporine or
Nephrotoxic medications, other
(inhibition of renal prostaglandin activity by NSAIDs may increase
the plasma concentration of cyclosporine and/or the risk of cyclosporine-induced nephrotoxicity; patients should be carefully monitored during concurrent use)
(the risk of adverse renal effects may also be increased when an
NSAID is used concurrently with other nephrotoxic medications)
Digitalis glycosides
(diclofenac and ibuprofen have been shown to increase serum
digoxin concentrations, and indomethacin has increased digitalis
concentrations in neonates being treated for patent ductus
arteriosus; the possibility should be considered that some of the
other NSAIDs also may increase digoxin concentrations, leading to
an increased risk of digitalis toxicity; increased monitoring and
dosage adjustments of the digitalis glycoside may be necessary
during and following concurrent NSAID therapy; however, studies
have failed to show that flurbiprofen, ketoprofen, piroxicam, or
tenoxicam increase digoxin concentrations, and phenylbutazone
may decrease digitalis concentrations)
Methotrexate
(NSAIDs may decrease protein binding and/or renal elimination of
methotrexate, resulting in increased and prolonged methotrexate
plasma concentrations and an increased risk of toxicity; severe,
sometimes fatal, methotrexate toxicity has been reported when
NSAIDs were used concurrently with low to moderate doses of
methotrexate, and especially with high-dose methotrexate infusion
therapy; caution in concurrent use and adjustment of dosing is
recommended)
Platelet aggregation inhibitors, other
(concurrent use of a platelet aggregation inhibitor with a NSAID may
increase the risk of bleeding because of additive interferences with
platelet function and/or the potential occurrence of NSAID-induced
gastrointestinal ulceration or hemorrhage)
Probenecid
(probenecid may decrease excretion and increase serum concentrations of NSAIDs, possibly enhancing effectiveness and/or increasing
the potential for toxicity; a decrease in dosage of the NSAID may be
necessary if adverse effects occur)
LABORATORY VALUE ALTERATIONS
The following have been selected on the basis of their potential clinical
significance (possible effect in parentheses where appropriate)—not
necessarily inclusive (» = major clinical significance):
Note: No laboratory value alterations have been reported with short-term
administration of etodolac to dogs at recommended dosages. Human
laboratory value alterations have been reported and are included
under Human laboratory value alterations below.
HUMAN LABORATORY VALUE ALTERATIONS{R-13}
The following laboratory value alterations have been reported in
humans, and are included in the human monograph Anti-inflam 2004 The United States Pharmacopeial Convention, Inc.
matory Drugs, Nonsteroidal (Systemic) in the USP DI Volume I; these
laboratory value alterations are intended for informational purposes
only and may or may not be applicable to the use of etodolac in
the treatment of animals:
With diagnostic test results
Bilirubin, urine, determinations
(phenolic metabolites of etodolac may cause false-positive test
results)
Ketones, urine, determinations
(false-positive test results may occur with dipstick method of
determination)
With physiology/laboratory test values
Bleeding time
(may be prolonged by most NSAIDs because of suppressed platelet
aggregation)
Hematocrit or
Hemoglobin
(values may be decreased, possibly because of gastrointestinal
bleeding or microbleeding and/or hemodilution caused by fluid
retention)
Leukocyte count or
Platelet count
(may be decreased)
Liver function tests, including:
Alkaline phosphatase, serum
Lactate dehydrogenase (LDH), serum
Transaminases, serum
(values may be increased; liver function test abnormalities may
return to normal despite continued use; however, if significant
abnormalities occur, clinical signs and symptoms consistent with
liver disease develop, or systemic manifestations such as eosinophilia
or rash occur, the medication should be discontinued)
Potassium, serum, concentrations
(may be increased)
Renal function tests, including:
Blood urea nitrogen (BUN)
Creatinine, serum
Electrolyte, blood and urine, concentrations
Urine volume
(NSAIDs may decrease renal function, resulting in increased BUN,
serum creatinine, and serum electrolyte concentrations and in
decreased urine volume and urine electrolyte concentrations;
however, in some cases, water retention may exceed that of sodium,
resulting in dilutional hyponatremia)
Uric acid concentrations
(serum uric acid concentrations may be decreased and urine
concentrations increased by etodolac; in clinical trials with etodolac, the serum concentration was usually decreased by 1 to 2 mg
per 100 mL [59 to 118 micromoles/L] after 4 weeks of therapy with
600 to 1000 mg per day and the reduction was maintained during
the study period)
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
given in parentheses where appropriate)—not necessarily inclusive
(» = major clinical significance).
All rights reserved
ETODOLAC Veterinary—Systemic 67
Except under special circumstances, this medication should not be
used when the following medical problems exist:
» Hypersensitivity to etodolac{R-1}
(animals previously found to be hypersensitive should not receive
etodolac)
Risk-benefit should be considered when the following medical
problems exist:
Bleeding disorders or
Blood dyscrasias or
Gastrointestinal disease
(may be exacerbated){R-1}
Cardiovascular disorders or
Dehydration or
Hepatic dysfunction or
Renal dysfunction
(animals with the above medical problems can be at higher risk for
renal toxicity){R-1}
(cardiovascular disorders or hepatic dysfunction may be exacerbated){R-1}
PATIENT MONITORING
The following may be especially important in patient monitoring (other
tests may be warranted in some patients, depending on condition; » =
major clinical significance):
Blood chemistry and
Complete blood count (CBC) and
Urinalysis
(particularly in older dogs, dogs with a history of liver or renal
disease, or dogs expected to receive long-term therapy, baseline CBC,
blood chemistry, and urinalysis testing before initiation of etodolac
administration as well as regular follow-up blood chemistry testing
should be considered)
SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their
potential clinical significance (possible signs and, for humans, symptoms in parentheses where appropriate)—not necessarily inclusive:
THOSE INDICATING NEED FOR MEDICAL ATTENTION
Incidence unknown
Dogs (categories listed in decreasing order of frequency)
Gastrointestinal effects (vomiting, diarrhea, inappetance, gastroenteritis, gastrointestinal bleeding, melena, gastrointestinal ulceration,
hypoproteinemia, elevated pancreatic enzymes); hepatic effects
(abnormal liver function tests, elevated hepatic enzymes, icterus,
acute hepatitis); hematologic effects (anemia, hemolytic anemia,
thrombocytopenia, prolonged bleeding time); neurologic/behavioral/
special sense effects (ataxia, paresis, aggression, sedation, hyperactivity, disorientation, hyperesthesia, seizures, vestibular signs, keratoconjunctivitis sicca); renal effects (polydipsia, polyuria, urinary
incontinence, azotemia, acute renal failure, proteinuria, hematuria);
dermatologic/immunologic (pruritis, dermatitis, edema, alopecia,
urticaria); cardiovascular/respiratory (tachycardia, dyspnea)
Note: The above were drawn from post-approval adverse drug experience
reporting.{R-1}
The primary adverse effect appears to be gastrointestinal toxicity.{R-4} In
a preapproval, placebo-controlled clinical field trial using the labeled
2004 The United States Pharmacopeial Convention, Inc.
dose for 8 days in 116 dogs, vomiting was the most common adverse
effect, seen in 4.3% of dogs compared to 1.7% in placebo-treated
dogs.{R-1} However, as with other nonsteroidal anti-inflammatory
drugs (NSAIDS), varying adverse effects may occur in individual
animals with administration of etodolac.
In the same preapproval clinical field trail, three dogs treated with
etodolac developed hypoproteinemia; for two of them, an underlying
cause could not be found and blood protein returned to normal when
etodolac treatment ended.{R-4}
Postapproval cases of keratoconjunctivitis sicca (KCS) in association with
etodolac administration have been reported.{R-14} The frequency of
these reports between 1998 and 2002, based on tablets sold, was
estimated by the manufacturer to be approximately 1 in 3000 dogs
treated.{R-15} However, the relationship between etodolac administration and the development of KCS has not been defined.
Note: Long-term administration—Dogs administered 10 mg/kg a day for
twelve months or 15 mg/kg a day for 6 months, developed mild weight
loss; loose, mucoid, mucosanguineous feces or diarrhea; and hypoproteinemia in some dogs.{R-1} Erosions were found in the small
intestine of the dogs treated with 15 mg/kg a day for 6 months.{R-1}
However, when etodolac was administered for only 9.5 weeks at the
labeled dose, there was no increase reported in the incidence of fecal
abnormalities.{R-1}
HUMAN SIDE/ADVERSE EFFECTS{R-13}
In addition to the above side/adverse effects reported in animals, the
following side/adverse effects have been reported in humans, and are
included in the human monograph Anti-inflammatory Drugs, Nonsteroidal (Systemic) in USP DI Volume I; these side/adverse effects are
intended for informational purposes only and may or may not be
applicable to the use of etodolac in the treatment of animals:
Incidence more frequent
Abdominal cramps, pain, or discomfort, mild to moderate;
bleeding from rectum; bloated feeling or gas; constipation;
diarrhea; fluid retention and edema; headache, mild to moderate; indigestion; nausea; nervousness or irritability
Incidence less frequent
Blurred or double vision or any change in vision; cystitis;
decreased appetite or loss of appetite; dizziness; drowsiness;
general feeling of discomfort or illness; increased sweating;
mental depression; ringing or buzzing in ears; skin rash;
stomatitis, aphthous; trouble in sleeping; vomiting
Incidence rare
Agranulocytosis [granulocytopenia]; anaphylaxis or anaphylactoid reactions; anemia, hemolytic; bitter taste or other taste
change; bleeding from vagina; blood in urine; bronchospastic
allergic reactions; bulbous eruptions/blisters; cardiac arrythmias; confusion; congestive heart failure or exacerbation of;
conjunctivitis; decreased hearing or any change in hearing;
dermatitis, allergic; dermatitis, exfoilative; dry, irritated, or
swollen eyes; erythema or other skin discoloration; eye
pain; fast heartbeat; forgetfulness; gastritis; gastrointestinal
bleeding, gastrointestinal perforation and/or ulceration; hallucinations; hemoptysis; hepatitis or jaundice, toxic; hives;
hypocoagulability; increased blood pressure; interstitial
nephritis; irritation, dryness, or soreness of mouth; itching;
laryngeal edema, lightheadedness/vertigo; loosening or split-
All rights reserved
68 ETODOLAC Veterinary—Systemic
ting of fingernails or other nail disorders; migraine; muscle
cramps; nephrotic syndrome; neuropathy, peripheral; nosebleeds, unexplained; pancreatitis; photoallergic or photosensitive dermatologic reaction; pounding heartbeat; renal
impairment or failure; rhinitis, allergic; shortness of breath
or troubled breathing; syncope; thirst, continuing; thrombocytopenia with or without purpura, trembling or twitching;
weight loss, unexplained
Incidence unknown
Abdominal distention; amblyopia, toxic; angioedema; angitis;
anxiety; aplastic anemia [pancytopenia]; bladder pain; bone
marrow depression; chestpain; cholistatic hepatitis or jaundice; colitis or exacerbation of; convulsions; corneal deposits or
opacity; crystalluria, renal calculi, or ureteral obstruction;
desquamation; disorientation; disseminated intravascular
coagulation; dysarthria (trouble in speaking); dysphagia;
dysuria; ecchymosis/bruising; eczema; edema, pulmonary;
eosinophilia; epigastric pain; enteritis, regional or exacerbation of; enterocolitis; erythema multiforme; erythema nodosum; esophagitis; feeling of depersonalizaton or muzziness;
fever; flushing or hotflashes; frequent urge to urinate; gastroenteritis; gingival ulceration; glomerulitis or glomerulonephritis; glossitis; headache, severe, especially in the morning;
heartburn; hyperkalemia; incontinence; leukopenia [neutropenia]; Loeffler syndrome [eosinophilic pneumonitis]; lymphadenopathy; meningitis, aseptic; muscle weakness; nephrosis;
oliguria/anuria; palpedral edema; pericarditis; petechia; photophobia; photosensitivity reactions; polyuria; proteinuria;
psychotic reaction; renal papillary or tubular nephrosis;
retinal or macular disturbances; scotomata; serum sicknesslike reaction; Stevens-Johnson syndrome (bleeding or crusting
sores on lips; chest pain; fever with or without chills; muscle
cramps or pain; retinal hemorrhage; skin rash; sores, ulcers, or
white spots in mouth; sore throat); strong-smelling urine;
swelling of lips and tongue, syncope; systemic lupus erythematosus [SLE]-like syndrome; toxic epidermal necrolysis;
trembling or twitching; unusual weakness with no other signs
or symptoms; urethritis or urinary tract infection; vasculitis
OVERDOSE
For information in cases of overdose or unintentional ingestion, contact
the American Society for the Prevention of Cruelty to Animals
(ASPCA) National Animal Poison Control Center (888-426-4435
or 900-443-0000; a fee may be required for consultation) and/or the
drug manufacturer.
CLINICAL EFFECTS OF OVERDOSE
The following effects have been selected on the basis of their potential
clinical significance (possible signs in parentheses where appropriate)—not necessarily inclusive:
Dogs
With a dose of 40 mg/kg a day for 52 weeks:{R-1;4}
Decreased erythroid parameters, including red blood cell
count, hematocrit, and hemoglobin; decreased total serum
protein and individual serum albumin and globulin concentrations; fecal occult blood; gastrointestinal erosion or ulceration; increased fibrinogen concentration; increased leukocyte
counts; vomiting; weight loss
2004 The United States Pharmacopeial Convention, Inc.
With a dose of 80 mg/kg a day for 52 weeks:{R-1; 4}
Gastrointestinal ulceration (weight loss, frequent abnormal stools
or vomiting, decreased food intake, pale mucous membranes, and
profound changes in hematological and serum biochemical parameters, including decreased erythrocyte counts, increased leukocyte
and platelet counts and hypoproteinemia, death); renal tubular
necrosis—noted in one dog that died
Note: Six out of eight dogs in this study died from gastrointestinal
ulceration; one within 3 weeks and the others after 3 to 9
months of treatment.{R-1; 4}
CLIENT CONSULTATION
A client information sheet developed specifically for dog owners
administering etodolac to their pet is provided by the United States
manufacturer.
In providing consultation, consider emphasizing the following selected
information:
Returning patients for periodic rechecks while they are on medication
Keeping water readily available during the treatment period to avoid
dehydration
Counseling clients to contact their veterinarian and discontinue
medication if any of the following are observed: decreased appetite,
vomiting, diarrhea, dark or tarry stools, increased water consumption, increased urination, pale gums due to anemia, yellowing of
gums, skin or whites of the eyes due to jaundice, lethargy,
incoordination, seizure, or behavioral changes{R-1}
Keeping tablets out of the reach of children{R-1}
VETERINARY DOSING INFORMATION
FOR TREATMENT OF ADVERSE EFFECTS
Recommended treatment consists of the following:
For anaphylaxis
• Parenteral epinephrine.{R-6}
• Oxygen administration and respiratory support.
ORAL DOSAGE FORMS
ETODOLAC TABLETS USP
Usual dose:
Inflammation, musculoskeletal1; or
Pain, musculoskeletal1—Dogs: Oral, 10 to 15 mg per kg of body weight a
day.{R-1} The dose is adjusted, based on clinical response and
tolerance;{R-1} if longer-term administration is necessary, the minimum effective dose is the goal.
Size(s) usually available:
U.S.—{R-1}
Veterinary-labeled product(s):
150 mg (Rx) [Etogesic (scored)].
300 mg (Rx) [Etogesic (scored)].
500 mg (Rx) [Etogesic (scored)].
Canada—
Veterinary-labeled product(s):
Not commerically available.
Packaging and storage: Store between 15 and 30 C (59 and 86
F),{R-1} unless otherwise specified by the manufacturer.
All rights reserved
ETODOLAC Veterinary—Systemic 69
USP requirements: Preserve in tight containers. Contain the labeled
amount, within ± 10%. Meet the requirements for Identification,
Uniformity of dosage units, and Dissolution (80% in 30 minutes in
phosphate buffer [pH 6.8] in Apparatus 1 at 100 rpm).{R-3}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
Developed: 2/6/04
REFERENCES
1. Etogesic Tablets package insert (Fort Dodge—US), Rev 3/01.
2. USP dictionary of USAN and international drug names, 2002 ed. Rockville,
MD: The United States Pharmacopeial Convention Inc; 2002.
3. The United States Pharmacopeia. The national formulary. USP 26th revision
(January 1, 2003). NF 21st ed. (January 1, 2003). Rockville, MD: The United
States Pharmacopeial Convention Inc, 2002. p. 770.
4. Freedom of Information Summary. Etogesic. NADA 141–108. Sponsor: Fort
Dodge Animal Health. Approval Date: July 22, 1998.
5. Ricketts AP, Lundy KM, Seibel SB. Evaluation of selective inhibition of canine
cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J Vet Res 1998 Nov; 59(11): 1441–6.
6. Koupai-Abyazani MR, Esaw B, Laviolette B. Etodolac in equine urine
and serum: determination by high-performance liquid chromatography
with ultraviolet detection, confirmation, and metabolite identification by
atmospheric pressure ionization mass spectrometry. J Anal Tox 1999 May/
Jun; 23(3): 200–9.
7. Ferdinandi ES, Cochran D, Gedamke R. Identification of the etodolac
metabolite, 4-ureidoetodolac, in mouse, rat, dog, and man. Drug Metab
Dispos 1987 Nov/Dec; 15(6): 921–4.
2004 The United States Pharmacopeial Convention, Inc.
8. Cayen MN, Kraml M, Ferdinandi ES, et al. The metabolic disposition of etodolac
in rats, dogs, and man. Drug Metab Rev 1981; 12(2): 339–62.
9. Budsberg SC, Johnston SA, Schwarz PD, et al. Efficacy of etodolac for the
treatment of osteoarthritis of the hip joints in dogs. J Am Vet Med Assoc 1999
Jan 15; 214(2): 206–10.
10. Kraml M, Cosyns L, Hicks DR, et al. Bioavailability studies with etodolac in
dogs and man. Biopharm Drug Dispos 1984 Jan–Mar; 5(1): 63–74.
11. Reimer ME, Johnston SA, Leib MS, et al. The gastroduodenal effects of buffered
aspirin, carprofen, and etodolac in healthy dogs. J Vet Intern Med 1999; 13:
472–7.
12. Nishihara K, Kikuchi H, Kanno T, et al. Comparison of the upper gastrointestinal effects of etodolac and aspirin in healthy dogs. J Vet Med Sci 2001;
63(10): 1131–3.
13. Klasco RK, editor. USP DI Drug information for the healthcare professional.
Volume I. Greenwood Village, CO: Thomson MICROMEDEX, Inc.; 2003.
14. Cumulative Adverse Drug Experience Summaries: 1987 to May 1, 2003. Food
and Drug Administration Center for Veterinary Medicine. Available at
www.fda.gov/cvm. Accessed on May 15, 2003.
15. Letter sent to veterinary ophthalmologists. Fort Dodge Animal Health. March
19, 2002.
16. Campbell N, Papich M, Blikslager A. Etodolac pharmacokinetics in horses.
Publication pending.
17. Manufacturer comment (Fort Dodge), Rec 8/26/03.
18. Simmons, et al. Analysis of nonsteroidal anti-inflammatory drugs in modified
canine whole blood assays. In: Eighth international veterinary emergency and
critical care symposium. San Antonio, Texas: Veterinary Emergency and
Critical Care Society, 2002.
19. Tomlinson J, Blikslager A. Role of nonsteroidal anti-inflammatory drugs in
gastrointestinal tract injury and repair. J Am Vet Med Association 2003 Apr 1;
222(7): 946–51.
All rights reserved
70 FLUNIXIN Veterinary—Systemic
FLUNIXIN Veterinary—Systemic
Some commonly used brand names for veterinary-labeled products
are: Banamine; Compamine; Cronyxin; Equiphar Equigesic; Equileve;
Flumeglumine; Flunazine; Flu-nix; Flunixamine; Influx-50; and
Suppressor.
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
REGULATORY CONSIDERATIONS
INDICATIONS
U.S.—
Flunixin is not labeled for use in lactating or dry dairy cows, calves to
be processed for veal, or horses intended for food. A withdrawal
period has not been established for use in preruminating calves.
Federal law restricts this drug to use by or on the order of a licensed
veterinarian.{R-1; 2; 3}
Canada—
Flunixin is not labeled for use in lactating or dry dairy cows, calves to
be processed for veal, or horses intended to be slaughtered for food.{R24}
This drug is restricted to use by or on the order of a licensed
veterinarian.{R-24}
Note: Bracketed information in the Indications section refers to uses that
either are not included in U.S. product labeling or are for products not
commercially available in the U.S.
CHEMISTRY
CATEGORY:
Analgesic; anti-inflammatory (nonsteroidal); antipyretic.
Chemical name: Flunixin meglumine—3-Pyridinecarboxylic acid, 2[[2-methyl-3-(trifluoromethyl)phenyl]amino]-, compd. with 1-deoxy1-(methylamino)-D-glucitol (1:1).{R-6}
ACCEPTED
Fever (treatment)—
Cattle: Flunixin injection is indicated for control of fever associated
with bovine respiratory disease and endotoxemia.{R-1; 24}
[Dogs]1 and [horses]1: Flunixin is used for control of fever.
Inflammation, endotoxemia-associated (treatment)—
Cattle: Flunixin injection is indicated for control of inflammation in
endotoxemia.{R-1; 24}
[Dogs]1 and [horses]1: Flunixin is used for control of inflammation in
endotoxemia.{R-34-41}
Inflammation, musculoskeletal (treatment)—Horses: Flunixin granules,
paste1, and injection are indicated for control of inflammation
associated with musculoskeletal disorders.{R-1; 2; 3; 24; 25}
Pain, colic-associated (treatment)—Horses: Flunixin injection is indicated
for control of pain associated with colic.{R-1}
Pain, musculoskeletal (treatment)—Horses: Flunixin granules, paste1,
and injection are indicated for control of pain in equine musculoskeletal disorders.{R-1; 2; 3; 4; 24; 25}
[Sepsis (treatment adjunct)]1—Cattle, dogs,{R-47; 48} and horses: Flunixin
is used as adjunctive therapy in the treatment of sepsis.
ACCEPTANCE NOT ESTABLISHED
[Emphysema, acute bovine pulmonary (treatment)]1—Cattle: Although
the efficacy has not been established, one study using an experimental
model in calves suggests flunixin may reduce the pulmonary effects of
this disorder.{R-49; 50}
[Mastitis, acute coliform (treatment adjunct)]1—Cattle: There is
some evidence to suggest that flunixin, as an adjunct to appropriate
antimicrobial and supportive therapy, may aid in the reduction
of fever and improve appetite; however, it has not been shown
to improve clinical outcomes in cows with acute coliform
mastitis.{R-42-46}
1
Molecular formula: Flunixin meglumine—C14H11F3N2O2 Æ
C7H17NO5.{R-6; 24}
Molecular weight: Flunixin meglumine—491.46.{R-6; 24}
Description: Flunixin Meglumine USP—White to off-white crystalline
powder.{R-20}
pKa: 5.82.{R-23; 24}
Solubility: Flunixin Meglumine USP—Soluble in water, in alcohol, and
in methanol; practically insoluble in ethyl acetate.{R-20}
PHARMACOLOGY/PHARMACOKINETICS
Mechanism of action/Effect: The precise site and mode of action is
unknown. Flunixin acts via analgesic and anti-inflammatory mechanisms. Analgesic actions may involve blocking pain impulse
generation via a peripheral action by inhibition of the synthesis of
prostaglandins and possibly inhibition of the synthesis or actions of
other substances, which sensitize pain receptors to mechanical or
chemical stimulation. Flunixin may act peripherally in inflamed
tissue, probably by inhibiting the enzyme cyclooxygenase to decrease the formation of precursors of prostaglandins,{R-7} and possibly by inhibiting other local mediators of the inflammatory
response.
Absorption: Flunixin is rapidly and relatively completely absorbed from
the gastrointestinal tract of the horse. Flunixin has also been shown to
be rapidly absorbed from the gastrointestinal tract following oral administration to dogs, monkeys, and rats. Rapid absorption following
parenteral administration to cattle, dogs, monkeys, pigs, and rats has
also been shown.
Not included in Canadian product labeling or product not commercially
available in Canada.
Ó 2004 The United States Pharmacopeial Convention, Inc.
All rights reserved
FLUNIXIN Veterinary—Systemic 71
Horses: The effects of flunixin on reproduction in horses have not been
studied.
Pharmacokinetic data:
Species
{R-11}
Cows
{R-14}
{R-22}
Cows, lactating{R-28}
Dogs{R-12}
Horses{R-29}
{R-30}
{R-31}
Half-life of
elimination
(hours)
3.8
5.2
8.1
3.1
3.7 ± 1.2
3.4 ± 1.1
4.2 ± 2.1
VolD, steady
state (L/kg)
Clearance
(mL/min/kg)
0.42
0.78 ± 0.24
0.50
0.40 ± 0.11
0.18 ± 0.08
2.4
1.9 ± 0.2
1.5
2.5 ± 1.0
1.1 ± 0.2
1.0 ± 0.1
1.1 ± 0.2
1.5 ± 0.002
0.15 ± 0.05
0.15 ± 0.01
Protein binding:
Cattle—Protein binding in bovine plasma has been determined to be
>99% over a concentration range of 3 to 24 micrograms per milliliter
(mcg/mL).{R-11}
Dogs—92.2% at 5 mcg/mL.{R-10}
Goats—84.8% at 5 mcg/mL.{R-10}
Horses—86.9% at 5 mcg/mL.{R-10}
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily
inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications,
depending on the amount present, may also interact with this
medication.
» Anti-inflammatory analgesics, nonsteroidal, other
(concurrent use with other nonsteroidal anti-inflammatory medications may increase the risk of severe gastrointestinal side effects,
including ulceration or hemorrhage, without providing additional
improvement, and is generally not recommended)
(because it is highly protein bound, the possibility exists that flunixin
may displace other medications from their protein-binding sites or
flunixin itself may be displaced, leading to increased action of the
displaced medication; interactions based on this mechanism have not
been documented.)
Onset of action: Variable.{R-4; 13}
Concentrations:
Cattle—
Following a single intravenous dose of 2.2 mg per kg of body weight
(mg/kg), plasma concentration was initially 16.16 ± 5.28 mcg/mL,
declined to 1.22 ± 0.16 mcg/mL by 2 hours, and reached 0.5 ± 0.02
mcg/mL by 30 hours.
Following a single oral dose of 2.2 mg/kg, a peak concentration (Cmax) of
0.9 ± 0.05 mcg/mL occurred 3.5 ± 1.0 hours (Tmax) after the dose;
serum concentration declined to 0.06 ± 0.01 mcg/mL by 30 hours.{R-14}
Dogs—
With intravenous administration of 1.1 mg/kg, serum concentration
was approximately 6 mcg/mL at 1 hour post-injection and 0.3 mcg/
mL at 8 hours post-injection.{R-12}
Following a single oral dose of 1.1 mg/kg, a peak serum concentration
of 5.03 ± 0.99 mcg/mL at 1.10 ± 0.2 hours was measured.{R-9}
Twenty-four hours after dosing, serum concentration was below the
level of detection (<0.05 mcg/mL).{R-9}
Horses—
Following a single intravenous dose of 1.1 mg/kg, plasma concentration 1 hour post-injection was 1.6 mcg/mL (mean) and gradually
diminished to 0.065 mcg/mL at 8 hours post-injection.{R-13}
Following a single intravenous dose of 1 mg/kg, plasma concentration
was initially 10 mcg/mL and decreased to 0.1 mcg/mL after 12 hours.
Peak plasma concentration of approximately 3 mcg/mL was reached
about 30 minutes after a 1 mg/kg oral dose.
Elimination: Cattle—Hepatic, primarily by biliary secretion.{R-15}
PRECAUTIONS TO CONSIDER
PREGNANCY/REPRODUCTION
Cattle: Administration of flunixin to bulls intended for breeding is not
recommended because reproductive effects have not been studied.{R-1}
In cows, nonsteroidal anti-inflammatory drugs have the potential to
affect the onset of the estrus cycle or of parturition.{R-1}
Ó 2004 The United States Pharmacopeial Convention, Inc.
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
given in parentheses where appropriate)—not necessarily inclusive (»
= major clinical significance).
Except under special circumstances, this medication should not be
used when the following medical problems exist:
All species
Bleeding disorders
(because nonsteroidal anti-inflammatory drugs [NSAIDs] have been
associated with inhibition of platelet aggregation, their administration to animals with bleeding problems, including coagulation or
platelet function disorders, could increase the risk of adverse effects)
Gastrointestinal bleeding or ulceration
(many NSAIDs are known to increase the risk of gastrointestinal
disease, particularly ulceration;{R-1} therefore, the presence of lesions
before treatment may put an animal at risk of exacerbation or
perforation)
Hypersensitivity to flunixin meglumine{R-1}
(previous development of adverse effects from flunixin may be an
indication of increased risk of future sensitivity)
Risk-benefit should be carefully considered when the following
medical problems exist:
All species
Cardiovascular disease or
Hepatic dysfunction or
Renal dysfunction
(because NSAIDs have been associated with renal toxicity, risk to
patients with cardiovascular, hepatic, or renal compromise may be
increased) {R-1; 16}
Dehydration{R-1}
(dehydration could increase the risk of renal toxicity with NSAID
administration)
All rights reserved
72 FLUNIXIN Veterinary—Systemic
SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their
potential clinical significance (possible signs in parentheses where
appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence unknown
Cattle
Hematochezia, hematuria
Note: Hematochezia and hematuria were reported when cattle were
treated for longer than the maximum three days recommended.{R-1}
Dogs
Ulceration, gastric{R-8}
Horses
Anorexia;{R-32} depression; local tissue reactions (induration,
swelling, stiffness, sweating)—with intramuscular administration in
some horses, particularly if given in the neck;{R-1} oral and gastric
ulceration—with very high doses or long-term use
Note: In rare cases, infections, sometimes clostridial, have been
associated with the local tissue reactions seen with intramuscular
administration.{R-1}
Oral or gastric ulcerations are unlikely to occur when flunixin is
administered at the recommended dose for 2 weeks.{R-13}
Incidence rare
Cattle and horses
Anaphylactic-like reactions—primarily with intravenous administration{R-1}
OVERDOSE
For information in cases of overdose or unintentional ingestion, contact
the American Society for the Prevention of Cruelty to Animals
(ASPCA) National Animal Poison Control Center (888-426-4435
or 900-443-0000; a fee may be required for consultation) and/or the
drug manufacturer.
Packaging and storage: Store between 2 and 30 °C (36 and 86 °F),
unless otherwise specified by the manufacturer.{R-3}
USP requirements: Preserve in well-closed containers. Label Granules
to indicate that they are for veterinary use only. Contain an amount of
flunixin meglumine equivalent to the labeled amount of flunixin,
within ±10%. Meet the requirements for Identification, Dissolution
(75% in 30 minutes in 0.1 N hydrochloric acid in Apparatus 2 at 50
rpm), and Uniformity of dosage units.{R-20}
FLUNIXIN MEGLUMINE PASTE USP
Usual dose: Horses—
Inflammation, musculoskeletal1; or
Pain, musculoskeletal1: Oral, 1.1 mg per kg of body weight,
administered once a day for up to five days.{R-2}
Strength(s) usually available:{R-2; 5}
U.S.—
Veterinary-labeled product(s):
1.5 gram per 30-gram tube (Rx) [Banamine].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Packaging and storage: Store between 2 and 30 °C (36 and 86 °F),
unless otherwise specified by the manufacturer.{R-2} Protect from
freezing.
USP requirements: Preserve in a well-closed container. Label the Paste
to indicate that it is for veterinary use only. Contains an amount of
flunixin meglumine equivalent to the labeled amount of flunixin,
within ±10%. Meets the requirements for Identification and Microbial
limits.{R-20}
1
VETERINARY DOSING INFORMATION
Not included in Canadian product labeling or product not commercially
available in Canada.
Dogs: Because dogs are quite sensitive to the toxic effects of other
nonsteroidal anti-inflammatory analgesics,{R-17; 18} one reference
suggests administering only a single dose of flunixin, and another
suggests daily treatment for no more than 3 days.{R-19}
PARENTERAL DOSAGE FORMS
ORAL DOSAGE FORMS
FLUNIXIN MEGLUMINE INJECTION USP
FLUNIXIN MEGLUMINE GRANULES USP
Usual dose:
Cattle—
Fever;{R-1}
Inflammation, endotoxemia-associated;{R-1} or
[Sepsis (treatment adjunct)]1: Intravenous, administered slowly, 2.2
mg per kg of body weight every twenty-four hours, or 1.1 mg per kg
of body weight every twelve hours, for up to three days.{R-1}
Note: In cattle, intramuscular injection is not recommended;{R-1; 24}
local tissue reactions may result. Repeated intramuscular injections
result in prolonged half-life, potentially lengthening residue withdrawal periods, and should be avoided.
Caution is advised when dehydration or other factors increasing the
risk of nephrotoxicity are present (see also the Medical considerations/
Contraindications section of this monograph).{R-1}
Usual dose: Horses—
Inflammation, musculoskeletal; or
Pain, musculoskeletal: Oral, 1.1 mg per kg of body weight,
administered once a day for up to five days.{R-3; 25}
Strength(s) usually available:{R-3; 5; 25}
U.S.—
Veterinary-labeled product(s):
25 mg per gram of granules (Rx) [Banamine].
Canada—
Veterinary-labeled product(s):
25 mg per gram of granules (Rx) [Banamine].
Ó 2004 The United States Pharmacopeial Convention, Inc.
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
All rights reserved
FLUNIXIN Veterinary—Systemic 73
[Emphysema, acute bovine pulmonary]1—Although the efficacy has
not been established, a study that showed some potential for
reduction of pulmonary effects in an experimental model of the
disorder in calves used an intravenous dose of 2.2 mg per kg of body
weight a day for three days.{R-49; 50}
[Mastitis, acute coliform (treatment adjunct)]1—Studies of cows with
induced disease have used an intravenous dose of flunixin, 1.1 mg
per kg of body weight, administered once, or, if necessary, repeated at
twelve hour intervals.{R-42-46} See also the Withdrawal times section
below.
Horses—
Inflammation, musculoskeletal;{R-1}
Pain, colic-associated;{R-1}
Pain, musculoskeletal;{R-1}
[Fever]1;
[Inflammation, endotoxemia-associated]1;{R-36-41} or
[Sepsis (treatment adjunct)]1: Intramuscular or intravenous, 1.1 mg
per kg of body weight once a day for up to five days.{R-1}
Note: Intramuscular administration of flunixin meglumine injection
has been reported to cause local tissue reactions (including induration,
swelling, stiffness, and sweating) in some horses, especially if
administered in the neck.{R-1} Infections, sometimes clostridial, have
been associated with intramuscular administration in rare cases.{R-1}
Intra-arterial injection should be avoided.{R-1}
For colic-associated pain, intravenous administration is recommended; in a few animals, one or two additional doses may be
necessary if signs of colic return while underlying causes are
determined and treated.{R-1}
For treatment of endotoxemia or sepsis in horses, an intravenous
dosage regimen similar to that for colic-associated pain might be
used, with additional doses every six to twelve hours after the initial
one dependent on the clinical course. The dose recommendation is
based on studies performed with experimentally induced models of
endotoxemia in horses.{R-37; 39; 41}
Other studies using models of endotoxemia in horses have shown
that 0.25 mg of flunixin per kg of body weight every eight hours will
provide suppression (dose-dependent) of eicosanoid synthesis while
not relieving (masking) all clinical signs; the level of pain relief
provided by this dose was not assessed.{R-36; 38; 40; 51}
[Dogs]1—
Fever;
Inflammation, endotoxemia-associated; or
Sepsis (treatment adjunct): Intramuscular or intravenous, 0.5 to 1 mg
per kg of body weight as a single dose, or, if necessary, once a day for
no more than three days.{R-19}
Note: The dose listed above for treatment of endotoxemia or sepsis in
dogs is based on studies performed with experimentally induced
models of disease.{R-34; 35; 47; 48}
Strength(s) usually available:{R-1; 5}
U.S.—
Veterinary-labeled product(s):
50 mg per mL (Rx) [Banamine; Compamine; Equi-Phar Equigesic;
Equileve; Flumeglumine; Flu-nix; Flunixamine; Suppressor; generic].
Canada—
Veterinary-labeled product(s):
50 mg per mL (Rx) [Banamine; Cronyxin; Flunazine; Influx-50;
generic].
Ó 2004 The United States Pharmacopeial Convention, Inc.
Withdrawal times:{R-1; 24}
U.S.—
Withdrawal time
Species
Meat (days)
Cattle
4
Note: Product labeling listing the above withdrawal time states that it
applies to a dose of 2.2 mg per kg of body weight once a day or 1.1
mg per kg of body weight every twelve hours for a maximum of 3
days.{R-1}
Product labeling states that flunixin injection is not for use in
lactating or dry dairy cows, calves to be processed for veal, or horses
intended for food.{R-1}
Canada—
Withdrawal time
Species
Meat (days)
Cattle
6
Note: Product labeling listing the above withdrawal time states that it
applies to a dose of 2.2 mg per kg of body weight a day for up to 3
days.{R-24}
Product labeling states that flunixin injection is not for use in
lactating or dry dairy cows, calves to be processed for veal, or horses
intended to be slaughtered for food.{R-24}
Note: Flunixin meglumine injection is not labeled for use in lactating
dairy cattle in the United States or Canada;{R-1; 24} therefore, there are
no established withdrawal times.
U.S.—If flunixin is administered to lactating dairy cattle at an
intravenous dose of 2.2 mg per kg of body weight a day for three
days, evidence has been compiled by the Food Animal Residue
Avoidance Databank (FARAD) that suggests a meat withdrawal time
of 4 days and a milk withholding time of 72 hours would be sufficient
to avoid residues.{R-26; 27}
Canada—If flunixin is administered to lactating dairy cattle at an
intravenous dose of 2.2 mg per kg of body weight a day for three days,
evidence has been compiled by the Canadian gFARAD that suggests a
meat withdrawal time of time of 6 days and a milk withholding time of
72 hours would be sufficient to avoid residues.{R-33}
Packaging and storage: Store between 2 and 30 °C (36 and 86 °F),
unless otherwise specified by the manufacturer.{R-1} Protect from
freezing.
USP requirements: Preserve in multiple-dose containers at controlled
room temperature. A sterile solution of Flunixin Meglumine in Water
for Injection. Label Injection to indicate that it is for veterinary use
only. Contains an amount of flunixin meglumine equivalent to the
labeled amount of flunixin, within ±10%. Meets the requirements for
Identification, Bacterial endotoxins, Sterility, and pH (7.8–9.0).{R-20}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
All rights reserved
74 FLUNIXIN Veterinary—Systemic
Revised: 04/30/93; 09/30/02
Interim revision: 07/18/94; 04/24/96; 06/02/97; 06/25/98; 2/6/04
REFERENCES
1. Banamine injectable solution package insert (Schering-Plough—US), Rev 4/
98, Rec 1/16/03.
2. Banamine paste package insert (Schering-Plough—US), Rev 1/99, Rec 1/16/
03.
3. Banamine granules package insert (Schering-Plough—US), Rev 11/89, Rec 1/
16/03.
4. Tobin T. Pharmacology review: the nonsteroidal anti-inflammatory drugs. II
Equipoxen, meclofenamic acid, flunixin, and others. J Equine Med Surg 1979
July; 3(7): 298–302.
5. Arrioja-Dechert A, editor. Compendium of Veterinary Products, CD edition.
Port Huron, MI: North American Compendiums, Inc., 2003.
6. USP dictionary of USAN and international drug names, 2002 ed. Rockville,
MD: The United States Pharmacopeial Convention Inc; 2002.
7. Lees P, Higgins AJ. Clinical pharmacology and therapeutic uses of nonsteroidal
anti-inflammatory drugs in the horse. Equine Vet J 1985 Mar; 17(2): 83–96.
8. Dow SW, Rosychuk RA, McChesney AE, et al. Effects of flunixin and flunixin
plus prednisone on the gastrointestinal tract of dogs. Am J Vet Res 1990 Jul;
51(7): 1131–8.
9. McKellar QA, Galbraith EA, Bogan JA, et al. Flunixin pharmacokinetics and
serum thromboxane inhibition in the dog. Vet Rec 1989; 124: 651–4.
10. Galbraith EA, McKellar QA. Protein binding and in vitro serum thromboxane
B2 inhibition by flunixin meglumine & meclofenamic acid in dog, goat & horse
blood. Res Vet Sci 1996; 61: 78–81.
11. Odensvik K, Johansson M. High-performance liquid chromatography method
for determination of flunixin in bovine plasma and pharmacokinetics after
single and repeated doses of the drug. Am J Vet Res 1995; 56: 489–495.
12. Hardie EM, Hardee GE, Rawlings CA. Pharmacokinetics of flunixin meglumine
in dogs. Am J Vet Res 1985 Jan; 46(1): 235–7.
13. Houdeshell JW, Hennessey PW. A new nonsteroidal anti-inflammatory
analgesic for horses. J Equine Med Surg 1977 Feb; 1(2): 57–63.
14. Odensvik K. Pharmacokinetics of flunixin and its effect on prostaglandin F2
alpha metabolite concentrations after oral and intravenous administration in
heifers. J Vet Pharmacol Ther 1995; 18: 254–9.
15. Kopcha M, Ahl AS. Experimental uses of flunixin meglumine and phenylbutazone in food-producing animals. J Am Vet Med Assoc. 1989; 194: 45–49.
16. Gunson DE. Renal papillary necrosis in horses. J Am Vet Med Assoc 1983 Feb
1; 182(3): 263–6.
17. Ewing GO. Indomethacin-induced gastrointestinal hemorrhage in a dog. J Am
Vet Med Assoc 1972 Dec 15; 161(12): 1665–8.
18. Roudebush P, Morse GE. Naproxen toxicosis in a dog. J Am Vet Med Assoc
1981 Oct 15; 179(8): 805–6.
19. Davis LE. Handbook of small animal therapeutics. Churchill Livingstone,
1985. p. 145, 690.
20. The United States Pharmacopeia. The national formulary. USP 26th revision
(January 1, 2003). NF 21st ed. (January 1, 2003). Rockville, MD: The United
States Pharmacopeial Convention Inc, 2002. p. 800, 801, 2561.
21. International symposium on nonsteroidal anti-inflammatory agents, 1986.
Veterinary Learning Systems Co., Inc.
22. Hardee GE, Smith JA, Harris SJ. Pharmacokinetics of flunixin meglumine in the
cow. Res Vet Sci 1985 Jul; 39(1): 110–2.
23. O’Neil MJ, editor. The merck index: an encyclopedia of chemicals, drugs, and
biologicals, 13th ed. Whitehouse Station, NJ: Merck & Company, Inc., 2001. p.
734.
24. Banamine solution injectable product labeling (Schering-Plough—Canada).
Downloaded from Schering-Plough Animal Health Label Retrieval Service on
7/28/03.
25. Banamine granules product labeling (Schering-Plough—Canada). Downloaded from Schering-Plough Animal Health Label Retrieval Service on 7/
28/03.
26. Haskell SR, Gehring R, Payne MA, et al. Update on FARAD food animal drug
withholding recommendations. J Am Vet Med Assoc 2003, Nov 1; 223(9):
1277–8.
27. Payne MA. Anti-inflammatory therapy in dairy cattle: therapeutic and
regulatory considerations. Calif Vet 2000; 55: 10–12.
28. Anderson KL, Neff-Davis CA, Davis LE, et al. Pharmacokinetics of flunixin
meglumine in lactating cattle after single and multiple intramuscular and
intravenous administrations. Am J Vet Res 1990 Sep; 51(9): 1464–7.
Ó 2004 The United States Pharmacopeial Convention, Inc.
29. Landoni MP, Lees P. Comparison of the anti-inflammatory actions of flunixin
and ketoprofen in horses applying PK/PD modelling. Equine Vet J 1995; 27(4):
247–56.
30. Toutain PL, Autefage A, Legrand C, et al. Plasma concentrations and
therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse:
pharmacokinetic/pharmacodynamic modelling. J Vet Pharmacol Ther 1994;
17: 459–69.
31. Soma LR, Behrend E, Rudy J, et al. Disposition and excretion of flunixin
meglumine in horses. Am J Vet Res 1988 Nov; 49(11): 1894–8.
32. Comparison of adverse effects of phenylbutazone, flunixin meglumine, and
ketoprofen in horses. J Am Vet Med Assoc 1993 Jan 1; 202(1): 71–7.
33. The Canadian gFARAD. Personal communication. Rec 11/24/03.
34. Stegelmeier BL, Bottoms GD, Denicola DB, et al. Effects of flunixin meglumine
in dogs following experimentally induced endotoxemia. Cornell Vet 1988 Jul;
78(3): 221–30.
35. Bottoms GD, Johnson MA, Toesel OF. Endotoxin-induced hemodynamic
changes in dogs: role of thromboxane and prostaglandin I2. Am J Vet Res
1983 Aug; 44(8): 1497–500.
36. Shuster R, Traub-Dargatz J, Baxter G. Survey of diplomates of the American
College of Veterinary Internal Medicine and the American College of
Veterinary Surgeons regarding clinical aspects and treatment of endotoxemia
in horses. J Am Vet Med Assoc 1997 Jan 1; 210(1): 87–92.
37. Ward DS, Fessler JF, Bottoms, GD, et al. Equine endotoxemia: cardiovascular,
eicosanoid, hematologic, blood chemical, and plasma enzyme alterations. Am J
Vet Res 1987 Jul; 48(7): 1150–6.
38. Semrad SD, Hardee GE, Hardee MM, et al. Low dose flunixin meglumine: effects
on eicosanoid production and clinical signs induced by experimental
endotoxaemia in horses. Equine Vet J 1987; 19(3): 201–6.
39. Templeton CB, Bottoms GD, Fessler JF, et al. Endotoxin-induced hemodynamic
and prostaglandin changes in ponies: effects of flunixin meglumine,
dexamethasone, and prednisolone. Circ Shock 1987; 23: 231–40.
40. Semrad SD, Moore JN. Effects of multiple low doses of flunixin meglumine on
repeated endotoxin challenge in the horse. Prostaglandins Leukot Med 1987;
27: 169–81.
41. Bottoms GD, Fessler JF, Roesel OF, et al. Endotoxin-induced hemodynamic
changes in ponies: effects of flunixin meglumine. Am J Vet Res 1981 Sep;
42(9): 1514–8.
42. Dascanio JJ, Mechor GD, Grohn YT, et al. Effect of phenylbutazone and flunixin
meglumine on acute toxic mastitis in dairy cows. Am J Vet Res 1995 Sep;
56(9): 1213–18.
43. Lohuis JACM, Van Leeuwen W, Verheijden JHM, et al. Flunixin meglumine
and flurbiprofen in cows with experimental Escherichia coli mastitis. Vet Rec
1989 Mar 25; 124(12): 305–8.
44. Anderson KL, Smith AR, Shanks RD, et al. Efficacy of flunixin meglumine for
the treatment of endotoxin-induced bovine mastitis. Am J Vet Res 1986 Jun;
47(6): 1366–72.
45. Anderson KL, Kindahl H, Smith AR, et al. Endotoxin-induced bovine mastitis:
Arachidonic acid metabolites in milk and plasma and effect of flunixin
meglumine. Am J Vet Res 1986 Jun; 47(6): 1373–7.
46. Anderson KL, Smith AR, Shanks RD, et al. Endotoxin-induced bovine mastitis:
immunoglobulins, phagocytosis, and effect of flunixin meglumine. Am J Vet
Res 1986 Nov; 47(11): 2405–10.
47. Hardie EM, Rawlings CA, Shotts EB, et al. Escherichia coli-induced lung and
liver dysfunction in dogs: effects of flunixin meglumine treatment. Am J Vet
Res 1987 Jan; 48(1): 56–62.
48. Hardie EM, Kolata RJ, Rawlings CA. Canine septic peritonitis: treatment with
flunixin meglumine. Circ Shock 1983; 11(2): 159–73.
49. Selman IE, Allan EM, Gibbs HA, et al. Effect of anti-prostaglandin therapy in an
acute respiratory distress syndrome induced by the oral administration of 3,
methylindole. Proceedings of the 13th World Congress on Diseases of Cattle.
Durban, South Africa. 1984; 1: 81–6.
50. Logan A, Selman IE, Wiseman EM, et al. Experimental production of diffuse
pulmonary fibrosis and alveolitis in cattle: the effects of repeated dosage with 3,
methyl indole. Res Vet Sci 1982; 34: 97–108.
51. Semrad SD, Hardee GE, Hardee MM, et al. Flunixin meglumine given in small
doses: pharmacokinetics and prostaglandin inhibition in healthy horses. Am J
Vet Res 1985 Dec; 46(12): 2474–9.
All rights reserved
KETOPROFEN Veterinary—Systemic 75
KETOPROFEN Veterinary—Systemic
Some commonly used brand names for veterinary-labeled products are:
Anafen and Ketofen.
Some commonly used brand names for human-labeled products are: ApoKeto; Apo-Keto-E; Novo-Keto-EC; Orudis; Orudis-E; Orudis KT; Orudis-SR;
Oruvail; Rhodis; and Rhodis-EC.
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
CATEGORY:
Analgesic; anti-inflammatory (nonsteroidal); antipyretic.
INDICATIONS
Note: Bracketed information in the Indications section refers to uses that
either are not included in U.S. product labeling or are for products not
commercially available in the U.S.
GENERAL CONSIDERATIONS
Ketoprofen is a potent anti-inflammatory, with analgesic effects on par
with carprofen or meloxicam.{R-67; 68; 70; 75}
ACCEPTED
Inflammation, musculoskeletal (treatment); or
Pain, musculoskeletal (treatment)—
Horses: Ketoprofen injection is indicated in the control of inflammation
and pain associated with musculoskeletal disorders.{R-2; 3; 8}
[Cats] and [dogs]: Ketoprofen is indicated in Canadian product labeling
for the alleviation of inflammation and pain associated with
musculoskeletal disorders.{R-4}
[Cattle]: Ketoprofen injection is indicated in Canadian product labeling
for the alleviation of inflammation and pain associated with arthritis
and traumatic musculoskeletal injuries.{R-3} See also the Regulatory
Considerations section of this monograph.
[Fever (treatment)]—
Cats and dogs: Ketoprofen is indicated in Canadian product labeling for
the symptomatic treatment of fever.{R-4; 29}
Cattle: Ketoprofen injection is indicated in Canadian product labeling
for the symptomatic treatment of fever.{R-3} See also the Regulatory
Considerations section.
[Inflammation (treatment)]; or
[Pain (treatment)]—Cattle: Ketoprofen injection is indicated in Canadian
product labeling for the alleviation of inflammation and pain associated with a variety of nonmusculoskeletal conditions.{R-3} See also the
Regulatory Considerations section.
[Mastitis, acute (treatment adjunct)]—Cattle: Ketoprofen is indicated in
Canadian product labeling for the alleviation of fever, pain, and
inflammation associated with acute clinical mastitis.{R-3; 31} It should
be administered in conjunction with primary therapy, including
antimicrobials, and supportive therapy.{R-31} One controlled, randomized study using repeated doses of ketoprofen showed significant
improvement in outcomes for cows with acute clinical mastitis,
including coliform mastitis.{R-31} See also the Regulatory Considerations
section.
[Pain, postoperative (treatment)]—Cats and dogs: Ketoprofen is indicated in
Canadian product labeling for the alleviation of postsurgical pain.{R-4}
Ó 2004 The United States Pharmacopeial Convention, Inc.
It can be effective when administered postoperatively, producing relief
from pain that lasts for at least 12 to 24 hours.{R-63; 69-71}
Another nonsteroidal anti-inflammatory drug, carprofen, has been
shown to have more efficacy in the control of postoperative pain if
administered before rather than after surgery.{R-64} However, ketoprofen is considered a potent and relatively nonselective cyclooxygenase isozyme inhibitor, thereby having a greater potential than some
nonsteroidal anti-inflammatory drugs for affecting renal and platelet
function.{R-63; 68; 69; 71} General health and age of the animal are
considered in timing of administration (preoperative versus postoperative), anesthetic regimen, and use of intraoperative supportive
therapy (see also Veterinary Dosing Information in this monograph).
Preoperative ketoprofen administration would not be expected to
significantly reduce the dose of thiopental required to induce anesthesia or the concentration of isoflurane required to maintain anesthesia
in dogs.{R-63}
[Pain, visceral (treatment)]1—Horses: Ketoprofen is used in the control of
mild to moderate pain associated with colic.{R-26; 27} The underlying
cause of colic should be determined and treated.
ACCEPTANCE NOT ESTABLISHED
[Endotoxemia (treatment adjunct)]—Calves: There are insufficient data to
establish the safety and efficacy of ketoprofen in the treatment of
endotoxemia in calves; some toxic effects may be decreased or prevented, based on studies with experimentally induced disease.{R-14; 30}
The treatment of endotoxemia should always include appropriate
fluid and antimicrobial therapy. While the rapid rise in prostaglandin
concentrations associated with endotoxemia is prevented by
ketoprofen administration, hemodynamic changes do not always
correlate with these concentrations and some animals may benefit
much more than others.{R-14} See also the Regulatory Considerations
section.
[Inflammation, general (treatment)]1—Goats and sheep: There are
insufficient data to establish the safety and efficacy of ketoprofen in
the treatment of inflammatory conditions in goats and sheep; however,
pharmacokinetic data available for lactating goats and sheep{R-47; 60;
61}
are somewhat comparable to those for cattle. The administration of
ketoprofen to the minor ruminant species might be considered, if
clinically necessary. See also the Regulatory Considerations section.
[Pain, postoperative (treatment)]1—Calves: There are insufficient data to
establish the safety and efficacy of ketoprofen in the treatment of
postoperative pain in calves; however, there is some evidence to
suggest that it can be effective for certain procedures, such as
castration or dehorning.{R-72-74}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
REGULATORY CONSIDERATIONS
U.S.—
Ketoprofen is not labeled for use in food-producing animals in the
U.S.{R-2} Under the Animal Medicinal Drug Use Clarification Act
(AMDUCA) amendments to the Food, Drug, and Cosmetic Act,
a nonsteroidal anti-inflammatory drug that is labeled for use in
All rights reserved
76 KETOPROFEN Veterinary—Systemic
food-producing animals would be preferred over this product for use
in those species.
The use of nonsteroidal anti-inflammatory drugs is restricted by
specific guidelines set down by horse show organizations and racing
commissions.{R-21}
Veterinary-labeled ketoprofen is available by prescription only.{R-2}
Some products labeled for human use are available over-the-counter.
See the Dosage Forms section.
Canada—
Ketoprofen is labeled for use in cattle but is not labeled for
administration to horses to be slaughtered for use in food.{R-3; 4}
Veterinary-labeled ketoprofen is available by prescription only.{R-3; 4}
CHEMISTRY
Chemical group: Propionic acid class of nonsteroidal anti-inflammatory agents.{R-17}
Chemical name: Benzeneacetic acid, 3-benzoyl-alpha-methyl-, (±)-.{R-1}
Molecular formula: C16H14O3.{R-1}
Molecular weight: 254.28.{R-1}
Description: White or off-white, odorless, nonhygroscopic, fine to
granular powder. Melts at about 95 °C.{R-45}
pKa: 5.02.{R-37}
Solubility: Freely soluble in ethanol, in chloroform, in acetone, and in
ether; soluble in strong alkali; practically insoluble in water at
20 °C.{R-45}
Other characteristics: Highly lipophilic.{R-45}
PHARMACOLOGY/PHARMACOKINETICS
Note: See also Table 1. Pharmacology/Pharmacokinetics, at the end of this
monograph.
Mechanism of action/Effect:
Anti-inflammatory—The mechanisms of action for the nonsteroidal antiinflammatory drugs (NSAIDs) have not been completely illuminated.{R-1; 15} The primary mechanism of action for ketoprofen is
considered to be inhibition of the cyclooxygenase pathway of arachidonic acid metabolism, leading to decreased production of prostaglandins.{R-2-4; 6; 15} Based on in vitro experiments, ketoprofen is
considered one of the more potent inhibitors of prostaglandin
synthesis.{R-51} It appears to be a relatively nonselective inhibitor of
cyclooxygenase isozymes; ketoprofen inhibits COX-1 slightly more
than COX-2 in some species and COX-2 slightly more than COX-1 in
other species.{R-53; 61}
Normally, cell membrane damage triggers arachidonic acid metabolism and, by action of cyclooxygenase, production of short-lived
endoperoxidases.{R-1; 15} The endoperoxidases are converted by other
enzymes to thromboxane, prostaglandin E2, prostaglandin F2a, prostacyclin, and oxygen radicals.{R-16} Inhibition of cyclooxygenase
prevents the formation of these prostaglandins and the inflammation
they cause.
Ó 2004 The United States Pharmacopeial Convention, Inc.
However, certain nonsteroidal agents produce only minor antagonism
of cyclooxygenase and still produce a significant anti-inflammatory
effect.{R-6} It is not clear by what other pathways inflammatory
mediators are blocked, although alteration of cellular and humoral
immune responses and inhibition of other inflammatory mediators
have been considered.{R-41} Arachidonic acid metabolism by the
lipoxygenase pathway produces leukotrienes that are active in the
inflammatory process and it is possible some NSAIDs inhibit lipoxygenase;{R-15} however, in vivo tests have not confirmed the inhibition
of lipoxygenase by ketoprofen that was seen in some in vitro
studies.{R-17; 19; 28; 38}
Antipyretic—Reduction of fever is believed to occur by inhibition of
prostaglandins in the hypothalamus.{R-46}
Analgesic—The action of NSAIDs, such as ketoprofen, in the relief of pain
is believed to be the interruption of mediators of inflammation, such as
bradykinin, and prevention of their effect on peripheral pain endings.{R-93} NSAIDs also reduce the hyperalgesia that occurs in
inflammation.{R-8; 15} Some evidence suggests that certain NSAIDs
may produce some centrally induced analgesia, such as a spinal
antinociceptive effect.{R-25}
Other actions/effects:
Antithrombosis—Ketoprofen is effective in inhibiting the production of
thromboxane B2,{R-19; 60; 61} a platelet aggregation promoter.
Gastrointestinal—The NSAIDS, such as ketoprofen, can cause gastrointestinal irritation that may lead to ulceration. Endogenous prostaglandins are believed to be part of the gastric defense system.{R-15}
They inhibit gastric acid secretion and stimulate the production of
protective mucus in the stomach and duodenum.{R-22} The decrease in
prostaglandins caused by NSAIDs may decrease gastrointestinal
cytoprotection, secretion of bicarbonate, and repair of tissue, eventually leading to vascular compromise in the gastrointestinal mucosa
and subsequent tissue necrosis.{R-9; 10; 22; 23}
Renal—Prostaglandins produce or maintain vasodilation in the kidneys
when necessary.{R-15} Animals with compromised hemodynamics
become more vulnerable to ischemia and acute renal damage from the
inhibition of prostaglandins.{R-15} Compromised animals chronically
administered NSAIDs may be more susceptible to renal papillary
necrosis.{R-15}
Chirality: Ketoprofen contains an asymmetrical carbon atom and exists
in two enantiomeric forms. Differences in pharmacokinetics and
pharmacodynamics between the two enantiomers occur in animals
and can also vary significantly among species.{R-50} Currently, commercially available products contain a racemic (50:50) mixture of the
two enantiomers, S(+) and R(–).
Conversion of R(–)-ketoprofen to S(+)-ketoprofen occurs in many
species{R-50} but the extent varies from species to species, and in
some circumstances, from animal to animal within a species. The
percentage of total plasma ketoprofen identified as the S(+)enantiomer 3 hours after administration of 20 mg of R(–)ketoprofen per kg: gerbil (33%), mouse (44%), monkey (45%),
guinea pig (47%), rabbit (51%), rat (74%), hamster (81%), dog
(91.9%).{R-50} The chiral inversion of R(–)- to S(+)-ketoprofen after
an intravenous dose of R-ketoprofen is reported to be 31% in calves,
37% in cats, 6 to 14% in sheep, 20% in horses with induced
synovitis, and 49% in horses with only mild local inflammation.{R33; 39; 54; 58; 60; 61}
As the differing equine inversion percentages
All rights reserved
KETOPROFEN Veterinary—Systemic 77
from two studies listed above suggest, conditions within an
individual animal may change the extent of chiral inversion. This
has also been demonstrated in a single study of dairy cattle, in
which the percentage inversion was compared after an intravenous
R(–)-enantiomer-dose of 0.5 mg/kg: preruminant calves (51%), cows
in early lactation (33%), and cows in gestation (26%).{R-59}
The reverse process, conversion of S(+)-ketoprofen to R(–)-ketoprofen,
has only been demonstrated in mice to date.{R-52}
Looking at inhibition of prostaglandin E2 production in an in vitro
cellular model as an assessment of activity, the S(+)-enantiomer was
found to be 250 times more potent than the R(–)-enantiomer.{R-50} In
an in vivo study of sheep with induced inflammation in tissue cages,
S(+)-ketoprofen caused a much stronger inhibition for more than 4
times the duration of R(–)-ketoprofen.{R-60} Using a lipoxygenase
assay, neither enantiomer had a significant effect.{R-50} Both enantiomers, administered separately, have a significant analgesic effect in
mouse and rat models; some researchers believe R(–)-ketoprofen may
produce analgesic effects but others suggest the effect seen is from
R(–)-enantiomer converted to the S(+) or from S(+) contamination in
R(–) isolates.{R-60}
The S(+)-enantiomer predominates in plasma, exudate and transudate,
when the racemic mixture is administered intravenously to horses;{R19}
however, in sheep, R(–)-ketoprofen is found at a consistently higher
concentration than S(–)-ketoprofen in plasma, exudate, and transudate.{R-60; 61}
Studies in dogs, horses, and sheep suggest that administration of the
racemic mixture does not significantly affect the pharmacokinetics of
each enantiomer.{R-51; 58; 60}
Absorption: Oral—
Cats and dogs: Veterinary-labeled tablets available in Canada are
essentially completely absorbed and can be administered with or
without food.{R-4}
Horses: An oil-based paste of micronized ketoprofen powder was not
bioavailable to horses when administered orally; the same powder
formulated in a hard gelatin capsule had an oral bioavailability of only
about 52%.{R-57}
S(+)-ketoprofen—0.58 ± 0.29 mcg/mL at 1 hour;{R-55} 0.41 ± 0.06
mcg/mL at 1 hour.{R-56}
Horses with synovitis—
Peak synovial ketoprofen concentration of 2.53 ± 0.39 mcg/mL at
1 hour after the 2.2 mg/kg intravenous dose.{R-35} At 3 hours after
the dose, synovial fluid concentrations tend to be greater than
plasma concentrations.{R-35}
Note: At 3 and 6 hours after the dose, synovial concentrations were
not significantly different between healthy horses and horses with
synovitis, but horses with synovitis also had more gradually
declining concentrations, in this study requiring up to 9 hours to
fall to 0.06 mcg/mL.{R-35}
In a study of stereospecific pharmacokinetics with induced synovitis,
concentrations were no longer measurable after 4 to 6 hours. Peaks
were:
R(–)-ketoprofen—0.32 ± 0.06 mcg/mL at 1 hour.{R-58}
S(+)-ketoprofen—0.49 ± 0.07 mcg/mL at 1 hour.{R-58}
Duration of action: There is no standardized method of measuring or
predicting the duration of action of the NSAIDs. Serum concentrations
may wane a considerable time before exudate or tissue concentrations
and therefore are not predictive of duration of action at the treatment
site.{R-18} For horses, the half-life of ketoprofen in plasma is about one
twentieth that in induced exudates.{R-19}
Dogs: Postoperative analgesia, when administered preoperatively, is
considered to be at least 12 to 20 hours.{R-67; 69}
Horses: Anti-inflammatory effect, as measured using an induced carpitis
model, reaches a maximum at 12 hours and is still measurable at 24
hours when administered at a dose of 1.1 to 3.3 mg/kg.{R-2}
Elimination: Cattle—Eighty percent of a parenteral dose is eliminated in
the urine within 24 hours of administration, primarily as conjugated
metabolite.{R-3}
PRECAUTIONS TO CONSIDER
SPECIES SENSITIVITY
Protein binding: Horses—High (92%).{R-19; 55}
Biotransformation: Primarily hepatic, although excretion of metabolites into the urine also occurs.{R-41}
Onset of action:
Oral—Cats and dogs: 1 hour.{R-4}
Parenteral—Horses: Within 2 hours, with intramuscular or intravenous
injection of 2.2 mg per kg of body weight (mg/kg).{R-2; 3}
Concentrations: Synovial fluid concentrations—Horses: Penetration of
the S(+)-enantiomer into synovial fluid appears to be unaffected by
intravenous administration with the R(–)-enantiomer in a racemic
mixture.{R-58}
Healthy horses—
Peak synovial ketoprofen concentration of 0.39 ± 0.03 microgram per
mL (mcg/mL) at 1 hour after a 2.2 mg/kg intravenous dose of
racemic ketoprofen.{R-35}
Stereospecific ketoprofen assays performed on synovial fluid after a
2.2 mg/kg intravenous dose of racemic ketoprofen:
R(–)-ketoprofen—0.47 ± 0.26 mcg/mL at 1 hour;{R-55} 0.40 ± 0.05
mcg/mL at 1 hour.{R-56}
Ó 2004 The United States Pharmacopeial Convention, Inc.
Equids—Ketoprofen has not been evaluated in foals and ponies, which
are susceptible to gastric ulceration from nonsteroidal anti-inflammatory drugs (NSAIDs).{R-3}
PREGNANCY/REPRODUCTION
The effect of ketoprofen on fertility, pregnancy, or fetal health has not
been determined in most species.{R-2-4}
Cattle: A dose of 6 mg per kg of body weight (mg/kg), administered
during the sixth week of gestation or administered between the second
and ninth month of gestation, had no effect on measured parameters,
such as fetal development, length of gestation, parturition, or calf
viability.{R-3} Effects on the fertility of bulls has not been evaluated.{R-3}
LACTATION
Cattle—Ketoprofen is distributed into milk in small amounts in some
lactating cattle.{R-37} In healthy cattle administered an intravenous
dose of 3.3 mg/kg, only a few milk samples collected up to 2 hours
later contained a detectable amount of ketoprofen, between 27 and 90
nanograms per mL (nanograms/mL).{R-37}
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78 KETOPROFEN Veterinary—Systemic
Goats—Ketoprofen concentrations in milk were less than the 25
nanograms/mL limit of detection from eight to twenty-four
hours after intravenous administration of 2.2 mg/kg to six lactating
goats.{R-47}
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications,
depending on the amount present, may also interact with this
medication.
Anti-inflammatory drugs, nonsteroidal
(concurrent use of more than one NSAID may greatly increase the risk
of gastrointestinal ulceration and renal papillary necrosis){R-5; 11}
Corticosteroids{R-22; 23}
(concurrent administration of corticosteroids with NSAIDs can
exacerbate injury to the gastrointestinal tract caused by those
medications){R-22; 23}
HUMAN DRUG INTERACTIONS AND/OR RELATED
PROBLEMS{R-49}
In addition to the above drug interactions reported in animals, the
following drug interactions have been reported in humans, and are
included in the human monograph Anti-inflammatory Drugs, Nonsteroidal (Systemic) in USP DI Volume I; these drug interactions are
intended for informational purposes only and may or may not be
applicable to the use of ketoprofen in the treatment of animals:
Note: All of the following interactions have not been documented with
every NSAID. However, they have been reported with several and
should be considered potential precautions to the use of any NSAID,
especially with chronic administration.
Anticoagulants, coumarin- or indandione-derivative or
Heparin or
Thrombolytic agents
(inhibition of platelet aggregation by NSAIDs, and the possibility of
NSAID-induced gastrointestinal ulceration or bleeding, may be
hazardous to patients receiving anticoagulant or thrombolytic
therapy)
Antidiabetic agents, oral or
Insulin
(NSAIDs may increase the hypoglycemic effect of these medications
because prostaglandins are directly involved in regulatory mechanisms of glucose metabolism)
Antihypertensives, including angiotensin-converting enzyme (ACE)
inhibitors, or
Diuretics
(NSAIDs may decrease the diuretic, natriuretic, and antihypertensive
effects of diuretics, probably by inhibiting renal prostaglandin
synthesis)
(concurrent use of an NSAID and a diuretic may increase the risk of
renal failure secondary to a decrease in renal blood flow caused by
inhibition of renal prostaglandin synthesis)
Aspirin or
Ó 2004 The United States Pharmacopeial Convention, Inc.
NSAIDS, two or more concurrently
(concurrent use of two or more NSAIDS, including aspirin, is not
recommended; concurrent therapy may increase the risk of gastrointestinal toxicity, including ulceration or hemorrhage, without
providing additional symptomatic relief)
(concurrent administration of two or more NSAIDs may alter the
pharmacokinetic profile of at least one of the medications, which
may alter the therapeutic effect and/or increase the risk of adverse
effects; specifically, aspirin decreases protein binding of ketoprofen
and etodolac [but does not alter etodolac clearance], increases
plasma clearance of ketoprofen, and interferes with the formation
and excretion of ketoprofen conjugates)
Corticosteroids, glucocorticoid or
Corticotropin (chronic therapeutic use) or
Potassium supplements
(concurrent use with an NSAID may increase the risk of gastrointestinal side effects, including ulceration or hemorrhage; however,
concurrent use with a glucocorticoid or corticotropin in the
treatment of arthritis may provide additional therapeutic benefit
and permit reduction of glucocorticoid or corticotropin dosage)
Cyclosporine or
Nephrotoxic medications, other
(inhibition of renal prostaglandin activity by NSAIDs may increase
the plasma concentration of cyclosporine and/or the risk of cyclosporine-induced nephrotoxicity)
(the risk of adverse effects may also be increased when an NSAID is
used concurrently with other nephrotoxic medications)
Digitalis glycosides
(diclofenac and ibuprofen have been shown to increase serum digoxin
concentrations, and indomethacin has increased digitalis concentrations in neonates being treated for patent ductus arteriosus; the
possibility should be considered that some of the other NSAIDs also
may increase digoxin concentrations, leading to an increased risk of
digitalis toxicity; increased monitoring and dosage adjustments of the
digitalis glycoside may be necessary during and following concurrent
NSAID therapy; however, studies have failed to show that flurbiprofen,
ketoprofen, piroxicam, or tenoxicam increase digoxin concentrations,
and phenylbutazone may decrease digitalis concentrations)
Methotrexate
(NSAIDs may alter the pharmacokinetics of methotrexate)
Platelet aggregation inhibitors, other
(concurrent use with an NSAID may increase the risk of bleeding
because of additive inhibition of platelet aggregation, as well as the
potential for NSAID-induced gastrointestinal ulceration or hemorrhage)
(concurrent use of sulfinpyrazone with NSAIDs may also increase the
risk of gastrointestinal ulceration or hemorrhage)
Probenecid
(concurrent use of probenecid with ketoprofen is not recommended;
probenecid decreases ketoprofen’s renal clearance [by approximately
66%] and protein binding [by 28%], and inhibits formation and renal
clearance of ketoprofen conjugates, leading to greatly increased
ketoprofen plasma concentration and risk of toxicity)
LABORATORY VALUE ALTERATIONS
The following have been selected on the basis of their potential clinical
significance (possible effect in parentheses where appropriate)—not
necessarily inclusive (» = major clinical significance):
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KETOPROFEN Veterinary—Systemic 79
Note: Laboratory value alterations relating specifically to the use of
ketoprofen in animals have been rarely reported in veterinary
literature. Human laboratory value alterations have been reported
and are included in the following section.
HUMAN LABORATORY VALUE ALTERATIONS{R-49}
The following laboratory value alterations have been reported in
humans, and are included in the human monograph Anti-inflammatory Drugs, Nonsteroidal (Systemic) in USP DI Volume I; these laboratory
value alterations are intended for informational purposes only and
may or may not be applicable to the use of ketoprofen in the treatment
of animals:
With diagnostic test results
Albumin, urine, determinations and
Bile salts, urine, determinations and
17-Ketosteroid (17-KS), urine, determinations and
17-Hydroxycorticosteroid (17-OHCS), urine, determinations
(ketoprofen metabolites in urine may interfere with test procedures
that rely on acid precipitation as an end point or on color reactions
of carbonyl groups; no interference occurs in tests for urinary
protein using commercially available dye-impregnated test strips)
With physiology/laboratory test values
Bleeding time
(may be prolonged by most NSAIDs [with ketoprofen, by 3 to 4
minutes above baseline values] because of suppressed platelet
aggregation)
Hematocrit or
Hemoglobin
(values may be decreased, possibly because of gastrointestinal
bleeding or microbleeding and/or hemodilution caused by fluid
retention)
Leukocyte count and
Platelet count
(may be decreased)
Liver function tests, including:
Alkaline phosphatase and
Lactate dehydrogenase (LDH) and
Transaminases, serum
(values may be increased; liver function test abnormalities may
return to normal despite continued use; however, if significant
abnormalities occur, clinical signs and symptoms consistent with
liver disease develop, or systemic manifestations such as eosinophilia or rash occur, the medication should be discontinued)
Potassium, serum
(concentrations may be increased)
Renal function tests, including:
Blood urea nitrogen (BUN)
Creatinine, serum
Electrolytes, blood and urine
Urine volume
(NSAIDs may decrease renal function, resulting in increased BUN,
serum creatinine, and serum electrolyte concentrations and in
decreased urine volume and urine electrolyte concentrations;
however, in some cases, water retention may exceed that of
sodium, resulting in dilutional hyponatremia)
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
Ó 2004 The United States Pharmacopeial Convention, Inc.
given in parentheses where appropriate)—not necessarily inclusive
(» = major clinical significance).
Except under special circumstances, this medication should not be
used when the following medical problems exist:
» Hypersensitivity to ketoprofen{R-3; 4}
(previous development of adverse effects from ketoprofen may be an
indication of increased risk of future sensitivity)
» Gastrointestinal ulceration{R-4}
(many NSAIDs are known to increase the risk of gastrointestinal
disease, particularly ulceration;{R-4} therefore, the presence of
pretreatment lesions may put an animal at risk of exacerbation or
perforation)
» Hepatic disease, severe{R-4}
(ketoprofen is metabolized by the liver)
» Renal disease, severe{R-4}
(because some NSAIDs are known to cause renal papillary necrosis in
some circumstances,{R-11} risk to patients with renal compromise may
be increased)
Risk-benefit should be considered when the following medical
problem exists:
Coagulation disorders{R-4; 65; 67; 68}
(ketoprofen has antithrombotic effects; platelet aggregation is measurably decreased and under some circumstances, buccal mucosal
bleeding time may be prolonged)
PATIENT MONITORING
The following may be especially important in patient monitoring (other
tests may be warranted in some patients, depending on condition; » =
major clinical significance):
Hemoglobin determinations{R-1} and
Hematocrit determinations{R-1}
(may be indicative of chronic gastrointestinal blood loss)
Occult blood, fecal{R-1}
Stools, observe for black or tarry{R-19; 24}
(if black or tarry stools are observed, the cessation of therapy should
be considered;{R-19} if stools are normal with long-term administration, to determine if chronic blood loss is occurring, positive fecal
occult blood results in animals on a meatless diet should be followed
by serum hemoglobin and hematocrit measurements;{R-1} fecal
occult blood tests may be more sensitive than other noninvasive tests
for detecting lower intestinal injury{R-23} but are unlikely to detect
stomach blood loss{R-24})
SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their
potential clinical significance (possible signs and, for humans, symptoms in parentheses where appropriate)—not necessarily inclusive:
THOSE INDICATING NEED FOR MEDICAL ATTENTION
Incidence more frequent
Cats and dogs
Vomiting (10.7% in cats; 4 to 6% in dogs in clinical efficacy
studies){R-4}
Incidence less frequent
Cats and dogs
Diarrhea (2.6% in cats; 2% in dogs in clinical efficacy studies){R-4}
Incidence rare
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80 KETOPROFEN Veterinary—Systemic
Dogs
Anorexia (0.7%);{R-4} thirst, increased (0.7%){R-4}
HUMAN SIDE/ADVERSE EFFECTS{R-49}
In addition to the above side/adverse effects reported in animals, the
following side/adverse effects have been reported in humans, and are
included in the human monograph Anti-inflammatory Drugs, Nonsteroidal (Systemic) in USP DI Volume I; these side/adverse effects are
intended for informational purposes only and may or may not be
applicable to the use of ketoprofen in the treatment of animals:
Incidence more frequent
Abdominal cramps, pain, or discomfort, mild to moderate;
bleeding from rectum; bloated feeling or gas; constipation;
diarrhea; fluid retention and edema; headache, mild to moderate; indigestion; nausea; nervousness or irritability
Incidence less frequent
Blurred or double vision or any change in vision; cystitis;
decreased appetite or loss of appetite; dizziness; drowsiness;
general feeling of discomfort or illness; increased sweating;
mental depression; ringing or buzzing in ears; skin rash;
stomatitis, aphthous; trouble in sleeping; vomiting
Incidence rare
Agranulocytosis [granulocytopenia]; anaphylaxis or anaphylactoid reactions; anemia, hemolytic; bitter taste or other taste
change; bleeding from vagina; blood in urine; bronchospastic
allergic reactions; bulbous eruptions/blisters; cardiac arrythmias; confusion; congestive heart failure or exacerbation of;
conjunctivitis; decreased hearing or any change in hearing;
dermatitis, allergic; dermatitis, exfoilative; dry, irritated, or
swollen eyes; erythema or other skin discoloration; eye pain; fast
heartbeat; forgetfulness; gastritis; gastrointestinal bleeding,
gastrointestinal perforation and/or ulceration; hallucinations;
hemoptysis; hepatitis or jaundice, toxic; hives; hypocoagulability; increased blood pressure; interstitial nephritis; irritation,
dryness, or soreness of mouth; itching; laryngeal edema,
lightheadedness/vertigo; loosening or splitting of fingernails
or other nail disorders; migraine; muscle cramps; nephrotic
syndrome; neuropathy, peripheral; nosebleeds, unexplained;
pancreatitis; photoallergic or photosensitive dermatologic reaction; pounding heartbeat; renal impairment or failure; rhinitis,
allergic; shortness of breath or troubled breathing; syncope;
thirst, continuing; thrombocytopenia with or without purpura,
trembling or twitching; weight loss, unexplained
Incidence unknown
Abdominal distention; amblyopia, toxic; angioedema; angitis;
anxiety; aplastic anemia [pancytopenia]; bladder pain; bone
marrow depression; chestpain; cholistatic hepatitis or jaundice;
colitis or exacerbation of; convulsions; corneal deposits or
opacity; crystalluria, renal calculi, or ureteral obstruction;
desquamation; disorientation; disseminated intravascular
coagulation; dysarthria (trouble in speaking); dysphagia;
dysuria; ecchymosis/bruising; eczema; edema, pulmonary;
eosinophilia; epigastric pain; enteritis, regional or exacerbation of; enterocolitis; erythema multiforme; erythema nodosum; esophagitis; feeling of depersonalizaton or muzziness;
fever; flushing or hotflashes; frequent urge to urinate; gastroenteritis; gingival ulceration; glomerulitis or glomerulone-
Ó 2004 The United States Pharmacopeial Convention, Inc.
phritis; glossitis; headache, severe, especially in the morning;
heartburn; hyperkalemia; incontinence; leukopenia [neutropenia]; Loeffler syndrome [eosinophilic pneumonitis]; lymphadenopathy; meningitis, aseptic; muscle weakness; nephrosis;
oliguria/anuria; palpedral edema; pericarditis; petechia;
photophobia; photosensitivity reactions; polyuria; proteinuria;
psychotic reaction; renal papillary or tubular nephrosis;
retinal or macular disturbances; scotomata; serum sicknesslike reaction; Stevens-Johnson syndrome (bleeding or crusting
sores on lips; chest pain; fever with or without chills; muscle
cramps or pain; retinal hemorrhage; skin rash; sores, ulcers, or
white spots in mouth; sore throat); strong-smelling urine;
swelling of lips and tongue, syncope; systemic lupus erythematosus [SLE]-like syndrome; toxic epidermal necrolysis;
trembling or twitching; unusual weakness with no other signs
or symptoms; urethritis or urinary tract infection; vasculitis
OVERDOSE
For more information in cases of overdose or unintentional ingestion,
contact the American Society for the Prevention of Cruelty to
Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation)
and/or the drug manufacturer.
CLINICAL EFFECTS OF OVERDOSE
The following effects have been selected on the basis of their potential
clinical significance (possible signs in parentheses where appropriate)—not necessarily inclusive:
Calves, nonruminating
With a dose of 9 mg/kg once a day for 6 days:{R-3}
Abomasal erosions
Dogs
With a dose of up to 20 mg/kg a day for up to 90 days, mild selflimiting evidence of the following were present:{R-4}
Anorexia; diarrhea; melena; weight loss
With a dose of 36 mg/kg a day, clinical signs and histopathology
results indicated gastrointestinal, liver, and kidney toxic effects were
present.{R-4}
Horses
With a dose of 2.2 mg/kg every 8 hours for 12 days:
Erosions or ulcerations, gastric or oral{R-24}
With a dose of 33 mg/kg a day for 5 days:
Laminitis{R-2; 3}—in one of two horses treated
With a dose of 55 mg/kg a day for 5 days:
Abdominal swelling;{R-2} depression;{R-2} icterus;{R-2} inappetence;{R-21} recumbency{R-3}
Note: Postmortem findings included gastritis, hepatitis, and nephritis.{R-2; 3}
TREATMENT OF OVERDOSE
Acute
To decrease absorption—Gastric lavage to remove unabsorbed drug
from stomach.
Supportive care—Administration of fluids.
CLIENT CONSULTATION
In providing consultation, consider emphasizing the following selected
information:
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KETOPROFEN Veterinary—Systemic 81
Keeping water readily available during the treatment period to avoid
dehydration
Never exceeding the prescribed daily amount without veterinary
consultation
Familiarizing clients with signs that an adverse reaction may be
occurring; instructing them to contact their veterinarian and
discontinue medication if a reaction is suspected
Not administering nonsteroidal anti-inflammatory drugs labeled for
human use to animals without guidance from a veterinarian; human
dosages may be toxic or fatal for animals
VETERINARY DOSING INFORMATION
The side effects associated with nonsteroidal anti-inflammatory agents
(NSAIDs) often make it prudent to treat chronic inflammation with the
lowest effective dose over the shortest period of time to control signs.{R-1}
FOR PARENTERAL DOSAGE FORMS ONLY
Avoid intra-arterial injection.{R-3; 4}
KETOPROFEN CAPSULES
Usual dose: See Ketoprofen Tablets.
Strength(s) usually available:
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-49}
25 mg (Rx) [Orudis (lactose); generic].
50 mg (Rx) [Orudis (lactose); generic].
75 mg (Rx) [Orudis (lactose); generic].
Canada—
Veterinary-labeled product(s):{R-4}
Not commercially available.
Human-labeled product(s):{R-49}
50 mg (Rx) [Apo-Keto; Orudis; Rhodis].
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), in a tight container, unless
otherwise specified by manufacturer.
FOR PERIOPERATIVE ADMINISTRATION
Because NSAIDs can produce renal disturbances in animals prone to
them, intravenous fluid therapy can be an appropriate precaution in
some animals at risk for renal disease.{R-1} Ketoprofen, like other
NSAIDs, may contribute to a decrease in glomerular filtration rate for
up to 48 hours when administered before surgery without the benefit
of intravenous fluid support.{R-62} Healthy dogs treated with ketoprofen that were not administered fluid therapy during protracted
student-performed ovariohysterectomies did, in some cases, develop
transient signs of renal trauma, including mild azotemia and urine
sediment renal tubular epithelial cells, the first postoperative day;
however, the risk was not found to be higher than that seen with other
analgesics, such as morphine.{R-66}
Platelet aggregation measured postoperatively is significantly decreased in
healthy dogs administered ketoprofen before elective ovariohysterectomy.{R-65} Studies differ on whether buccal mucosal bleeding time
(BMBT) is significantly changed by preoperative ketoprofen administration; however, for healthy dogs with no other risk factors, the possibility
of bleeding during surgery may be low.{R-62; 65; 68} Concurrent
administration of other drugs that inhibit platelet function, such as
cephalosporins, should be avoided when ketoprofen is administered
preoperatively.{R-63} Preoperative administration of NSAIDs to animals
with potential bleeding disorders should be avoided.{R-68}
USP requirements: Not in USP.{R-48}
KETOPROFEN EXTENDED-RELEASE CAPSULES
Usual dose:
Note: Bioavailability in animals has not been specifically demonstrated
for delayed-release, enteric coated, or extended-release dosage forms
developed for human therapy; therefore, these products are not
recommended for veterinary use.
Strength(s) usually available:
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-49}
100 mg (Rx) [Oruvail; Generic].
150 mg (Rx) [Oruvail].
200 mg (Rx) [Oruvail; Generic].
Canada—
Veterinary-labeled product(s):{R-4}
Not commercially available.
Human-labeled product(s):{R-49}
150 mg (Rx) [Oruvail].
200 mg (Rx) [Oruvail].
TREATMENT OF ADVERSE EFFECTS
If gastrointestinal signs appear, including decreased appetite, soft stool, or
diarrhea, medication should be discontinued until the signs disappear.{R-1} If the adverse effects are mild, medication may be reinitiated
at a lower dose, with observation for recurrence of adverse effects.{R-1}
If treatment is necessary, misoprostol or sucralfate can be used in the
treatment of gastrointestinal ulceration.{R-42}
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), in a well-closed container,
unless otherwise specified by manufacturer.
USP requirements: Not in USP.{R-48}
ORAL DOSAGE FORMS
KETOPROFEN TABLETS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
Human products have been listed for this dosage form based on
relevance to veterinary practice.
Usual dose:
[Fever];
[Musculoskeletal inflammation]; or
[Postsurgical pain]—Cats and dogs: As stated on Canadian product
labeling, oral, 1 mg per kg of body weight every twenty-four
Ó 2004 The United States Pharmacopeial Convention, Inc.
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82 KETOPROFEN Veterinary—Systemic
hours.{R-4} It is recommended that ketoprofen treatment be limited to a
maximum of five consecutive days to reduce the risk of adverse
gastrointestinal effects.
Strength(s) usually available:
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-49}
12.5 mg (OTC) [Orudis KT].
Canada—
Veterinary-labeled product(s):{R-4}
5 mg (Rx) [Anafen; generic].
10 mg (Rx) [Anafen].
20 mg (Rx) [Anafen; generic].
Human-labeled product(s):
Not commercially available.
Packaging and storage: Store below 40 °C (104 °F), preferably between
15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise
specified by manufacturer. Protect from direct sunlight.{R-4}
USP requirements: Not in USP.{R-48}
Strength(s) usually available:
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-49}
Not commercially available.
Canada—
Veterinary-labeled product(s):{R-4}
Not commercially available.
Human-labeled product(s):
200 mg (Rx) [Orudis-SR; generic].
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), in a well-closed container,
unless otherwise specified by manufacturer.
USP requirements: Not in USP.{R-48}
PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
KETOPROFEN DELAYED-RELEASE TABLETS
Usual dose:
Note: Bioavailability in animals has not been specifically demonstrated
for delayed-release, enteric coated, or extended-release dosage forms
developed for human therapy; therefore, these products are not
recommended for veterinary use.
Strength(s) usually available:
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):{R-49}
Not commercially available.
Canada—
Veterinary-labeled product(s):{R-4}
Not commercially available.
Human-labeled product(s):
50 mg (Rx) [Apo-Keto-E; Novo-Keto-EC; Orudis-E; Rhodis-EC;
generic].
100 mg (Rx) [Apo-Keto-E; Novo-Keto-EC; Orudis-E; Rhodis-EC;
generic].
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), in a well-closed container,
unless otherwise specified by manufacturer.
USP requirements: Not in USP.{R-48}
KETOPROFEN EXTENDED-RELEASE TABLETS
Usual dose:
Note: Bioavailability in animals has not been specifically demonstrated
for delayed-release, enteric coated, or extended-release dosage forms
developed for human therapy; therefore, these products are not
recommended for veterinary use.
Ó 2004 The United States Pharmacopeial Convention, Inc.
KETOPROFEN INJECTION
Usual dose:
Note: For cats, dogs, and horses, it is recommended that ketoprofen
treatment be limited to a maximum of five consecutive days to reduce
the risk of gastrointestinal effects.
Inflammation, musculoskeletal; or
Pain, musculoskeletal —
Horses: Intravenous, 2.2 mg per kg of body weight every twenty-four
hours.{R-2}
Note: A controlled study has demonstrated that a dose of 3.63 mg
per kg of body weight significantly relieved the pain associated with
laminitis in horses for up to twenty-four hours while 2.2 mg per kg
of body weight did not.{R-8}
[Cats]: As stated on Canadian product labeling, subcutaneous, 2 mg
per kg of body weight as a single dose, followed by ketoprofen tablets
at a maintenance dose of 1 mg per kg of body weight every twentyfour hours.{R-4} Alternatively, in severe cases, the parenteral dose
can be given once a day for up to 3 days.{R-4}
[Cattle]: As stated on Canadian product labeling, intramuscular or
intravenous, 3 mg per kg of body weight every twenty-four hours for
up to three days.{R-3} See also the Withdrawal times section below.
[Dogs]: As stated on Canadian product labeling, intramuscular,
intravenous, or subcutaneous, 2 mg per kg of body weight as a
single dose, followed by ketoprofen tablets at a maintenance dose of
1 mg per kg of body weight every twenty-four hours.{R-4} Alternatively, in severe cases, the parenteral dose can be given once a day
for up to 3 days.{R-4}
[Fever]—
Cats: As stated on Canadian product labeling, subcutaneous, 2 mg per
kg of body weight{R-4} as a single dose, followed by ketoprofen tablets
at a maintenance dose of 1 mg per kg of body weight every twentyfour hours.{R-4} Alternatively, in severe cases, the parenteral dose
can be given once a day for up to 3 days.{R-4}
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KETOPROFEN Veterinary—Systemic 83
Cattle: As stated on Canadian product labeling, intramuscular or
intravenous, 3 mg per kg of body weight every twenty-four hours for
up to three days.{R-3} See also the Withdrawal times section below.
Dogs: As stated on Canadian product labeling, intramuscular, intravenous, or subcutaneous, 2 mg per kg of body weight as a single
dose, followed by ketoprofen tablets at a maintenance dose of 1 mg
per kg of body weight every twenty-four hours.{R-4} Alternatively, in
severe cases, the parenteral dose can be given once a day for up to 3
days.{R-4}
[Inflammation, general];
[Mastitis, acute]; or
[Pain, general]—Cattle: As stated on Canadian product labeling, intramuscular or intravenous, 3 mg per kg of body weight every twentyfour hours for up to three days.{R-3; 31} See also the Withdrawal times
section below.
[Postoperative pain]—
Cats: As stated on Canadian product labeling, subcutaneous, 2 mg per
kg of body weight as a single dose, followed by ketoprofen tablets at a
maintenance dose of 1 mg per kg of body weight every twenty-four
hours.{R-4} Alternatively, in severe cases, the parenteral dose can be
given once a day for up to 3 days.{R-4}
Dogs: As stated on Canadian product labeling, intramuscular, intravenous, or subcutaneous, 2 mg per kg of body weight as a single
dose, followed by ketoprofen tablets at a maintenance dose of 1 mg
per kg of body weight every twenty-four hours.{R-4} Alternatively, in
severe cases, the parenteral dose can be given once a day for up to
3 days.{R-4}
[Visceral pain]1—Horses: Intravenous, 2.2 mg per kg of body
weight.{R-26; 27} The dose may be repeated in two to twelve hours,
depending on clinical signs.{R-26}
Note: [Calves]1—Although the safety and efficacy of ketoprofen have not
been established for the treatment of endotoxemia in calves, an
intramuscular or intravenous dose of 2.2 to 6 mg per kg of body
weight has been used, based on efficacy in experimentally induced
disease.{R-14; 30} See also the Withdrawal times section below.
Although the safety and efficacy have not been established in the
treatment of postoperative pain in calves, an intravenous dose of 3 mg
per kg of body weight, administered thirty minutes before surgery, has
been suggested, based on controlled studies that recorded behavioral
changes and physiologic markers of stress associated with certain
procedures.{R-72-74} See also the Withdrawal times section below.
[Goats]1 and [sheep]1—Although the safety and efficacy have not been
established for treatment of inflammatory conditions in goats and sheep,
an intramuscular or intravenous dose of 3 mg per kg of body weight
every twenty-four hours for up to three days has been suggested, based
on pharmacokinetic data.{R-43; 47} See also the Withdrawal times
section below.
Note: In Canada, the 10-mg-per-mL solution is labeled only for use in
cats and dogs, while the 100-mg-per-mL solution is labeled only for
use in cattle and horses.{R-3}
Withdrawal times:
U.S.—There are no established withdrawal times for animals in the
United States because ketoprofen is not labeled for use in foodproducing animals.{R-2} Under the Animal Medicinal Drug Use
Clarification Act (AMDUCA) amendments to the Food, Drug, and
Cosmetic Act, a nonsteroidal anti-inflammatory drug that is labeled for
use in food-producing animals would be preferred over this product for
use in those species.
If ketoprofen is administered to cattle, goats, or sheep in the United
States at a dose of 3.3 mg per kg of body weight every twenty-four
hours for up to three days, evidence has been compiled by the Food
Animal Residue Avoidance Databank (FARAD) that suggests a meat
withdrawal time of 7 days and a milk withholding time of 24 hours
would be sufficient to avoid residues.{R-32; 37-39; 43; 47}
At this time, there are insufficient data to make a residue withdrawal
recommendation for calves less than 20 weeks of age that are treated
with ketoprofen.
Canada—{R-3}
Withdrawal time
Species
Meat (days)
Cattle
1
Note: Although Canadian product labeling does not specifically list a
residue withdrawal time for milk, the manufacturer states that there
is an established withdrawal of zero hours for cattle; the only
indication of this on product labeling is the lack of prohibition from
use in lactating dairy cattle.{R-76}
Product labeling listing the above withdrawal times states that they
apply to a dose of 3 mg per kg of body weight administered every
twenty-four hours for up to three days.{R-3}
This product is not labeled for use in horses to be slaughtered for
food.{R-3}
Packaging and storage: Store between 15 and 30 °C (59 and 86 °F),
unless otherwise specified by manufacturer.{R-2} Protect from direct
sunlight.{R-3}
Incompatibilities: Compatability with other medications is unknown;
therefore, administration with other medications in the same syringe is
not recommended.{R-3}
USP requirements: Not in USP.{R-48}
Strength(s) usually available:
U.S.—
Veterinary-labeled product(s):
100 mg per mL (Rx) [Ketofen].{R-2}
Canada—
Veterinary-labeled product(s):
10 mg per mL (Rx) [Anafen].{R-4}
100 mg per mL (Rx) [Anafen].{R-3}
Ó 2004 The United States Pharmacopeial Convention, Inc.
1
Not included in Canadian product labeling or product not commercially
available in Canada.
Developed: 2/6/04
All rights reserved
84 KETOPROFEN Veterinary—Systemic
Table 1. Pharmacology/Pharmacokinetics: Intravenous administration
Note: The commercial forms of ketoprofen contain a racemic mixture of R-(–) and S-(+) enantiomers. In some species, ketoprofen displays enantioselective
pharmacokinetics.{R-34;39} Two kinds of studies are listed in this table. Some studies looked at the pharmacokinetics of each enantiomer after administration of the racemic
mixture and others used the administration of each separate enantiomer to investigate the pharmacokinetics for each.{R-33;39}
Species
Camels{R-12}
{R-7}
Compound
administered
Dose
(mg/kg)
Compound
Assayed
Vdarea
(L/kg)
Vdss
(L/kg)
Elimination
half-life (hours)
Clearance
(mL/minÆkg)
Ketoprofen*
Ketoprofen
2
2
Ketoprofen
In females:
R(–)
S(+)
In males:
R(–)
S(+)
Ketoprofen
R(–)
S(+)
R())
S(+)
Ketoprofen
Ketoprofen
0.32
0.13
4.16
1.00
0.12
0.14
1.88
1.83
0.74
0.84
0.22
0.23
0.19 ± 0.03
0.26 ± 0.06
0.26 ± 0.05
0.23 ± 0.05
2.11
2.33
0.49
0.42 ± 0.09
0.42 ± 0.08
1.30 ± 0.27
2.19 ± 0.42
1.30 ± 0.75
0.32 ± 0.14
1.03
1.16
2.8
5.50 ± 0.50
5.50 ± 0.67
2.51 ± 0.60
1.98 ± 0.20
6.90 ± 1.65
12.3 ± 2.0
1.98
1.09
1.09 ± 0.19
1.51 ± 0.45
0.42 ± 0.18
0.37 ± 0.06
1.89 ± 0.82
1.00 ± 0.50
1.02 ± 0.47
5.77
6.62
4.62 ± 0.58
3.37 ± 0.37
7.40 ± 1.03
5.27 ± 0.35
9.33 ± 1.00
7.17 ± 1.00
3.08 ± 0.38
Cattle{R-32; 37}
Calves, 20 weeks
of age{R-38}
Calves, 20 weeks
of age{R-39}
Donkeys{R-40}
Goats{R-47}
Horses
Ketoprofen
Ketoprofen
3.3
1.5
R())
S(+)
Ketoprofen
Ketoprofen
1.5
{R-33}
R(–)
S(+)
Ketoprofen
2.2
{R-55}
Ketoprofen
2.2
{R-56}
Ketoprofen
2.2
Before induced
synovitis{R-35}
With induced
synovitis{R-35}
With induced
synovitis{R-58}
Ketoprofen
{R-19}
Multiple
dosing{R-36}
Foals, <24 hours
old{R-44}
Llamas{R-20}
2.2
2.2
0.11
0.20 ± 0.06
0.22 ± 0.06
2.2
R(–)
S(+)
R(–)
S(+)
R(–)
S(+)
R(–)
S(+)
Ketoprofen
0.28 ± 0.14
0.17 ± 0.03
0.14 ± 0.02
0.48 ± 0.16
0.22 ± 0.08
0.14 ± 0.05
Ketoprofen
2.2
Ketoprofen
0.20 ± 0.08
0.13 ± 0.03
0.63 ± 0.29
3.66 ± 0.39
Ketoprofen
2.2
R())
S(+)
Ketoprofen
0.44 ± 0.13
0.20 ± 0.03
0.79 ± 0.29
0.33 ± 0.13
1.87 ± 0.63
1.14 ± 0.18
2.63 ± 0.81
1.34 ± 0.52
6.67 ± 1.17
3.83 ± 0.67
6.50 ± 0.17
4.83 ± 1.16
Ketoprofen
1.1
1.1
2.2 every
12 hours
for 5 days
2.2
R(–)
S(+)
R())
S(+)
Ketoprofen
Day 1
Day 5
Ketoprofen
0.39
0.16
0.18
0.36
1.64
1.61
4.3
4.81
4.80
1.03
Ketoprofen
4.4
R())
S(+)
0.10 ± 0.01
0.10 ± 0.01
0.09 ± 0.01
0.10 ± 0.01
5.41 ± 0.94
5.49 ± 1.27
0.21 ± 0.03
0.22 ± 0.03
Ketoprofen
3
R())
S(+)
Ketoprofen
1.5
1.5
3
R())
S(+)
1.5
1.5
R())
S(+)
R())
S(+)
R())
S(+)
R())
S(+)
0.17 ± 0.02
0.26 ± 0.02
0.34 ± 0.05
0.47 ± 0.14
0.11 ± 0.01
0.18 ± 0.02
0.18 ± 0.04
0.23 ± 0.02
0.87 ± 0.10
0.86 ± 0.08
1.63 ± 0.34
3.23 ± 1.56
0.63 ± 0.05
0.63 ± 0.05
1.02 ± 0.23
0.94 ± 0.14
3.27 ± 0.53
5.85 ± 0.83
3.87 ± 0.50
4.77 ± 0.98
2.67 ± 0.33
4.67 ± 0.67
2.67 ± 0.17
5.33 ± 0.33
1.1
0.53
0.64
0.47 ± 0.15
0.49 ± 0.21
0.27 ± 0.09
0.16 ± 0.03
Sheep
{R-60}
{R-61}
*In this table, ketoprofen denotes the racemic mixture.
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All rights reserved
86 KETOPROFEN Veterinary—Systemic
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68. Grisneaux E, Pibarot P, Dupuis J, et al. Comparison of ketoprofen and carprofen
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All rights reserved
MELOXICAM Veterinary—Systemic 87
MELOXICAM Veterinary—Systemic
Some commonly used brand names are:
For veterinary-labeled product(s)—Metacam.
For human-labeled product(s)—Mobic; Mobicox.
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
CATEGORY:
pKa: 1.1 and 4.2. {R-5}
Solubility: Practically insoluble in water, in strong acids, and in bases;
slightly soluble in methanol.{R-5}
Other characteristics: Partition coefficient—0.1 in n-octanol/buffer
pH 7.5.{R-5}
Analgesic; anti-inflammatory (nonsteroidal).
INDICATIONS
PHARMACOLOGY/PHARMACOKINETICS
Note: Bracketed information in the Indications section refers to uses that
either are not included in U.S. product labeling or are for products not
commercially available in the U.S.
Mechanism of action/Effect: Anti-inflammatory—Meloxicam is a
nonsteroidal anti-inflammatory drug (NSAID) of the oxicam group.{R1; 3; 4}
It is a potent inhibitor of prostaglandin synthesis.{R-3; 4}
ACCEPTED
Absorption: Oral bioavailability—Dogs: Approaches 100% when
administered with food.{R-1}
Inflammation, musculoskeletal (treatment); or
Pain, musculoskeletal (treatment)—Dogs: Meloxicam oral suspension
and meloxicam injection are indicated in the control of pain and
inflammation associated with osteoarthritis.{R-1; 3; 4; 13; 15-17}
[Inflammation, postoperative (treatment)]; or
[Pain, postoperative (treatment)]—
Dogs: Meloxicam injection is indicated in the control of pain and
inflammation following orthopedic and soft tissue surgery.{R-4; 18-21}
Cats1: Meloxicam injection is used in the control of pain and
inflammation following orthopedic and soft tissue surgery.{R-9; 11}
ACCEPTANCE NOT ESTABLISHED
Inflammation, musculoskeletal (treatment); or
Pain, musculoskeletal (treatment)—[Cats]1: Meloxicam is used in the
control of acute musculoskeletal inflammation and pain. There is
evidence supporting its efficacy and safety with short-term administration.{R-9-11} Meloxicam is also used in the alleviation of chronic
pain and inflammation; however, additional research would more
clearly define dosage recommendations for cats.
Distribution: Dogs—Volume of distribution: 0.32 ± 0.07 L/kg.{R-14}
Protein binding: Dogs—97%.{R-1; 14}
Half-life: Elimination—Dogs: With a dose of 0.2 mg per kg of body
weight (mg/kg)—
Intravenous administration: 24.0 ± 6.3 hours.{R-22}
Oral: 23.7 ± 7.1 hours.{R-22}
Subcutaneous: 23.7 ± 4.3 hours.{R-22}
Note: When dogs are treated with meloxicam for more than 45 days,
there is evidence that terminal elimination half-life may be extended
and drug accumulation enhanced.{R-1}
Peak serum concentration: Dogs—With a dose of 0.2 mg/kg:
Oral administration—0.464 mcg/mL at approximately 7.5 hours.{R-1;
22}
Subcutanous—0.734 mcg/mL at approximately 2.5 hours.{R-14; 22}
Elimination: Dogs—Clearance: 0.17 ± 0.02 mL/min/kg.{R-22}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
REGULATORY CONSIDERATIONS
U.S. and Canada—
Meloxicam is labeled for use only by or on the order of a licensed
veterinarian.{R-1; 3; 4}
PRECAUTIONS TO CONSIDER
REPRODUCTION/PREGNANCY/LACTATION
Dogs: The safety of administering meloxicam to dogs during breeding,
pregnancy, or lactation has not been studied.{R-1; 3}
PEDIATRICS
CHEMISTRY
Chemical group: An oxicam derivative.{R-5}
Chemical name: 4-Hydroxy-2-methy-N-(5-methyl-2-thiazolyl)-2H1,2-benzothiazine-3-carboxamide 1,1-dioxide.{R-1}
Dogs: The safety of administering meloxicam to dogs younger than 6
months of age has not been studied.{R-1} Canadian product labeling
advises caution if considering administration of a nonsteroidal antiinflammatory drug to animals less than 6 weeks of age because of a
potential for increased risk.{R-4}
Molecular formula: C14H13N3O4S2.{R-6}
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
Molecular weight: 351.40.{R-6}
Description: A yellow solid.{R-5} The commercial oral formulation is a
yellowish viscous suspension with the odor of honey.{R-1}
Ó 2004 The United States Pharmacopeial Convention, Inc.
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
All rights reserved
88 MELOXICAM Veterinary—Systemic
Note: Combinations containing any of the following medications,
depending on the amount present, may also interact with this
medication.
Anticoagulants{R-3; 4}
(because nonsteroidal anti-inflammatory drugs [NSAIDs] have been
associated with inhibition of platelet aggregation and with the
potential for gastrointestinal ulceration or bleeding, concurrent
administration with an anticoagulant could increase the risk of
adverse effects; however, studies in dogs have indicated that effects
on thromboxane A2 [as measured by thromboxane B2] are minimal,
making antiplatelet effects unlikely when administered at recommended dosages;{R-23} also, it has been reported that no change in
buccal mucosal bleeding time occurs in healthy dogs with a single
0.2 mg/kg dose{R-14})
Anti-inflammatory drugs, nonsteroidal (NSAID) or
Corticosteroids
(concurrent administration of more than one NSAID or of corticosteroids with a NSAID may greatly increase the risk of adverse
effects){R-1-4}
Diuretics
(animals on diuretic therapy could have an increased risk of renal
toxicity with NSAID administration){R-1}
Nephrotoxic medications
(NSAIDs have been associated with renal toxicity; therefore, administration with other nephrotoxic medications should be viewed with
caution){R-1}
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
given in parentheses where appropriate)—not necessarily inclusive (»
= major clinical significance).
Except under special circumstances, this medication should not be
used when the following medical problems exist:
Bleeding disorders{R-3; 4}
(because nonsteroidal anti-inflammatory drugs [NSAIDs] have been
associated with inhibition of platelet aggregation and with the
potential for gastrointestinal ulceration or bleeding, their administration to animals with bleeding problems, including coagulation or
platelet function disorders, could increase the risk of adverse effects;
however, studies in dogs have indicated that effects on thromboxane
A2 [as measured by thromboxane B2] are minimal, making
antiplatelet effects unlikely when administered at recommended
dosages;{R-23} also, it has been reported that no change in buccal
mucosal bleeding time occurs in healthy dogs with a single 0.2
mg/kg dose{R-14})
Cardiovascular disease or
Hepatic dysfunction or
Renal dysfunction
(because NSAIDs have been associated with renal toxicity, risk to
patients with cardiovascular, hepatic, or renal compromise may be
increased) {R-1; 3; 4}
Dehydration{R-1}
(dehydration could increase the risk of renal toxicity with NSAID
administration)
Gastrointestinal bleeding or ulceration{R-3}
(many NSAIDs are known to increase the risk of gastrointestinal
disease, particularly ulceration;{R-1} therefore, the presence of lesions
Ó 2004 The United States Pharmacopeial Convention, Inc.
before treatment may put an animal at risk of exacerbation or
perforation)
Hypersensitivity to meloxicam{R-1; 2; 3; 14}
Hypersensitivity to peroxicam{R-24}
Hypersensitivity to aspirin or other NSAIDs{R-2}
(previous development of adverse effects from meloxicam may be an
indication of increased risk of future sensitivity; caution is advised
when an animal has previously reacted to other anti-inflammatory
medications)
PATIENT MONITORING
The following may be especially important in patient monitoring (other
tests may be warranted in some patients, depending on condition; » =
major clinical significance):
Blood chemistry and
Complete blood count (CBC)
(bloodwork pretreatment and periodically during treatment is
recommended){R-1}
Physical exam
(a physical exam and history are recommended before treatment){R-1}
SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their
potential clinical significance—not necessarily inclusive:
Note: Nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit
cyclooxygenase have been associated with gastrointestinal and renal
toxicity. Susceptibility to side effects varies among individual animals.
As with other NSAIDs, gastrointestinal toxicity is the most frequently
reported adverse effect with meloxicam administration in dogs.{R-1; 3}
The following events were reported in dogs during two field safety studies
involving a combined total of 306 dogs. One study of 224 client-owned
dogs compared placebo with meloxicam, administered by an initial
subcutaneous injection of 0.2 mg per kg of body weight (mg/kg) on the
first day, followed by 0.1 mg/kg orally once a day for 13 days. The
second study, of 82 dogs, used the same dosage regimen, except that
the initial dose was administered orally.{R-8 ; 13}
Incidence more frequent
Dogs
Diarrhea—reported in 12% of dogs treated with meloxicam and 7%
of placebo-treated dogs;{R-1} vomiting—reported in 25% of dogs
treated with meloxicam and 15% of placebo-treated dogs{R-1}
Incidence less frequent
Dogs
Inappetance—3% of dogs treated with meloxicam and <1% of
placebo-treated dogs{R-1}
Incidence rare—<1% of animals treated with meloxicam
Dogs
Bleeding gums after dental procedure; bloody stool; epiphora;
lethargy; swollen carpus
The following are drawn from postmarketing reports of suspected adverse
drug reactions (SADRs) monitored worldwide since 1995:{R-3}
Incidence unknown
Dogs (categories listed in decreasing order of frequency)
Gastrointestinal effects (vomiting, diarrhea, inappetence, melena,
hematemesis, gastrointestinal ulceration); central nervous system/
behavioral effects (ataxia, personality change, seizures, sleepiness,
hyperactivity, depression, trembling, lethargy in a nursing puppy{R-
All rights reserved
MELOXICAM Veterinary—Systemic 89
1}
); renal effects (elevated creatinine and blood urea nitrogen, acute
renal failure); dermatologic effects (pruritis, eczema, focal alopecia,
pyotraumatic moist dermatitis [hot spots], pyoderma{R-1}); hypersensitivity (urticaria, allergic dermatitis); hematologic effects
(immune-mediated hemolytic anemia, immune mediated thrombocytopenia); hepatic effects (elevated liver enzymes, jaundice);
polyarthritis{R-1}
OVERDOSE
For more information in cases of overdose or unintentional ingestion,
contact the American Society for the Prevention of Cruelty to
Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation)
and/or the drug manufacturer.
CLINICAL EFFECTS OF OVERDOSE
The following effects have been selected on the basis of their potential
clinical significance (possible signs in parentheses where appropriate)—not necessarily inclusive:
Dogs
With an oral dose of 0.3 to 0.5 milligram per kilogram (mg/kg) a day
for 6 weeks, the following were reported during the treatment
period:{R-1}
Renal changes
Note: This study of twenty-four dogs (six per treatment group) compared
untreated dogs with dogs given the labeled maintenance dose (0.1 mg/
kg a day), 3 times the labeled dose (0.3 mg/kg a day), or 5 times the
labeled dose (0.5 mg/kg a day). Gastrointestinal signs and histopathology were similar among the groups. There were no changes in
hematology, blood chemistry, urinalysis, clotting time or buccal
mucosal bleeding times associated with meloxicam treatment. Two of
six dogs receiving 0.3 mg/kg a day and two of six receiving 0.5 mg/kg a
day developed renal enlargement. When the kidneys were examined
microscopically, degeneration or slight necrosis at the tip of the papilla
was noted in three dogs receiving 0.5 mg/kg a day.{R-1; 8}
With an oral dose of 0.3 to 0.5 mg/kg a day for 6 months, the following
were reported in some dogs during the treatment period:{R-1}
Albumin, decreased—reported in dogs administered 0.5 mg/kg a
day, anemia, regenerative; blood urea nitrogen, increased—reported with 0.5 mg/kg a day; hematocrit, decreased; neutrophilia;
red blood cell count, decreased
Note: Like the study described above, this study of twenty-four dogs (six
per treatment group) compared untreated dogs with dogs given
meloxicam at a dose of 0.1, 0.3, or 0.5 mg/kg a day, but for a more
prolonged period of time. No significant clinical adverse effects were
demonstrated.{R-1; 3; 4} Gastrointestinal signs were noted in all groups,
including the dogs not given meloxicam. Gastric endoscopy results and
gross gastrointestinal changes at necropsy were similar among groups.
No gross or microscopic renal changes were observed.{R-1}
With an intravenous dose administered every two weeks, the first two
doses being 2 mg/kg, the second two, 6 mg/kg, and the final two 12
mg/kg, the following were reported during the treatment period:{R-8}
Pyloric gastric ulceration or perforation (fecal blood loss
increasing as dose increases; frequent vomiting; lethargy; recumbence)
With an intravenous dose of 0.2 to 0.6 mg/kg a day for 3 days: {R-14}
Gastrointestinal effects; renal changes
Ó 2004 The United States Pharmacopeial Convention, Inc.
Note: Histologic examination of the kidneys showed renal changes in
some dogs that included dilated medullary and cortical tubules,
interstitial inflammation, and renal papillary necrosis.
Other changes noted on histology in some dogs included gastrointestinal superficial mucosal hemorrhages, congestion, and erosions as
well as mesenteric lymphadenopathy.
With an intravenous dose of 1 mg/kg a day for 3 days: {R-13; 14}
Gastrointestinal effects (including fecal blood loss); renal compromise; renal failure, acute
Note: Dogs developed renal compromise, showing significant urinary
protein excretion and increases in blood urea nitrogen and creatinine. Dogs with significantly elevated creatinine developed acute renal
failure by the fourth day of the study.
CLIENT CONSULTATION
A tear-off client information sheet attached to the product insert is
provided by the United States manufacturer for clients administering
oral meloxicam to their dogs.{R-2}
In providing consultation, consider emphasizing the following selected
information:
Keeping water readily available during the treatment period to avoid
dehydration
Never exceeding the prescribed daily amount without veterinary
consultation; contacting a veterinarian if more than the daily dose is
consumed{R-2}
Familiarizing clients with signs that an adverse reaction may be
occurring, including vomiting, change in behavior, change in bowel
movements, change in drinking habits, change in the skin, change in
urination habits, a change in appetite, or yellowing of the gums, skin
or white of the eyes.{R-2} Instructing them to discontinue medication
and contact their veterinarian if a reaction is suspected
Not administering nonsteroidal anti-inflammatory drugs labeled for
human use to animals without guidance from a veterinarian; human
dosages may be toxic or fatal for animals
VETERINARY DOSING INFORMATION
ORAL ADMINISTRATION
Meloxicam has almost complete bioavailability when administered orally
with food. Administration with food is recommended for accurate
dosing in small dogs (see Oral Dosage Forms below).{R-1; 2}
FOR PERIOPERATIVE ADMINISTRATION
Perioperative fluid therapy was administered to adult dogs in clinical
trials that demonstrated the safety of perioperative administration.{R-4}
General health and age of the animal are considered in the decision to use
a nonsteroidal anti-inflammatory drug perioperatively. Potential
factors include pre-existing debilitation or stress; the concurrent
administration of other medications, including those used for anesthesia, that may lower blood pressure or increase the risk of hepatic or
renal toxicity; or surgery that may lead to reduced tissue perfusion.{R-4}
Canadian product labeling lists protocols that have been used for
anesthetizing dogs treated perioperatively with meloxicam.{R-4} No
adverse effects were reported when the following combinations were
used with meloxicam:
Acepromazine + Butorphanol/Thiopentone sodium/Halothane
Acepromazine/Ketamine + Diazepam/Halothane
Acepromazine/Thiopentone/Isoflurane
Diazepam/Propofol/Isoflurane
All rights reserved
90 MELOXICAM Veterinary—Systemic
ORAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
Veterinary-labeled product(s):
1.5 mg per mL (Rx) [Metacam].
Canada—{R-3}
Veterinary-labeled product(s):
1.5 mg per mL (Rx) [Metacam].
MELOXICAM ORAL SUSPENSION
Usual dose:
Inflammation, musculoskeletal; or
Pain, musculoskeletal—Dogs: Oral, 0.2 mg per kg of body weight as an
initial dose, followed by 0.1 mg per kg of body weight every twentyfour hours.{R-1; 3}
Note: The manufacturer gives specific instructions for administering
meloxicam to dogs with the tools provided,{R-1} as follows:
Shake the bottle well before using.
Be aware that in the United States, the dropper bottle delivers 0.05 mg
of meloxicam per drop while in Canada, as of early 2004, the dropper
bottle delivers 0.1 mg per drop. The Canadian dropper is expected to
change in 2004 so that it delivers the same amount per drop, 0.05
mg, as the dropper marketed in the United States.{R-12} The
concentration delivered by a particular dropper can be found in
the product labeling.
For dogs weighing less than 2.3 kg (5 pounds), the dose is measured by
using the dropper bottle to count the appropriate number of drops
onto the food. It should not be administered into the dog’s mouth.
For dogs weighing between 2.3 and 4.5 kg (5 and 10 pounds), the
medication is also administered onto the food, rather than into the
mouth. However, the dose can be measured by using either the
dropper bottle or the syringe provided. Using the dropper, the dose is
measured by the number of drops for the dog’s weight, as described
above. With the syringe available in the U.S., the dose is measured by
increments marked for each 5 pounds of body weight, rounded down
to the nearest 5 pounds. {R-1} In Canada, the syringe is marked in
increments based on kilograms of body weight.{R-3} In both
countries, the syringe is scaled to deliver the maintenance dose of
0.1 mg/kg. {R-1; 3}
For dogs weighing more than 10 pounds, the medication may be
administered on the food or into the mouth, using either the dropper
bottle or syringe, as described above. {R-1}
Note: [Cats]1—Although there is evidence to support the safety and
efficacy of the short-term (less than one week) administration of
meloxicam to cats,{R-9-11} there are insufficient data to establish the
best recommendation for long-term administration in the treatment of
pain and inflammation. Therefore, clinicians have recommended
beginning treatment with a dose of 0.1 mg per kg of body weight
and, depending on clinical response, extending the time between doses
so that the medication is given every other day or every third day.
Because of limited data, there is no consensus on the minimum
effective dose; however, some clinicians will begin with the dose of 0.1
mg per kg of body weight a day and gradually taper it to a daily dose as
low as 0.03 to 0.05 mg per kg of body weight, sometimes administered
as 0.1 mg per cat a day. There are anecdotal reports of successful
management in some cats, even when this low dose is given every
other day or every third day.
For dosing recommendations in the control of postoperative inflammation and pain in cats, see Meloxicam Injection below.
Strength(s) usually available:
U.S.—{R-1}
Ó 2004 The United States Pharmacopeial Convention, Inc.
Caution: Keep out of the reach of children.{R-1}
Packaging and storage: Store between 15 and 30 °C (59 and
86 °F){R-1}, unless otherwise specified by manufacturer.
USP requirements: Not in USP.{R-7}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
MELOXICAM TABLETS
Usual dose: See Meloxicam Oral Suspension.
Strength(s) usually available:
U.S.—{R-1}
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):
7.5 mg (Rx) [Mobic].
15 mg (Rx) [Mobic].
Canada—{R-3}
Veterinary-labeled product(s):
Not commercially available.
Human-labeled product(s):
7.5 mg (Rx) [Mobicox; generic].
15 mg (Rx) [Mobicox; generic].
Packaging and storage: Store between 15 and 30 °C (59 and 86 °F),
in a dry place, unless otherwise specified by manufacturer.
USP requirements: Not in USP.{R-7}
PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
MELOXICAM INJECTION
Usual dose:
Inflammation, musculoskeletal; or
Pain, musculoskeletal—Dogs: Intravenous or subcutaneous, 0.2 mg
per kg of body weight as an initial dose. Product labeling recommends
that meloxicam oral suspension be used for continuation of treatment,
administered orally at a dose of 0.1 mg per kg of body weight every
twenty-four hours.{R-4; 14}
[Inflammation, postoperative]; or
[Pain, postoperative]—
Dogs: Intravenous or subcutaneous, 0.2 mg per kg of body weight,
administered before surgery.{R-4}
Note: Perioperative fluid therapy was administered to adult dogs in
clinical trials that demonstrated the safety of perioperative administration.{R-4}
All rights reserved
MELOXICAM Veterinary—Systemic 91
Cats1: Subcutaneous, 0.2 mg per kg of body weight, administered as a
single dose.{R-11}
Strength(s) usually available:
U.S.— {R-14}
Veterinary-labeled product(s):
5 mg per mL (Rx) [Metacam].
Canada—{R-4}
Veterinary-labeled product(s):
5 mg per mL (Rx) [Metacam].
Caution: Keep out of the reach of children.{R-4}
Packaging and storage: Store at or below 25 °C (77 °F){R-4}, unless
otherwise specified by manufacturer.
USP requirements: Not in USP.{R-7}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
Developed: 2/6/04
REFERENCES
1. Metacam Oral Suspension package insert (Boehringer Ingelheim/Merial—US),
Rev 3/03, Rec 9/9/03.
2. Client information for Metacam oral suspension (Boehringer Ingelheim/
Merial—US), Rev 3/03, Rec 9/9/03.
3. Metacam Oral Suspension package insert (Boehringer Ingelheim—Canada),
Rec 10/29/03.
4. Metacam 0.5% Injection package insert (Boehringer Ingelheim—Canada), Rec
10/29/03.
5. Klasco RK, editor. USP DI Drug information for the healthcare professional.
Volume III. Greenwood Village, CO: Thomson MICROMEDEX, Inc.; 2003.
6. USP dictionary of USAN and international drug names, 2002 ed. Rockville,
MD: The United States Pharmacopeial Convention, Inc., 2002.
7. The United States pharmacopeia. The national formulary. USP 26th revision
(January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United
States Pharmacopeial Convention, Inc., 2002.
Ó 2004 The United States Pharmacopeial Convention, Inc.
8. Metacam (meloxicam) 0.5 and 1.5 mg/mL Oral Suspension freedom of
information summary (NADA #141-213). Sponsor: Boehringer Ingelheim
Vetmedica, Inc. Approval date: 4/15/03.
9. Slingsby LS, Waterman-Pearson AE. Comparison between meloxicam and
carprofen for postoperative analgesia after feline ovariohysterectomy. J Small
Anim Pract 2002 Jul; 43(7): 286–9.
10. Lascelles BD, Henderson AJ, Hackett IJ. Evaluation of the clinical efficiency of
meloxicam in cats with painful locomotor disorders. J Small Anim Pract 2001
Dec; 42(12): 587–93.
11. Slingsby LS, Waterman-Pearson AE. Postoperative analgesia in the cat after
ovariohysterectomy by use of carprofen, ketoprofen, meloxicam or tolfenamic
acid. J Small Anim Pract 2000 Oct; 41(10): 447–50.
12. Manufacturer comment from Boehringer-Ingelheim (Canada), Rec 11/4/03.
13. Metacam (meloxicam) 5 mg/mL Solution for Injection freedom of information
summary (NADA #141-219). Sponsor: Boehringer Ingelheim Vetmedica, Inc.
Approval date: 12/10/03.
14. Metacam 5 mg/mL Solution for Injection (Boehringer Ingelheim/Merial—US),
Rev 7/03, Rec 12/17/03.
15. Moreau M, Dupuis J, Bonneau NH, et al. Clinical evaluation of a nutraceutical,
carprofen and meloxicam for the treatment of dogs with osteoarthritis. Vet Rec
2003 Mar 15; 152(11): 323–9.
16. Doig PA, Purbrick KA, Hare JE, et al. Clinical efficacy and tolerance of
meloxicam in dogs with chronic osteoarthritis. Can Vet J 2000 Apr; 41(4):
296–300.
17. Cross AR, Budsberg SC, Keefe TJ. Kinetic gait analysis assessment of
meloxicam efficacy in a sodium urate-induced synovitis model in dogs. Am J
Vet Res 1997 Jun; 58(6): 626–31.
18. Fowler D, Isakow K, Caulkett N, et al. An evaluation of the analgesic effects of
meloxicam in addition to epidural morphine/mepivacaine in dogs undergoing
cranial cruciate ligament repair. Can Vet J 2003 Aug; 44(8): 643–8.
19. Caulkett N, Read M, Fowler D, et al. A comparison of the analgesic effects of
butorphanol with those of meloxicam after elective ovariohysterectomy in
dogs. Can Vet J 2003 Jul; 44(7): 565–70.
20. Budsberg SC, Cross AR, Quandt JE, et al. Evaluation of intravenous
administration of meloxicam for perioperative pain management following
stifle joint surgery in dogs. Am J Vet Res 2002 Nov; 63(11): 1557–63.
21. Mathews KA, Pettifer G, Foster R, et al. Safety and efficacy of preoperative
administration of meloxicam, compared with that of ketoprofen and butorphanol in dogs undergoing abdominal surgery. Am J Vet Res 2001 Jun; 62(6):
882–8.
22. Busch U, Schmid J, Heinzel G, et al. Pharmacokinetics of meloxicam in animals
and the relevance to humans. Drug Metab Dispos 1998 Jun; 26(6): 576–84.
23. Jones CJ, Streppa HK, Harmon BG, et al. In vivo effects of meloxicam and
aspirin on blood, gastric mucosal, and synovial fluid prostanoid synthesis in
dogs. Am J Vet Res 2002 Nov; 63(11): 1527–31.
24. Committee comment, Rec 12/1/03.
All rights reserved
92 PHENYLBUTAZONE Veterinary—Systemic
PHENYLBUTAZONE Veterinary—Systemic
Some commonly used brand names for veterinary-labeled products are:
Butaject; Butapaste; Butasone 400; Butasone 1000; Butasone Conc;
Butatabs-D; Butatabs-E; Butatron Tablets; Butequine; Buzone Concentrate
Powder; Equiphar Phenylbutazone 1 Gram Tablets; Equiphar Phenylbutazone Injection 20%; Equiphen Paste; Phenylbute Injection 20%; Phenylbute
Paste; Phenylbute Tablets 1 Gram; Phenylbute Tablets 100 Mg; Phenylbute
Tablets 200 Mg; Phenylzone Paste; Pributazone Tablets; Pro-Bute Injection; and Pro-Bute Tablets.
Some commonly used brand names for human-labeled products are ApoPhenylbutazone and Butazolidin.
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
CATEGORY:
Anti-inflammatory, nonsteroidal; analgesic; antipyretic.
INDICATIONS
Note: Bracketed information in the Indications section refers to uses that
either are not included in U.S. product labeling or are for products not
commercially available in the U.S.
ACCEPTED
Note: Relief of inflammatory conditions associated with the musculoskeletal system is a common labeled indication for the use of
phenylbutazone in dogs and horses. For the purpose of this resource,
the USP Veterinary Medicine Committee has interpreted this to mean
the following unbracketed indications are labeled uses.
Inflammation, musculoskeletal (treatment); or
Pain (treatment)—Dogs, horses, and [cattle]1: Phenylbutazone is indicated
for the relief of musculoskeletal inflammation and mild to moderate
somatic or [visceral]1 pain. It seems especially of value for the
treatment of pain of musculoskeletal and inflammatory origin in dogs,
horses, and [cattle]1. Such conditions commonly include arthritis and
laminitis.{R-2} See also the Regulatory Considerations section below.
[Fever (treatment)]1; or
[Inflammation, general (treatment)]1—Although they are not labeled
indications, phenylbutazone, as a nonsteroidal anti-inflammatory
drug, would be expected to lower fever and suppress inflammation
other than musculoskeletal inflammation in those species where
information exists for proper dosing.
1
Not included in Canadian product labeling or product not commercially
available in Canada.
REGULATORY CONSIDERATIONS
U.S.—
The extra-label use of phenylbutazone in female dairy cattle 20
months of age or older is prohibited by the United States Food and
Drug Administration.{R-34} Although other extra-label uses in foodproducing animals, as stated in Animal Medicinal Drug Use
Clarification Act (AMDUCA) guidelines, are legal at this writing,
the practitioner should check current statutes to be sure restrictions
on the use of phenylbutazone in food-producing animals have not
been broadened.
Ó 2004 The United States Pharmacopeial Convention, Inc.
The Food and Drug Administration has not approved the use of
phenylbutazone in food-producing animals; therefore, there are no
established withdrawal times on product labeling for food-producing
species. Phenylbutazone is not permitted at any concentration (zero
tolerance) in meat, milk, or eggs intended for human consumption.
(See also the Dosage Forms section of this monograph.)
Federal law restricts phenylbutazone to use by or on the order of a
licensed veterinarian.
Canada—
Phenylbutazone is not labeled for use in food-producing animals;
therefore, there are no established withdrawal times on product
labeling for food-producing species. Phenylbutazone is not permitted
at any concentration (zero tolerance) in meat, milk, or eggs intended
for human consumption. (See suggested withdrawals for extra-label
use in the Dosage Forms section of this monograph.)
Federal law restricts phenylbutazone to use by or on the order of a
licensed veterinarian.
CHEMISTRY
Chemical group: Pyrazolone derivative.{R-3}
Chemical name: 3,5-Pyrazolidinedione, 4-butyl-1,2-diphenyl-.{R-32}
Molecular formula: C19H20N2O2.{R-32}
Molecular weight: 308.37.{R-32}
Description: Phenylbutazone USP—White to off-white, odorless, crystalline powder.{R-4}
pKa: 4.5 (in water).{R-5}
pH of aqueous solution: 8.2.{R-5}
Solubility: Phenylbutazone USP—Very slightly soluble in water; freely
soluble in acetone and in ether; soluble in alcohol.{R-4}
PHARMACOLOGY/PHARMACOKINETICS
Note: See also Table 1. Pharmacology/Pharmacokinetics, at the end of this
monograph.
Mechanism of action/Effect: Inhibition of the arachidonic acid cascade at the level of prostaglandin H synthase and prostacyclin synthase results in decreased production of prostaglandins and
thromboxane. Phenylbutazone also inhibits urate crystal phagocytosis
by synoviocytes.{R-6}
Other actions: Phenylbutazone reversibly inhibits platelet aggregation.
It induces hepatic microsomal enzyme activity. This drug also has
uricosuric activity.{R-1}
Absorption:
Cattle—Average oral bioavailability ranged from 54 to 69% in one
study.{R-7; 8}
All rights reserved
PHENYLBUTAZONE Veterinary—Systemic 93
Horses—Approximately 70%. Feed, especially hay, delays time to peak
effect and decreases peak plasma concentrations.
Distribution: Phenylbutazone is distributed mainly into plasma and
extracellular fluid, as indicated by the relatively small volume of distribution. This low volume of distribution is also indicative of only
nominal tissue binding.{R-9}
Protein binding:
Cattle—93 to 98%.{R-9}
Horses—Greater than 98%.
Other species—Protein binding is thought to be very high in other species
as well.
Biotransformation: Hepatic. Rate may differ significantly among species and breeds. Phenylbutazone is known to induce hepatic microsomal enzyme activity. Paradoxically, however, mixed function
oxidase activity may become saturated, leading to decreasing metabolic rates.
Time to peak plasma concentration:
Cattle—Peak plasma concentration is reached in 8.9 to 10.5 hours in
cattle following oral administration.{R-8; 9}
Human data—Peak plasma concentration is reached in about 2 hours
after oral administration and 6 to 10 hours after intramuscular
injection in humans.{R-12}
Peak plasma concentration:
Dogs—A peak plasma phenylbutazone concentration of 49 to 75 mcg/
mL occurred following a dose of 15 mg per kg of body weight (mg/kg)
given orally to greyhounds.
Human data—A mean peak plasma concentration of 33 mcg/mL was
reached 3 hours after oral administration of 300 mg to 6 healthy
subjects.{R-13}
Serum concentration: Cattle—The mean minimum concentration at
steady state in cows given 5 mg per kg of body weight (mg/kg) twice a
day for 8 days was 100.4 ± 7.3 mcg/mL.{R-10} Six bulls given a loading
dose of 12 mg/kg followed by an oral maintenance dose of 6 mg/kg for
7 additional days had a mean minimum plasma concentration of 75.06
mcg/mL. A minimal plasma drug concentration (minimum effective
concentration, MEC) of 50 to 100 mcg/mL of phenylbutazone has been
suggested for analgesia in cattle and humans.{R-9}
Peak tissue concentration: Rabbits—After an intra-arterial dose of 8
mg/kg in rabbits, concentrations in muscle ranged from 0.16 to 1.3
mcg/gram with detectable levels present up to 7 hours post-administration. Concentrations in the cortex of the kidney ranged from 0.21 to
14.5 mcg/gram with detectable levels present at the end of the study,
22.25 hours post-administration. Levels in the renal medulla ranged
from 0.085 to 5.1 mcg/gram and were also present at the end of the
study, 22.25 hours post-administration.{R-14}
Liver concentrations: Rabbits—After intra-arterial administration of 8
mg/kg, concentrations ranged from 12.4 mcg/gram at 40 minutes to
0.15 mcg/gram 18 hours after administration.{R-14}
Milk concentrations: Cattle—Concentrations in milk do not exceed 1%
of plasma concentrations.{R-10} The lowest detected concentration of
phenylbutazone in milk appeared 5 days after the last dose in a regiÓ 2004 The United States Pharmacopeial Convention, Inc.
men of 5 mg/kg twice a day for eight days, and was found to be 0.05 ±
0.01 mcg/mL.{R-10} The total amount of phenylbutazone excreted into
milk during plasma steady state was 0.35 ± 0.07% of the amount
administered during the same period.{R-10; 37}
Elimination: It is important to note that phenylbutazone follows zeroorder (dose-dependent) kinetics in dogs and horses. Whether this
occurs in other species is unknown. Drugs with zero-order elimination
typically have longer elimination half-lives as the dose increases.
As such, it is important that the recommended doses not be
exceeded.
Pigs: Only 0.13% of phenylbutazone and 6.8% of oxyphenylbutazone
administered to pigs were excreted renally.{R-21}
PRECAUTIONS TO CONSIDER
SPECIES SENSITIVITY
Cats: Not recommended for use in cats. Phenylbutazone is rapidly
converted to the active metabolite oxyphenbutazone; oxyphenbutazone is very slowly eliminated by the cat.{R-11}
PREGNANCY/REPRODUCTION
Fetotoxicity, but not teratogenicity, has been demonstrated in animal
studies.{R-1}
LACTATION
Phenylbutazone is distributed into milk (see Milk concentrations above); it
may cause blood dyscrasias or other adverse effects in nursing human
infants.{R-1}
GERIATRICS
Phenylbutazone appears to be eliminated more slowly from the plasma of
aged animals, leading to higher plasma levels.
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
» Anesthetics
(respiratory arrest has been observed in cattle pretreated with
phenylbutazone when anesthetic induction was the combination of
guaifenesin, xylazine, and ketamine; a reinduction of anesthesia has
been observed when horses just recovered from barbiturate-glyceryl
guaiacolate [guaifenesin] anesthesia were administered phenylbutazone; the mechanism for this interaction is unknown, but may be
due to displacement of protein bound anesthetic to its free [active]
form by the phenylbutazone){R-15}
» Anti-inflammatory analgesics, nonsteroidal, other, or
Corticosteroids or
Dipyrone or
Salicylates
(concurrent use with phenylbutazone may increase the risk of
gastrointestinal side effects, including ulceration or hemorrhage;
also, salicylates may increase the risk of bleeding at sites other than
the gastrointestinal tract, due to additive inhibition of platelet
aggregation)
All rights reserved
94 PHENYLBUTAZONE Veterinary—Systemic
Chloramphenicol
(the administration of chloramphenicol sodium succinate to mares
reduced mean phenylbutazone clearance from 0.6 to 0.34 mg per
minute per kg and increased mean half-life from 4.06 to 6.18 hours;
the volume of distribution was unchanged){R-16}
» Furosemide
(premedication with phenylbutazone has been reported to significantly reduce the diurectic and hemodynamic effects of furosemide
in horses){R-40}
» Gentamicin
(repeated administration of phenylbutazone to horses at recommended dosages has been reported to significantly reduce the
distribution and elimination of a single intravenous bolus of
gentamicin; care should be taken when considering aminoglycoside
administration to horses being treated with phenylbutazone){R-38}
Thyroid hormones
(concurrent administration with phenylbutazone may inhibit conversion of T4 to T3)
» Warfarin or related coumarins
(phenylbutazone has caused bleeding episodes in animals previously
stable on warfarin anticoagulation therapy; this is due to displacement of the warfarin from its protein binding sites by phenylbutazone)
HUMAN DRUG INTERACTIONS AND/OR RELATED
PROBLEMS{R-1}
In addition to the above drug interactions reported in animals, the
following drug interactions have been reported in humans, and are
included in the human monograph Anti-inflammatory Drugs, Nonsteroidal (Systemic) in USP DI Volume I; these drug interactions are
intended for informational purposes only and may or may not be
applicable to the use of phenylbutazone in the treatment of animals:
Anticoagulants, coumarin- or indanedione-derivative
(higher risk of bleeding when phenylbutazone is administered with
coumarin- or indanedione-derivative anticoagulants than with other
nonsteroidal anti-inflammatory drugs [NSAIDs] because phenylbutazone inhibits the anticoagulant’s metabolism; concurrent use not
recommended)
Anticonvulsants, hydantoin
(increased risk of toxicity with hydantoin anticonvulsants, such as
phenytoin, because phenylbutazone may displace them from proteinbinding sites and inhibit their metabolism)
Barbiturates or
Cortisone and possibly other corticosteroids or
Digitalis glycosides or
Estrogen-containing oral contraceptives
(by inducing hepatic microsomal enzymes, phenylbutazone may
decrease the effects of these medications)
Cholestyramine
(cholestyramine may decrease absorption of phenylbutazone; administration of phenylbutazone 1 hour before or 4 to 6 hours after
cholestyramine is recommended)
Dermatitis-causing medications
(increased risk of severe dermatologic reactions when phenylbutazone is administered concurrently with other dermatitis-causing
medications)
Hepatic microsomal enzyme inducers, other
(other hepatic enzyme inducers may increase phenylbutazone
metabolism and decrease its half-life)
Ó 2004 The United States Pharmacopeial Convention, Inc.
Methotrexate
(concurrent use with phenylbutazone may increase the risk of
agranulocytosis or bone marrow depression)
Penicillamine
(concurrent use with phenylbutazone may increase the risk of
serious hematologic and/or renal adverse effects)
Sulfonamides
(concurrent use with phenylbutazone may potentiate the effects of
either or both medications)
Other medications, oral
(antacids in buffered phenylbutazone formulations may interfere
with absorption of many other medications)
LABORATORY VALUE ALTERATIONS
The following have been selected on the basis of their potential clinical
significance (possible effect in parentheses where appropriate)—not
necessarily inclusive (» = major clinical significance):
With diagnostic test results
Thyroid function tests
(phenylbutazone may decrease total and free T4 concentrations)
Note: A study in horses showed that phenylbutazone significantly
decreased the baseline total and free thyroxine concentration
after five days of treatment. Total T4 values remained decreased
for up to ten days after discontinuation. Free T4 concentrations
returned to baseline by the third day following discontinuation
of the drug.{R-17}
A study in dogs showed that phenylbutazone at a plasma
concentration of 50 mcg/mL had no significant effect on the free
fraction of thyroxine in plasma.{R-18}
With physiology/laboratory test values
Bleeding time
(may be prolonged due to suppressed platelet aggregation)
HUMAN LABORATORY VALUE ALTERATIONS{R-1}
The following laboratory value alterations have been reported in
humans, and are included in the human monograph Anti-inflammatory Drugs, Nonsteroidal (Systemic) in the USP DI Volume I; these
laboratory value alterations are intended for informational purposes
only and may or may not be applicable to the use of phenylbutazone in
the treatment of animals:
With diagnostic test results
Thyroid function tests
(phenylbutazone may interfere with thyroid function tests; specifically, decreasing 24-hour 131I thyroidal uptake or increasing resin or
red cell triiodothyronine uptake)
With physiology/laboratory test values
Glucose concentrations
(phenylbutazone may increase blood glucose concentrations)
Uric acid concentrations
(phenylbutazone may decrease serum concentrations and increase
urine concentrations of uric acid)
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
given in parentheses where appropriate)—not necessarily inclusive (»
= major clinical significance).
All rights reserved
PHENYLBUTAZONE Veterinary—Systemic 95
Risk-benefit should be considered when the following medical
problems exist:
Blood dyscrasias (or history of) or
Bone marrow suppression or
Gastrointestinal ulcer disease, active or
Hepatic or renal disease, severe
(phenylbutazone is not recommended for use in patients with the
problems listed above)
PATIENT MONITORING
The following may be especially important in patient monitoring (other
tests may be warranted in some patients, depending on condition):
Hydration status
(assure adequate patient hydration)
Monitor for signs of gastrointestinal ulceration
(for example, anorexia, melena, vomiting)
With chronic administration or for patients with a history of renal disease,
liver disease, bone marrow suppression, or gastrointestinal ulceration
Complete blood count (CBC) with platelets and
Liver enzymes, including alkaline aminotransferase (ALT [SGPT]) and
Total protein and
Urinalysis
(periodic testing should be considered)
SIDE/ADVERSE EFFECTS
The following side/adverse effects have been selected on the basis of their
potential clinical significance (possible signs in parentheses where
appropriate)—not necessarily inclusive:
THOSE INDICATING NEED FOR MEDICAL ATTENTION
Incidence more frequent
Gastroenteropathy or gastrointestinal ulcers—especially in
horses;{R-11} inflammation, severe, with tissue necrosis, abscessation and eventual sloughing of the vein—with perivascular
injection
Incidence less frequent
Blood dyscrasias—in small animals;{R-11; 19} impaired hepatic
function—may occur at high doses, especially in small animals;
lesions, oral; necrotizing phlebitis in the portal vein—in horses
receiving high doses over extended periods of time; plasma pH,
bicarbonate, and total carbon dioxide decrease; renal papillary
necrosis; sodium and chloride retention; toxic neutropenia—especially with restricted water intake
Note: Seven suspected phenylbutazone-induced blood dyscrasias in dogs
have been reported in the literature. These included pancytopenias
with marrow aplasia or hypoplasia, thrombocytopenias, nonregenerative anemias, and neutropenias. Approximately half of
these animals recovered with discontinuation of the drug and
supportive therapy.{R-19}
HUMAN SIDE/ADVERSE EFFECTS{R-1}
In addition to the above side/adverse effects reported in animals, the
following side/adverse effects have been reported in humans, and
are included in the human monograph Anti-inflammatory Drugs,
Nonsteroidal (Systemic) in USP DI Volume I; these side/adverse effects
Ó 2004 The United States Pharmacopeial Convention, Inc.
are intended for informational purposes only and may or may not
be applicable to the use of phenylbutazone in the treatment of
animals:
Note: Due to the long list of reported human side/adverse effects, some
effects specific to people have not been included in the list below.
Incidence more frequent
Abdominal or stomach cramps; fluid retention/edema
Incidence less frequent or rare
Abdominal distension; agranulocytosis; amblyopia, toxic, or
retinal or macular disturbances; anaphylaxis or anaphylactoid
reactions; anemia, hemolytic; angioedema; blood in urine;
blurred vision or double vision; bronchospastic allergic reaction;
change in hearing; cholestatic hepatitis or jaundice; colitis or
regional enteritis; congestive heart failure or exacerbation of;
constipation; crystalluria, renal calculi, or ureteral obstruction;
dermatitis, allergic; dermatitis, exfoliative; diarrhea; dizziness;
drowsiness; dry irritated or swollen eyes; erythema multiforme;
erythema nodosum; esophagitis; fever; gastritis; gastrointestinal
hemorrhage or ulceration; glomerulonephritis; headache; hepatitis; increased blood pressure; muscle cramps or pain; nephritis,
interstitial; nephrotic syndrome; nervousness or irritability;
neuropathy, peripheral; neutropenia; oliguria/anuria; pancreatitis, acute; pancytopenia; pericarditis; petechiae; proteinuria;
regional enteritis or exacerbation of; renal impairment or
failure; renal papillary or tubular necrosis; retinal hemorrhage;
ringing or buzzing in ears; scotomata; serum sickness–like
reaction; Stevens-Johnson syndrome; stomatitis, aphthous; systemic lupus erythematosus [SLE]–like syndrome; thrombocytopenia with or without purpura; toxic epidermal necrolysis;
trembling; troubled breathing; unusual weakness; vasculitis;
vomiting
Incidence unknown
Anxiety; bladder pain; bleeding from vagina; cardiac arrhythmias; colitis or exacerbation of; conjunctivitis; convulsions;
corneal opacity; cystitis, urethritis, or urinary tract infection;
decreased appetite or loss of appetite; desquamation; disseminated intravascular coagulation; dry, irritated, or swollen eyes;
dysphagia; dysuria; ecchymosis/bruising; enterocolitis; eosinophilia; eosinophilic pneumonitis; erythema or other skin discoloration; fast heartbeat; gastroenteritis; gastrointestinal
perforation; gingival ulceration; glossitis; hemoptysis; hyperkalemia; hypocoagulability; incontinence; increased sweating;
irritation, dryness, or soreness of mouth; laryngeal edema;
lightheadedness/vertigo; loosening or splitting of fingernails;
lymphadenopathy; meningitis, aseptic; muscle weakness;
nephrosis; nosebleeds, unexplained; photophobia; photosensitivity reactions resembling porphyria cutanea tarda and epidermyolysis bullosa; polyuria; pounding heartbeat; rhinitis,
allergic; strong-smelling urine; swelling of the lips and tongue;
syncope; taste change; thirst, continuing; weight loss, unexplained
Note: The risk of anaphylaxis may be increased when previously
discontinued therapy with a nonsteroidal anti-inflammatory medication is reinstituted.
Patients 40 years of age and older may be more susceptible to the toxic
effects of phenylbutazone. In patients 60 years of age and older, there
is an increased risk of severe, possibly fatal, toxic reactions.
All rights reserved
96 PHENYLBUTAZONE Veterinary—Systemic
Laboratory findings in overdose may reveal respiratory or metabolic
acidosis or alkalosis, other electrolyte disturbances, impaired hepatic or
renal function, and abnormalities of formed blood elements.
Canada—
Veterinary-labeled product(s):
333 mg per mL (Rx) [Butequine].
Additional information: Higher blood levels of phenylbutazone have
been reported with the paste formulation.
OVERDOSE
For information in cases of overdose or unintentional ingestion, contact
the American Society for the Prevention of Cruelty to Animals
(ASPCA) National Animal Poison Control Center (888-426-4435
or 900-443-0000; a fee may be required for consultation) and/or the
drug manufacturer.
Signs of overdose
Anorexia; depression; diarrhea or soft feces; edema, ventral
abdominal; ulceration, oral
CLIENT CONSULTATION
In providing consultation, consider emphasizing the following selected
information:
Returning patients for periodic rechecks while they are on medication
Keeping water readily available during the treatment period to avoid
dehydration
Never exceeding the recommended daily amount without veterinary
consultation
Familiarizing clients with signs that an adverse reaction may be
occurring and instructing them to contact their veterinarian and
discontinue treatment if a reaction is suspected
Not administering nonsteroidal anti-inflammatory drugs labeled for
human use to animals without guidance from a veterinarian; human
dosages may be toxic or fatal for animals
Withdrawal times: There are no established withdrawal times for foodproducing animals in the United States or Canada because phenylbutazone is not approved for use in those species. Phenylbutazone
residues are not permitted at any concentration (zero tolerance) in
meat, milk, or eggs for human consumption.
U.S—The extra-label use of phenylbutazone in female dairy cattle 20
months of age or older is prohibited by the United States Food and
Drug Administration.{R-34} Although other extra-label uses in foodproducing animals, as stated in Animal Medicinal Drug Use
Clarification Act (AMDUCA) guidelines, are legal at this writing,
the practitioner should check current statutes to be sure restrictions
on the use of phenylbutazone in food-producing animals have not
been broadened.
Because phenylbutazone is prohibited from use in adult dairy cattle
and use in other food animals is highly discouraged, the Food
Animal Residue Avoidance Databank (FARAD) in the United States
does not make recommendations for phenylbutazone residue
withdrawals with extra-label use in food-producing species.{R-27}
Canada—If phenylbutazone is administered orally to cattle at the dose of
10 mg per kg of body weight as a single loading dose followed by 5 mg
per kg of body weight every forty-eight hours or, if necessary,
administered at the dose of 3 mg per kg of body weight every twentyfour hours, evidence has been compiled by the Canadian gFARAD that
suggests a meat withdrawal time of 60 days and a milk withholding
time of 10 days would be sufficient to avoid residues.{R-42}
ORAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), unless otherwise specified by
the manufacturer.
USP requirements: Not in USP.{R-4}
PHENYLBUTAZONE ORAL PASTE
Usual dose:
Inflammation; or
Pain—
Horses: Oral, 4.4 mg per kg of body weight every twelve hours initially,
followed by 2.2 mg per kg of body weight every twelve hours.{R-20}
For maintenance, use the lowest dose required to produce the desired
clinical response.
[Cattle]1: Oral, 10 mg per kg of body weight as a loading dose, followed
by 5 mg per kg of body weight every forty-eight hours. In severely
painful conditions, a maintenance dose of 3 mg per kg of body weight
every twenty-four hours may be necessary to prevent breakthrough
pain.{R-15} For maintenance, use the lowest dose required to produce
the desired clinical response. (See also the Withdrawal times section
below.)
PHENYLBUTAZONE ORAL POWDER
Usual dose: See Phenylbutazone Oral Paste.
Strength(s) usually available:{R-2}
U.S.—
Veterinary-labeled product(s):
Not commercially available.
Canada—
Veterinary-labeled product(s):
67 mg per gram of powder (Rx) [generic].
100 mg per gram of powder (Rx) [Butasone 400].
267 mg per gram of powder (Rx) [Butasone Conc; Buzone Concentrate
Powder].
Withdrawal times: See Phenylbutazone Oral Paste.
{R-2}
Strength(s) usually available:
U.S.—
Veterinary-labeled product(s):
200 mg per cc (200 mg per gram; 20% paste) (Rx) [Butapaste;
Equiphen Paste, Phenylbute Paste; Phenylzone Paste].
Ó 2004 The United States Pharmacopeial Convention, Inc.
Packaging and storage: Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the
manufacturer.
USP requirements: Not in USP.{R-4}
All rights reserved
PHENYLBUTAZONE Veterinary—Systemic 97
PHENYLBUTAZONE TABLETS USP
PHENYLBUTAZONE INJECTION USP
Usual dose:
Inflammation; or
Pain—
Dogs1: Oral, 15 mg per kg of body weight every eight hours, up to a
maximum total daily dose of 800 mg, regardless of weight. For
maintenance, the lowest dose required to produce the desired
clinical response is used.
Horses: Oral, 4.4 mg per kg of body weight every twelve hours
initially followed by 2.2 mg per kg of body weight every twelve
hours.{R-20} For maintenance, the lowest dose required to produce
the desired clinical response is used.
[Cattle]1: Oral, 10 mg per kg of body weight as a loading dose,
followed by 5 mg per kg of body weight every forty-eight hours. In
severely painful conditions, a maintenance dose of 3 mg per kg of
body weight every twenty-four hours may be necessary to prevent
breakthrough pain.{R-15} For maintenance, use the lowest dose
required to produce the desired clinical response. (See also the
Withdrawal times section below.)
Usual dose:
Inflammation; or
Pain—
Horses: Intravenous, 2.2 to 4.4 mg per kg of body weight every twelve
hours. The dose is reduced after the first forty-eight to ninety-six
hours. Administration should be limited to a maximum of five
successive days. Oral administration may follow.
[Dogs]: Intravenous, 8 mg per kg of body weight every eight hours,
not to exceed 800 mg daily regardless of weight. Intravenous
injections should be limited to two successive days. Oral administration may follow.
[Cattle]1: Intravenous, 10 mg per kg of body weight loading dose.
Maintenance dose of 5 mg per kg of body weight every forty-eight
hours if oral administration is not feasible. (See also the
Withdrawal times section below.)
Note: Although phenylbutazone injection has been administered
intramuscularly in cattle, no residue studies exist to establish
appropriate slaughter withdrawals following such administration. Therefore, this route of administration is not recommended.{R-15; 36}
Strength(s) usually available:{R-1; 2}
U.S.—
Veterinary-labeled product(s):
100 mg (Rx) [Butatabs-D; Butatron Tablets; Phenylbute Tablets 100
Mg; generic].
200 mg (Rx) [Phenylbute Tablets 200 Mg; generic].
1 gram (Rx) [Butatabs-E; Butatron Tablets; Equiphar Phenylbutazone 1
Gram Tablets; Phenylbute Tablets 1 Gram; Pributazone Tablets; ProBute Tablets; generic].
Human-labeled product(s):
100 mg (Rx) [generic].
Canada—
Veterinary labeled product(s):
1 gram (Rx) [Butasone 1000; generic].
Human-labeled product(s):
100 mg (Rx) [Apo-Phenylbutazone; Butazolidin].
Withdrawal times: See Phenylbutazone Oral Paste.
Packaging and storage: Store below 40 °C (104 °F), preferably
between 15 and 30 °C (59 and 86 °F), unless otherwise specified by
the manufacturer.
USP requirements: Preserve in tight containers. Contain the labeled
amount, within ±7%. Meet the requirements for Identification, Dissolution (70% in 30 minutes in simulated intestinal fluid TS [without
the enzyme] in Apparatus 1 at 100 rpm), and Uniformity of dosage
units.{R-4}
1
Not included in Canadian product labeling or product not available in
Canada.
PARENTERAL DOSAGE FORMS
Note: Bracketed information in the Dosage Forms section refers to uses
that either are not included in U.S. product labeling or are for products
not commercially available in the U.S.
Ó 2004 The United States Pharmacopeial Convention, Inc.
Strength(s) usually available:{R-2}
U.S.—
Veterinary-labeled product(s):
200 mg per mL (Rx) [Butaject; Equiphar Phenylbutazone Injection
20%; Phenylbute Injection 20%; Pro-Bute Injection; generic]
Canada—
Veterinary-labeled product(s):
200 mg per mL (Rx) [generic].
Withdrawal times: There are no established withdrawal times for foodproducing animals in the United States or Canada because phenylbutazone is not approved for use in those species. Phenylbutazone
residues are not permitted at any concentration (zero tolerance) in
meat, milk, or eggs for human consumption.
U.S.—The extra-label use of phenylbutazone in female dairy cattle 20
months of age or older is prohibited by the United States Food and
Drug Administration.{R-34} Although other extra-label uses in foodproducing animals, as stated in Animal Medicinal Drug Use
Clarification Act (AMDUCA) guidelines, are legal at this writing,
the practitioner should check current statutes to be sure restrictions
on the use of phenylbutazone in food-producing animals have not
been broadened.
Because phenylbutazone is prohibited from use in adult dairy cattle
and use in other food animals is highly discouraged, the Food Animal
Residue Avoidance Databank (FARAD) does not make recommendations for phenylbutazone residue withdrawals with extra-label use
in food-producing species in the United States.{R-27}
Canada—If phenylbutazone is administered to cattle as a single
intravenous loading dose of 10 mg per kg of body weight, evidence
has been compiled by the Canadian gFARAD that suggests a meat
withdrawal time of 60 days and a milk withholding time of 10 days
would be sufficient to avoid residues.{R-42}
Packaging and storage: Store between 8 and 15 °C (46 and 59 °F).
Protect from light.
All rights reserved
98 PHENYLBUTAZONE Veterinary—Systemic
Revised: 04/30/93; 09/30/02
Interim revision: 07/21/94; 06/05/95; 07/01/96; 05/07/97;
07/21/98; 2/6/04
USP requirements: Preserve in single-dose or in multiple-dose containers, preferably of Type I glass. Protect from light, and store in a
refrigerator. A sterile solution of Phenylbutazone in Sterile Water for
Injection. Label Injection to indicate that it is for veterinary use only.
Contains the labeled amount, within ±10%. Meets the requirements
for Clarity of solution, Identification, Sterility, Bacterial endotoxins,
and pH (9.5–10), and for Injections.{R-4}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
Table 1. Pharmacology/Pharmacokinetics*
Note: Zero-order (dose-dependent) kinetics, especially for the elimination half-life, have been reported in dogs and horses. Such an occurrence cannot be discounted as
possible in other species. For such drugs, larger doses typically lead to longer elimination half-lives.
Protein
Binding (%)
Species
{R-22}
Baboons
Cattle
Bulls{R-9}
Half-life of
Elimination (hr)
Volume of
Distribution (L/kg)
Clearance
(mL/min/kg)
Route; Dose
(mg/kg)
IV; 10
Oral; 10
IV; 6
IM; 4.4
IV; 4.4
Oral; 4.4
IV; 5
Oral; 5
Oral; 5
IV; 6
Oral; 6
Vss 0.134
0.025
Vss 0.14
0.053
35.9
Vc 0.06 Varea 0.08
0.046
{R-23}
55
Vc 0.052 Varea 0.092
0.021
{R-10}
93
38.6
42.4
60.3
99.5
6
2.5
14.5
10.4
Steers{R-35}
Cows{R-8}
98
Dogs{R-22}
{R-24}
Goats{R-25}
{R-30}
{R-31}
15.3
22.0
3.5
Horses{R-26}
{R-41}
Humans{R-22}
Llamas{R-28}
Pigs{R-21}
Rabbits{R-14}
Rats{R-22}
Sheep{R-29}
Cmax
(mcg/mL)
F (%)
8.9
47.13
73
7.5
42.3
99
10.5
23.9
54
8
32
68
12.8
38.2
69
1
31.5
3.47
27.2
5
21
4.3
4.39
5
61.6
62.6
34
{R-7}
Tmax (hr)
98
Varea 0.097
Vc 0.28
Vc 0.18
Varea 0.28
Vss 0.27
Vss 0.088
0.027
0.217
0.074
5.5
72
2.52**
Vss 0.141
0.3
Vss 0.155 Varea 0.190
1.11
3.5
1.9
6
17.92
0.18à
0.183§
0.65
Vss 0.099 Varea 0.117
0.076
Oral; 14.6
IV; 33
IV; 10
IV; 4.4
Oral; 4.4
IV; 4.4
Oral; 8.8
IV; 4.4
IV; 5
Oral; 5
IV; 20
IA; 8
61
70
IV; 4.4
*
Abbreviations: IA = Intra-arterial, IM = Intramuscular, IV = Intravenous, Tmax = Time to peak serum concentration, Cmax = Peak serum concentration, F = Bioavailability;
percent absorbed
Estimated from graph
à
One-compartment model
§
Method of Vd calculation not specified
**
For oral administration, a flip-flop model may exist with an absorption half-life of 7.09 hours.
REFERENCES
1. Klasco RK, editor. USP DI Drug Information for the health care professional.
Volume I. Greenwood Village, CO: Thomson MICROMEDEX, Inc.; 2003.
2. Arrioja-Dechert A, editor. Compendium of Veterinary Products, CD edition.
Port Huron, MI: North American Compendiums, Inc.; 2003.
3. Butazolidin (Geigy—US), Rev 7/90. In: PDR Physicians’ desk reference. 48th
ed. 1992. Montvale, NJ: Medical Economics Data Production Company; 1992.
p. 1027.
4. The United States pharmacopeia. The national formulary. USP 26th revision
(January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United
States Pharmacopeial Convention, Inc.; 2002. p. 1457, 1458, 2574.
Ó 2004 The United States Pharmacopeial Convention, Inc.
5. O’Neil MJ, editor. The Merck index: an encyclopedia of chemicals, drugs, and
biologicals. 13th ed. Whitehouse Station, NJ: Merck 2001. p. 1306.
6. Katzyng BG, editor. Basic and Clinical Pharmacology. 6th ed. Norwalk,
Connecticut: Appleton and Lange; 1995.
7. Ebhardson B, Olsson G, Appelgren LE, et al. Pharmacokinetic studies of
phenylbutazone in cattle. J Vet Pharmacol Ther 1979 Mar; 2(1): 31–7.
8. Lees P, Ayliffe T, Maitho TE, et al. Pharmacokinetics, metabolism and
excretion of phenylbutazone in cattle following intravenous, intramuscular
and oral administration. Res Vet Sci 1988; 44: 57–67.
All rights reserved
PHENYLBUTAZONE Veterinary—Systemic 99
9. Williams RJ, Smith JA, Boudinot F, et al. Pharmacokinetics of phenylbutazone
in mature Holstein bulls: Steady-state kinetics after multiple oral dosing. Am J
Vet Res 1990 Mar; 51(3): 367–70.
10. Martin K, Anderson L, Stridsberg M, et al. Plasma concentration, mammary
excretion and side-effects of phenylbutazone after repeated oral administration
in healthy cows. J Vet Pharmacol Ther 1984; 7: 131–38.
11. Panel comment, Rec 2/27/95.
12. Reynolds JF, editor. Martindale. The Extra Pharmacopeia. 28th ed. London:
The Pharmaceutical Press.
13. Boothe DM. Small Animal Clinical Pharmacology and Therapeutics. Philadelphia, PA: WB Saunders Company; 2001. p. 293.
14. Toutain PL. Residue profile of phenylbutazone in the rabbit. A comparative
evaluation by tissue kinetics prior to and post mortem. J Vet Pharmacol Ther
1980; 3(4): 255–9.
15. Panel comment, Rec 9/18/01.
16. Gerken DF. Inhibitory effects of intravenous chloramphenicol sodium succinate on the disposition of phenylbutazone in horses. J Pharmacokinetics
Biopharm 1985; 13(5): 467-76.
17. Ramirez S. Duration of effects of phenylbutazone on serum total thyroxine and
free thyroxine concentrations in horses. J Vet Int Med 1997; 11(6): 371–4.
18. Ferguson DC. Influence of common drugs on the free thyroxine fraction in
canine serum. J Vet Int Med 1989; 3(2): 120.
19. Watson ADJ. Phenylbutazone-induced blood dyscrasias suspected in three
dogs. Vet Rec 1980 Sept 13; 107(11): 239-41.
20. Stover SM. Diseases of the bones, joints, and connective tissues. In: Smith BP,
editor. Large Animal Internal Medicine, 3rd ed. St. Louis: Mosby Publishing;
2002. p. 1085–148.
21. Hvidberg EF, Rasmussen F. Pharmacokinetics of phenylbutazone and
oxphenbutazone in the pig. Can J Comp Med 1975 Jan; 39(1): 80–8.
22. Dayton PG, Israili ZH, Perel JM. Influence of binding on drug metabolism and
distribution. Ann N Y Acad Sci 1973 Nov 26; 226: 172–94.
23. De Backer P, Braeckman R, Belpaire F, et al. Bioavailability and pharmacokinetics of phenylbutazone in the cow. J Vet Pharmacol Ther 1990; 3(1):
29–33.
24. Bruce RB, Maynard WR, Dunning LK. Oxyphenbutazone and phenylbutazone
determinations in plasma and urine by GLC. J Pharm Sci 1974; 63(3): 446–8.
25. Boulos BM, Jenkins WL, Davis LE. Pharmacokinetics of certain drugs in the
domesticated goat. Am J Vet Res 1972; 33(5): 943–52.
26. Piperno E, Ellis DJ, Getty SM, et al. Plasma and urine levels of phenylbutazone
in the horse. J Am Vet Med Assoc 1968; 153(2): 195–8.
27. The Food Animal Residue Avoidance Databank. Personal communication on
5/20/03.
Ó 2004 The United States Pharmacopeial Convention, Inc.
28. Navarre CB, Ravis WR, Nagilla R, et al. Pharmacokinetics of phenylbutazone
in llamas following single intravenous and oral doses. J Vet Pharmacol Ther
2001; 24(3): 227–231.
29. Cheng Z, McKeller Q, Nolan A. Pharmacokinetic studies of flunixin meglumine
and phenylbutazone in plasma, exudate and transudate in sheep. J Vet
Pharmacol Ther 1998; 21(4): 315–321.
30. Eltom SE, Guard CL, Schwark WS. The effect of age on phenylbutazone
pharmacokinetics, metabolism and plasma protein binding in goats. J Vet
Pharmacol Ther 1993; 16(2): 141–151.
31. Cheng Z, Welsh E, Nolan Q, et al. Pharmacokinetic and pharmacodynamic
studies on phenylbutazone and oxyphenbutazone in goats. Vet Rec 1997 Jan
11; 140(2): 40–3.
32. USP dictionary of USAN and international drug names, 2002 ed. Rockville,
MD: The United States Pharmacopeial Convention, Inc., 2002.
33. Payne MA. Anti-inflammatory therapy in dairy cattle: therapeutic and
regulatory considerations. California Veterinarian 2001; 55(2): 10–12.
34. Phenylbutazone Order of Prohibition. Federal Register. Washington, D.C.;
National Archives and Record Administration. February 28, 2003; 68(40):
9528–30.
35. De Veau IF, Pedersoli W, Cullison R, et al. Pharmacokinetics of phenylbutazone in beef steers. J Vet Pharmacol Ther 2002 Jun; 25(3): 195–200.
36. Pyorala S, Laurila T, Lehtonen S, et al. Local tissue damage in cows after
intramuscular administration of preparations containing phenylbutazone,
flunixin, ketoprofen and metamizole. Acta Vet Scand 1999; 40(2): 145–50.
37. De Veau EJ, Pedersoli W, Cullison R, et al. Pharmacokinetics of phenylbutazone in plasma and milk of lactating dairy cows. J Vet Pharmacol Ther 1998
Dec; 21(6): 437–43.
38. Whittem T, Firth EC, Hodge H, et al. Pharmacokinetic interactions between
repeated dose phenylbutazone and gentamicin in the horse. J Vet Pharmacol
Ther 1996 Dec; 19(6): 454–9.
39. Mills PC, Ng JC, Hrdlicka J, et al. Disposition and urinary excretion of
phenylbutazone in normal and febrile greyhounds. Res Vet Sci 1995 Nov;
59(3): 261–6.
40. Hinchcliff KW, McKeever KH, Muir WW 3rd, et al. Pharmacologic interaction
of furosemide and phenylbutazone in horses. Am J Vet Res 1995 Sep; 56(9):
1206–12.
41. Lees P, Taylor JB, Maitho TE, et al. Metabolism, excretion, pharmacokinetics
and tissue residues of phenylbutazone in the horse. Cornell Vet 1987 Apr;
77(2): 192–211.
42. The Canadian gFARAD. Personal communication on 5/13/03.
All rights reserved
100 TEPOXALIN Veterinary—Systemic
TEPOXALIN Veterinary—Systemic
A commonly used brand name for a veterinary-labeled product is Zubrin.
Note: For a listing of dosage forms and brand names by country
availability, see the Dosage Forms section(s).
diclofenac, indomethacin, or naproxen. The mechanism of action of
this benefit is uncertain, although tissue-selective prostaglandin
inhibition or a protective effect caused by 5-lipoxygenase inhibition
have been suggested.{R-6-8}
Not commercially available in Canada.
CATEGORY:
Analgesic; anti-inflammatory (nonsteroidal); antipyretic.
INDICATIONS
ACCEPTED
Inflammation, musculoskeletal (treatment)1; or
Pain, musculoskeletal (treatment)1—Dogs: Tepoxalin is indicated for the
control of pain and inflammation associated with osteoarthritis in
dogs.{R-1}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
REGULATORY CONSIDERATIONS
U.S.—
Tepoxalin is labeled only for use by or on the order of a licensed
veterinarian.{R-1}
CHEMISTRY
Chemical name: 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)N-methyl-1H-pyrazole-3-propanamide.{R-1; 5}
Molecular formula: C20H20ClN3O3.{R-1}
Molecular weight: 385.84.{R-1}
Description: White, crystalline material with a melting range of 125 to
130 °C.{R-1}
Solubility: Insoluble in water, soluble in alcohol and in most organic
solvents.{R-1}
PHARMACOLOGY/PHARMACOKINETICS
Note: The pharmacokinetic data for tepoxalin show large intrasubject
and intersubject variability.{R-1} An individual animal’s metabolism
and elimination of tepoxalin may vary significantly from the averages
reported in this section.
Mechanism of action/Effect:
Anti-inflammatory—Tepoxalin is believed to act through the inhibition
of cyclooxygenase activity and also the inhibition of lipoxygenase,
making it a dual inhibitor of arachidonic acid metabolism.{R-1} An ex
vivo whole blood eicosanoid production assay following oral administration to dogs demonstrated the inhibition of prostaglandin F2alpha
and leukotriene B4 by tepoxalin.{R-6}
Other effects—Studies in laboratory animals have demonstrated less
gastrointestinal ulcerogenic activity with tepoxalin administration
than with some nonsteroidal anti-inflammatories, including
Ó 2004 The United States Pharmacopeial Convention, Inc.
Absorption: Oral—Dogs: Tepoxalin is rapidly absorbed when administered orally.{R-1} Tablets available in the United States are composed of
micronized tepoxalin, which disintegrates quickly in the mouth.{R-1}
Because tepoxalin is insoluble in water, it is more effectively absorbed
when administered with food, especially meals high in fat, or within
one to two hours of feeding.{R-1}
Protein binding: Dogs—For tepoxalin and its acid metabolite: 98 to
99%.{R-9}
Biotransformation: Tepoxalin is quickly converted to an active acid
metabolite and other metabolites.{R-1}
Half-life: Elimination—
Cats: With a single oral dose of 10 mg per kg of body weight—
Tepoxalin: 4.7 ± 0.8 hours.{R-9}
Tepoxalin acid metabolite (active): 3.5 ± 0.4 hours.{R-9}
Dogs: With an oral dose of 20 mg per kg of body weight (mg/kg) on the
first day, followed by 10 mg/kg a day for 6 days—
Tepoxalin:
First day of treatment (reported as day 0): 2.0 ± 1.2 hours. {R-1}
Second day (reported as day 1): 2.3 ± 1.4 hours. {R-1}
Seventh day (reported as day 6): 1.6 ± 0.6 hours. {R-1}
Tepoxalin acid metabolite (active):
First day of treatment (reported as day 0): 13.7 ± 10.7 hours. {R-1}
Second day (reported as day 1): 12.4 ± 8.4 hours. {R-1}
Seventh day (reported as day 6): 13.4 ± 10.3 hours. {R-1}
Peak serum concentration:
Cats—With a single oral dose of 10 mg/kg:
Tepoxalin—2.3 ± 1.8 mcg/mL at 8.8 ± 4.3 hours.{R-9}
Tepoxalin acid metabolite (active)—1.8 ± 1.2 mcg/mL at 7.8 ± 4.9
hours.{R-9}
Dogs—With a single oral dose of 20 mg/kg on the first day, followed by
10 mg/kg a day for 6 days:
Tepoxalin—
First day of treatment (reported as day 0): 0.8 ± 0.5 mcg/mL at 2.3 ±
1.4 hours.{R-1}
Second day (reported as day 1): 0.5 ± 0.2 mcg/mL at 2.3 ± 1.9
hours.{R-1}
Seventh day (reported as day 6): 0.6 ± 0.3 mcg/mL at 2.8 ± 4.2
hours.{R-1}
Tepoxalin acid metabolite (active)—
First day of treatment (reported as day 0): 0.8 ± 0.4 mcg/mL at 4.7 ±
6.2 hours.{R-1}
Second day (reported as day 1): 1.0 ± 0.3 mcg/mL at 2.7 ± 1.9
hours.{R-1}
Seventh day (reported as day 6): 1.0 ± 0.5 mcg/mL at 6.8 ± 8.0
hours.{R-1}
All rights reserved
TEPOXALIN Veterinary—Systemic 101
Elimination: Tepoxalin is rapidly metabolized; the metabolites are
eliminated almost entirely in the feces.{R-1} The portion of the dose that
is recovered in the urine (1%) is made up of metabolites that have not
been identified.{R-1}
PATIENT MONITORING
PEDIATRICS
The following may be especially important in patient monitoring (other
tests may be warranted in some patients, depending on condition; » =
major clinical significance):
Blood chemistry, including serum bilirubin and
Complete blood count (CBC)
(periodic monitoring for anemia, icterus, or other evidence of adverse
effects is recommended during treatment; in geriatric animals,
pretreatment blood work may be advisable to rule out subclinical
disease or establish baseline values){R-1}
Physical exam
(periodic physical exams and history updates are recommended during
therapy to monitor efficacy and tolerance) {R-1; 2}
Dogs: The safety of administering tepoxalin to dogs younger than 6
months of age has not been studied.{R-1}
SIDE/ADVERSE EFFECTS
PRECAUTIONS TO CONSIDER
REPRODUCTION/PREGNANCY/LACTATION
Dogs: The safety of administering tepoxalin to dogs during breeding,
pregnancy, or lactation has not been studied.{R-1}
DRUG INTERACTIONS AND/OR RELATED PROBLEMS
The following drug interactions and/or related problems have been
selected on the basis of their potential clinical significance (possible
mechanism in parentheses where appropriate)—not necessarily
inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications,
depending on the amount present, may also interact with this
medication.
Anti-inflammatory drugs, nonsteroidal (NSAID) or
Corticosteroids
(concommitant administration of more than one NSAID or of
corticosteroids concurrently with a NSAID, such as tepoxalin, may
greatly increase the risk of adverse effects){R-1}
MEDICAL CONSIDERATIONS/CONTRAINDICATIONS
The medical considerations/contraindications included have been
selected on the basis of their potential clinical significance (reasons
given in parentheses where appropriate)—not necessarily inclusive (»
= major clinical significance).
Except under special circumstances, this medication should not be
used when the following medical problems exist:
Cardiovascular disease{R-1} or
Hepatic dysfunction{R-1} or
Renal dysfunction{R-1}
(because NSAIDs have been associated with renal toxicity in certain
circumstances, risk to patients with cardiovascular, hepatic, or renal
compromise may be increased; also, tepoxalin is metabolized by the
liver)
Dehydration{R-1}
(dehydration can increase the risk of renal toxicity)
Gastrointestinal ulceration
(many NSAIDs are known to increase the risk of gastrointestinal
disease, particularly ulceration;{R-1} therefore, the presence of
pretreatment lesions may put an animal at risk of exacerbation or
perforation)
Hypersensitivity to tepoxalin{R-1}
(previous development of adverse effects from tepoxalin may be an
indication of increased risk of future sensitivity)
Ó 2004 The United States Pharmacopeial Convention, Inc.
The following side/adverse effects have been selected on the basis of their
potential clinical significance (possible signs in parentheses where
appropriate)—not necessarily inclusive:
Note: As with other nonsteroidal anti-inflammatory drugs (NSAIDs),
adverse effects, sometimes severe, may occur in individual animals
with administration of tepoxalin.{R-2} Gastrointestinal side effects are
the most common;{R-2} however, safety studies have shown evidence
that tepoxalin can be tolerated by dogs, even with doses higher than
the recommended dose (see also the Overdose section below in this
monograph).
Because NSAIDS as a group are associated with adverse effects on
hemostasis, renal function, and hepatic function, studies have been
performed by the manufacturer to evaluate the effects of tepoxalin on
these systems. When tepoxalin was administered in a randomized,
blinded crossover study of ten healthy beagles at the recommended
dose of 10 mg per kg of body weight (mg/kg) for seven days, no
changes were seen in glomerular filtration rate as measured by renal
scintigraphy.{R-5}
Although tepoxalin is not labeled for preoperative administration, the
following study results are provided as additional information about
potential adverse effects. In a placebo-controlled study of twelve beagles,
each dog was administered a single oral dose of tepoxalin, 10 mg/kg, two
hours before undergoing surgery. The dogs were monitored for 48 hours
after recovery from surgery. No significant changes were recorded in tests of
hemostasis (hematology, platelet count, buccal mucosal bleeding time,
incisional bleeding), tests of renal function (serum blood urea nitrogen,
serum creatinine, creatinine clearance, urine gamma-glutamyltransferase/
creatinine ratio), or tests of hepatic function (serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase).{R-5}
THOSE INDICATING NEED FOR MEDICAL ATTENTION
Reported during treatment with tepoxalin for 1 week:
Incidence less frequent
Dogs
Diarrhea (4% of dogs treated);{R-1} vomiting (2%){R-1}
Incidence rare
Dogs
Incoordination (<1%){R-1}
Note: The effects listed above as reported during one week of therapy
were observed in dogs undergoing a field study of tepoxalin versus a
medication (carprofen) administered as an active control treatment.{R-1; 3}
All rights reserved
102 TEPOXALIN Veterinary—Systemic
Tepoxalin was administered at the labeled dose of 20 mg/kg on the first
day, followed by 10 mg/kg a day for six days.{R-1}
A nine-year-old dog died two days after completing the one-week
study. Necropsy revealed gastric ulcerations, anemia, and severe
diffuse gastroenteritis; however the death could not be definitely
attributed to tepoxalin administration. {R-1}
Reported during treatment with tepoxalin for 4 weeks:
Incidence more frequent
Dogs
Anorexia/inappetance (8% of dogs treated);{R-1} diarrhea
(22%);{R-1} vomiting (20%){R-1}
Incidence less frequent
Dogs
Enteritis (4%);{R-1} lethargy (3%){R-1}
Incidence rare
Dogs
Incontinence (<1%){R-1}
Note: The effects listed above as reported during 4 weeks of therapy were
observed in a group of 107 dogs undergoing a field safety study
without control animals. Dogs in this study were administered
tepoxalin at the labeled dose of 20 mg/kg on the first day followed
by 10 mg/kg a day for four weeks.{R-1}
A twelve-year-old dog was found to have elevated liver enzymes and
serum white cell count before entering the four-week study. Although
tepoxalin treatment was discontinued after 14 days due to signs of
drug intolerance (vomiting, diarrhea, inappetence, and gastrointestinal blood loss), dexamethasone was administered. The dog died the
next day.{R-1}
THOSE INDICATING NEED FOR MEDICAL ATTENTION
ONLY IF THEY CONTINUE OR ARE BOTHERSOME
Reported during treatment with tepoxalin for 4 weeks:
Incidence rare
Dogs
Appetite, increased (<1%);{R-1} eating grass (<1%);{R-1} flatulence
(<1%);{R-1} hairloss (<1%);{R-1} trembling (<1%){R-1}
OVERDOSE
For more information in cases of overdose or unintentional ingestion,
contact the American Society for the Prevention of Cruelty to
Animals (ASPCA) National Animal Poison Control Center (888426-4435 or 900-443-0000; a fee may be required for consultation)
and/or the drug manufacturer.
CLINICAL EFFECTS OF OVERDOSE
The following effects have been selected on the basis of their potential
clinical significance (possible signs in parentheses where appropriate)
—not necessarily inclusive:
Dogs
With a dose of 20 to 100 mg per kg of body weight (mg/kg) a day for
26 weeks, the following were reported during the treatment
period:{R-1}
Anemia; gastric irritation
Note: One of twenty-eight dogs treated in this dosage range (in the group
of six receiving a dose of 20 mg/kg) was reported to have anemia, as
demonstrated by decreased red blood cell count, serum hemoglobin,
and packed cell volume. The anemia resolved during the study.
Ó 2004 The United States Pharmacopeial Convention, Inc.
Gastric irritation (mucosal hemorrhage and congestion) was reported
in one of six dogs in the placebo-treated group, in one of six receiving
20 mg/kg a day, in three of six dogs receiving 100 mg/kg a day, and in
two of six receiving 300 mg/kg a day.
With a dose of 300 mg/kg a day for 26 weeks, the following were
reported during the treatment period:{R-1}
Gastric irritation or ulceration
Note: In this study, 3 out of 14 dogs that received the dose of 300 mg/
kg a day developed gastric ulceration.{R-1} Clinical pathology results
reported for these dogs included decreases in red blood cell counts,
serum hemoglobin, and packed cell volume; decreases in serum
albumin, total protein, and calcium; and neutrophilic leukocytosis.{R-1}
With a dose of 100 mg/kg a day for 52 weeks, the following were
reported:{R-1}
Gastric irritation or ulceration—ulceration was reported in 2 of 8
dogs treated
CLIENT CONSULTATION
A Client Information Sheet developed specifically for dog owners is
provided by the United States manufacturer for clients administering
oral tepoxalin to their dogs.{R-1}
In providing consultation, consider emphasizing the following selected
information:
Keeping water readily available during the treatment period to avoid
dehydration
Never exceeding the prescribed daily amount without veterinary
consultation; contacting a veterinarian if more than the daily dose is
consumed{R-2}
Familiarizing clients with signs that an adverse reaction may be
occurring, including decrease or increase in appetite, vomiting,
change in bowel movements, change in behavior, yellowing of gums,
skin, or whites of the eyes, change in drinking habits, change in
urination habits, or change in skin. {R-2} Instructing them to
discontinue medication and contact their veterinarian if a reaction is
suspected
Not administering nonsteroidal anti-inflammatory drugs labeled for
human use to animals without guidance from a veterinarian; human
dosages may be toxic or fatal for animals
VETERINARY DOSING INFORMATION
ORAL ADMINISTRATION
Because tepoxalin is insoluble in water, it is believed to be more
effectively absorbed when administered with food, especially meals
high in fat, or within one to two hours of feeding.{R-1; 2}
When tepoxalin tablets are administered into a dog’s mouth, it is
recommended that the mouth be kept closed for approximately 4
seconds to ensure the tablet is dispersed.{R-1}
The manufacturer states that dogs weighing less than 3 kg cannot be
accurately dosed with tepoxalin tablets.{R-1}
ORAL DOSAGE FORMS
TEPOXALIN TABLETS
Usual dose:
Inflammation, musculoskeletal1; or
All rights reserved
TEPOXALIN Veterinary—Systemic 103
Pain, musculoskeletal1—Dogs: Oral, 10 mg per kg of body weight every
twenty-four hours.{R-1} Alternatively, 20 mg per kg of body weight can
be administered as an initial dose, followed by 10 mg per kg of body
weight every twenty-four hours.{R-1}
Note: If a rapid analgesic effect is necessary, for example, for dogs in
severe osteoarthritic pain, it is recommended that the higher initial
dose, 20 mg per kg of body weight (mg/kg) the first day, be
administered to ensure that therapeutic concentrations are reached
quickly.{R-1}
Strength(s) usually available:
U.S.—{R-1}
Veterinary-labeled product(s):
30 mg (Rx) [Zubrin].
50 mg (Rx) [Zubrin].
100 mg (Rx) [Zubrin].
200 mg (Rx) [Zubrin].
Canada—
Veterinary-labeled product(s):
Not commercially available.
Caution: Keep out of the reach of children.{R-1}
Packaging and storage: Store between 2 and 30 °C (36 and 86 °F),{R-1}
unless otherwise specified by manufacturer.
Ó 2004 The United States Pharmacopeial Convention, Inc.
USP requirements: Not in USP.{R-4}
1
Not included in Canadian product labeling or product not commercially
available in Canada.
Developed: 2/6/04
REFERENCES
1. Zubrin package insert (Schering-Plough—US), Rev 2002, Rec 9/3/03.
2. Zubrin Client Information Sheet (Schering-Plough—US), Rev 2002. Available at
www.zubrinus.com. Accessed on September 1, 2003.
3. Zubrin (tepoxalin rapidly-disintegrating tablets) freedom of information summary (NADA # 141–193). Sponsor: Schering-Plough Animal Health. Approval
Date: 3/31/03.
4. The United States pharmacopeia. The national formulary. USP 26th revision
(January 1, 2003). NF 21st ed (January 1, 2003). Rockville, MD: The United
States Pharmacopeial Convention, Inc., 2002.
5. Communication from Schering-Plough Animal Health on November 6, 2003.
Unpublished data.
6. Argentieri DC, Ritchie DM, Ferro MP, et al. Tepoxalin: a dual cyclooxygenase/5lipoxygenase inhibitor of arachidonic acid metabolism with potent antiinflammatory activity and a favorable gastrointestinal profile. J Pharmacol Exp
Ther 1994 Dec; 271(3): 1399–408.
7. Wallace JL, McCafferty DM, Carter L, et al. Tissue-selective inhibition of
prostaglandin synthesis in rat by tepoxalin: anti-inflammatory without
gastropathy? Gastroenterology 1993 Dec; 105(6): 1630–6.
8. Wallace JL, Cirino G, Cicala C, et al. Comparison of the ulcerogenic properties of
tepoxalin with those of non-steroidal anti-inflammatory drugs (NSAIDs). Agents
Actions 1991 Sep; 34(1–2): 247–50.
9. Committee comment, Rec 11/17/03 and 12/5/03.
All rights reserved
104 Indications Index
Indications Index
Note: Both labeled and extra-labeled indications are included in this index
without differentiation. Please consult the individual monograph
Indications section for US and Canadian product labeling status for
each species and for more information on when use is appropriate.
This reference does not include every anti-inflammatory product
available; therefore, it should not be assumed that all medications
appropriate for a given indication are listed or that those not listed
are inappropriate. Because clinical variables play an important role
in choice of anti-inflammatory treatment, it cannot be assumed that
the agents listed for any indication are interchangeable in a
particular situation.
Indications may be found under more than one Indications
subheading (Accepted, Acceptance not established, Unaccepted) when
recommended for more than one species or medication within a
monograph.
Indications below can be found under the Accepted subheading of the
listed monograph’s Indications section for at least one species unless
"Not estab" is stated. "Not estab" signifies a drug monograph in
which the indication is listed under the Acceptance not established
subheading. Unaccepted uses have not been indexed. Listing as
Accepted, Acceptance not established, or Unaccepted in a monograph is
not meant to signify label versus extra-label status.
Abortion, induction of
Corticosteroids, 27
Adrenocortical insufficiency, acute (treatment)
Corticosteroids, 24
Allergic disorders (treatment)
Corticosteroids, 25
Anemia, immune-mediated hemolytic (treatment)
Corticosteroids, 27
Asthma, bronchial (treatment)
Corticosteroids, 25
Cardiomyopathy (treatment adjunct)
Aspirin, Not estab, 4
Chronic obstructive pulmonary disease (treatment)
Corticosteroids, Not estab, 28
Colitis, ulcerative (treatment)
Corticosteroids, 25
Dermatitis, allergic (treatment)
Corticosteroids, 25
Dermatoses, nonallergic (treatment)
Corticosteroids, 25
Disk disease, intervertebral (treatment)
Corticosteroids, 25
Emphysema, acute bovine pulmonary (treatment)
Flunixin, Not estab, 70
Endotoxemia (treatment adjunct)
Ketoprofen, Not estab, 75
See also Inflammation, endotoxemia-associated, below in this index.
Escherichia coli diarrhea (treatment)
Aspirin, Not estab, 4
Fever (treatment)
Aspirin, 4
Flunixin, 70
Ó 2004 The United States Pharmacopeial Convention, Inc.
Ketoprofen, 75
Phenylbutazone, 92
Glomerular disease (treatment)
Corticosteroids, Not estab, 28
Heartworm disease (treatment adjunct)
Aspirin, Not estab, 4
Hyperadrenocorticism (diagnosis)
Corticosteroids, 27
Inflammation (treatment)
Aspirin, 4
Corticosteroids, 25
Ketoprofen, 75
Phenylbutazone, 92
Inflammation, endotoxemia-associated (treatment)
Flunixin, 70
See also Endotoxemia (treatment adjunct), above in this index.
Inflammation, musculoskeletal (treatment)
Carprofen, 15
Corticosteroids, 26
Deracoxib, 61
Etodolac, 64
Flunixin, 70
Ketoprofen, 75
Meloxicam, 87
Phenylbutazone, 92
Tepoxalin, 100
Inflammation, neurologic (treatment)
Corticosteroids, Not estab, 28
Inflammation, ocular (treatment)
Corticosteroids, 26
Inflammation, postoperative (treatment)
Deracoxib, 61
Meloxicam, 87
Inflammatory bowel disease (treatment)
Corticosteroids, Not estab, 29
Ketosis (treatment)
Corticosteroids, 26
Laminitis (treatment)
Aspirin, Not estab, 4
Lupus erythematosus, systemic (treatment)
Corticosteroids, 27
Lymphoma (treatment adjunct)
Corticosteroids, 27
Mast cell tumors (treatment)
Corticosteroids, 27
Mastitis (treatment)
Corticosteroids, Not estab, 28
Mastitis, acute (treatment adjunct)
Ketoprofen, 75
Mastitis, acute coliform (treatment adjunct)
Flunixin, Not estab, 70
Otitis (treatment)
Corticosteroids, 25
Pain (treatment)
Aspirin, 4
All rights reserved
Indications Index 105
Ketoprofen, 75
Phenylbutazone, 92
Pain, colic-associated (treatment)
Flunixin, 70
Pain, musculoskeletal (treatment)
Carprofen, 15
Deracoxib, 61
Etodolac, 64
Flunixin, 70
Ketoprofen, 75
Meloxicam, 87
Tepoxalin, 100
Pain, postoperative (treatment)
Carprofen, 15
Deracoxib, 61
Ketoprofen, 75
Meloxicam, 87
Pain, visceral (treatment)
Ketoprofen, 75
Parturition, induction of
Corticosteroids, 28
Pemphigoid (treatment)
Corticosteroids, 28
Ó 2004 The United States Pharmacopeial Convention, Inc.
Pemphigus (treatment)
Corticosteroids, 28
Pruritus (treatment)
Corticosteroids, 25
Respiratory distress syndrome (treatment)
Corticosteroids, Not estab, 29
Sepsis (treatment adjunct)
Flunixin, 70
Shock, cardiogenic (treatment adjunct)
Corticosteroids, Not estab, 29
Shock, hemorrhagic (treatment adjunct)
Corticosteroids, Not estab, 29
Shock, septic (treatment adjunct)
Corticosteroids, 27
Spinal cord trauma, acute (treatment)
Corticosteroids, 28
Thrombocytopenia, immune-mediated (treatment)
Corticosteroids, 28
Thromboembolism (prophylaxis)
Aspirin, Not estab, 4
All rights reserved
106 Dosing Index
Dosing Index
Note: Both labeled and extra-labeled dosage recommendations are included in
this index without differentiation. Please consult the individual monograph for US and Canadian product labeling status for each species and
for more information on when use is appropriate.
Aspirin (Veterinary—Systemic), 4
Cats, dogs, horses
Aspirin Tablets, 12
Cattle, pigs
Aspirin Boluses, 11
Carprofen (Veterinary—Systemic), 15
Dogs, horses
Carprofen Injection, 21
Carprofen Tablets, 21
Deracoxib (Veterinary—Systemic), 61
Dogs
Deracoxib Tablets, 63
Dexamethasone—Included in Corticosteroids (Veterinary—
Systemic), 24
Cats
Dexamethasone Injection, 45
Dexamethasone Sodium Phosphate Injection, 47
Dexamethasone Tablets, 45
Cattle
Dexamethasone Injection, 45
Dexamethasone Oral Powder, 44
Dexamethasone 21 Phosphate Injection, 47
Dexamethasone Sodium Phosphate Injection, 47
Dogs
Dexamethasone Injection, 45
Dexamethasone Sodium Phosphate Injection, 47
Dexamethasone Tablets, 45
Horses
Dexamethasone Injection, 45
Dexamethasone Oral Powder, 44
Dexamethasone 21 Phosphate Injection, 47
Dexamethasone Sodium Phosphate Injection, 47
Pigs
Dexamethasone Sodium Phosphate Injection, 47
Sheep
Dexamethasone Injection, 45
Etodolac (Veterinary—Systemic), 64
Dogs
Etodolac Tablets, 68
Flumethasone—Included in Corticosteroids (Veterinary—Systemic), 24
Cats, cattle, dogs, horses
Flumethasone Injection, 48
Flunixin (Veterinary—Systemic), 70
Horses
Flunixin Granules, 72
Flunixin Injection, 72
Flunixin Paste, 72
Cattle, dogs
Flunixin injection, 72
Ó 2004 The United States Pharmacopeial Convention, Inc.
Hydrocortisone—Included in Corticosteroids (Veterinary—
Systemic), 24
Cats, dogs
Hydrocortisone Tablets, 49
Isoflupredone—Included
in
Corticosteroids
(Veterinary—
Systemic), 24
Cattle, horses, pigs
Isoflupredone Acetate Injectable Suspension, 49
Ketoprofen (Veterinary—Systemic), 75
Cats, dogs
Ketoprofen Injection, 82
Ketoprofen Tablets, 81
Calves, cattle, goats, horses, sheep
Ketoprofen Injection, 82
Meloxicam (Veterinary—Systemic), 87
Cats, dogs
Meloxicam Injection, 90
Meloxicam Oral Suspension, 90
Methylprednisolone—Included in Corticosteroids (Veterinary—Systemic), 24
Cats, dogs
Methylprednisolone Acetate Injectable Suspension, 51
Methylprednisolone Sodium Succinate For Injection, 51
Methylprednisolone Tablets, 50
Horses
Methylprednisolone Acetate Injectable Suspension, 51
Phenylbutazone (Veterinary—Systemic), 92
Cattle, horses
Phenylbutazone Injection, 97
Phenylbutazone Oral Paste, 96
Phenylbutazone Tablets, 97
Dogs
Phenylbutazone Injection, 97
Phenylbutazone Tablets, 97
Prednisolone—Included in Corticosteroids (Veterinary—Systemic),
24
Cats
Prednisolone Sodium Succinate For Injection, 53
Prednisolone Tablets, 52
Cattle
Prednisolone Acetate Injectable Suspension, 53
Dogs
Prednisolone Acetate Injectable Suspension, 53
Prednisolone Sodium Succinate For Injection, 53
Prednisolone Tablets, 52
Horses
Prednisolone Acetate Injectable Suspension, 53
Prednisolone Sodium Succinate For Injection, 53
Prednisolone Tablets, 52
Prednisone—Included in Corticosteroids (Veterinary—Systemic),
24
Cats, dogs, horses
Prednisone Tablets, 54
All rights reserved
Dosing Index 107
Tepoxalin (Veterinary—Systemic), 100
Dogs
Tepoxalin Tablets, 102
Triamcinolone—Included in Corticosteroids (Veterinary—Systemic), 24
Cats
Triamcinolone Acetonide Injectable Suspension, 55
Triamcinolone Tablets, 55
Cattle
Triamcinolone Acetonide Injectable Suspension, 55
Dogs
Triamcinolone Acetonide Injectable Suspension, 55
Triamcinolone Tablets, 55
Ó 2004 The United States Pharmacopeial Convention, Inc.
Horses
Triamcinolone Acetonide Injectable Suspension, 55
Withdrawal times, extra-label
Aspirin Boluses, 11
Dexamethasone Injection, 45
Dexamethasone Oral Powder, 44
Dexamethasone 21 Phosphate Injection, 47
Dexamethasone Sodium Phosphate Injection, 47
Flunixin Injection, 72
Ketoprofen Injection, 82
Phenylbutazone Injection, 97
Phenylbutazone Oral Paste, 96
All rights reserved
108 Veterinary Brand and Generic Name Index
Veterinary Brand and Generic Name Index
Note: Includes both United States and Canadian products.
Anafen—
Ketoprofen Injection, 82
Ketoprofen Tablets, 81
AniPrin F—Aspirin Oral Powder, 12
AniPrin P—Aspirin Oral Powder, 12
Arthricare—Aspirin Tablets, 12
Asen—Aspirin Oral Granules, 11
Asen 240 Bolus—Aspirin Boluses, 11
Aspirin (AniPrin F; AniPrin P; Arthricare; Asen; Asen 240 Bolus; Asp-Rin;
Centra ASA 240; Durasol; Equi-Phar ArthriBan; Equi-Prin; Equi-Spirin;
Health Measures; Palaprin 65; Palaprin 325; Vetrin)
See Aspirin (Veterinary—Systemic), 4
Boluses, 11
Delayed-Release Tablets, 13
Oral Granules, 11
Oral Paste, 11
Oral Powder, 12
Oral Solution, 12
Tablets, 12
Asp-Rin—Aspirin Oral Solution, 12
Azium Powder—Dexamethasone Oral Powder, 44
Azium Solution—Dexamethasone Injection, 45
Banamine—
Flunixin Injection, 72
Flunixin Oral Granules, 72
Flunixin Oral Paste, 72
Butaject—Phenylbutazone Injection, 97
Butapaste—Phenylbutazone Oral Paste, 96
Butequine—Phenylbutazone Oral Paste, 96
Butasone 400—Phenylbutazone Oral Powder, 96
Butasone 1000—Phenylbutazone Tablets, 97
Butasone Conc—Phenylbutazone Oral Powder, 96
Butatabs-D—Phenylbutazone Tablets, 97
Butatabs-E—Phenylbutazone Tablets, 97
Butatron Tablets—Phenylbutazone Tablets, 97
Buzone Concentrate Powder—Phenylbutazone Oral Powder, 96
Carprofen (Rimadyl; Rimadyl Caplets; Rimadyl Chewable Tablets)
See Carprofen (Veterinary—Systemic), 15
Injection, 21
Tablets, 21
Centra ASA 240—Aspirin Boluses, 11
Compamine—Flunixin Injection, 72
Cortalone—Triamcinolone Tablets, 55
Cronyxin—Flunixin Injection, 72
Depo-Medrol—Methylprednisolone Acetate Injectable Suspension, 51
Deracoxib (Deramaxx)
See Deracoxib (Veterinary—Systemic), 61
Tablets, 63
Deramaxx—Deracoxib Tablets, 63
Dexaject—Dexamethasone Injection, 45
Dexaject SP—Dexamethasone Sodium Phosphate Injection, 47
Ó 2004 The United States Pharmacopeial Convention, Inc.
Dexamethasone (Azium Powder; Azium Solution; Dexaject; Dexaject SP;
Dexamethasone 2; Dexamethasone 5; Dexasone; Dexazone 2 mg; Dexone;
Dextab; Hexadrol; Rafter Dex; Uni-Dex)
See Corticosteroids (Veterinary—Systemic), 24
Injection, 45
Oral Powder, 44
21 Phosphate Injection, 47
Sodium Phosphate Injection, 47
Tablets, 45
Dexamethasone 2—Dexamethasone Sodium Phosphate Injection, 47
Dexamethasone 5—Dexamethasone Sodium Phosphate Injection, 47
Dexasone—Dexamethasone Injection, 45
Dexazone 2 mg—Dexamethasone Injection, 45
Dexone—Dexamethasone Oral Powder, 44
Dextab—Dexamethasone Tablets, 45
Durasol—Aspirin Oral Solution, 12
Equileve—Flunixin Injection, 72
Equi-Phar ArthriBan—Aspirin Oral Granules, 11
Equi-Phar Equigesic—Flunixin Injection, 72
Equi-Phar Phenylbutazone 1 Gram Tablets—Phenylbutazone Tablets, 97
Equi-Phar Phenylbutazone Injection 20%—Phenylbutazone Injection, 97
Equiphen Paste—Phenylbutazone Oral Paste, 96
Equi-Prin—Aspirin Oral Paste, 11
Equi-Spirin—Aspirin Oral Granules, 11
Etodolac (Etogesic)
See Etodolac (Veterinary—Systemic), 64
Tablets, 68
Etogesic—Etodolac Tablets, 68
Flucort—Flumethasone Injection, 48
Flumeglumine—Flunixin Injection, 72
Flumethasone (Flucort)
See Corticosteroids (Veterinary—Systemic), 24
Injection, 48
Flunazine—Flunixin Injection, 72
Flu-nix—Flunixin Injection, 72
Flunixamine—Flunixin Injection, 72
Flunixin (Banamine; Compamine; Cronyxin; Equi-Phar Equigesic; Equileve;
Flumeglumine; Flunazine; Flu-nix; Flunixamine; Influx-50; Suppressor)
See Flunixin (Veterinary—Systemic), 70
Injection, 72
Oral Granules, 72
Oral Paste, 72
Health Measures—Aspirin Delayed-Release Tablets, 13
Influx-50—Flunixin Injection, 72
Isoflupredone (Predef 2X)
See Corticosteroids (Veterinary—Systemic), 24
Acetate Injectable Suspension, 49
Ketofen—Ketoprofen Injection, 82
Ketoprofen (Anafen; Ketofen)
See Ketoprofen (Veterinary—Systemic), 75
Injection, 82
Tablets, 81
Medrol—Methylprednisolone Tablets, 50
All rights reserved
Veterinary Brand and Generic Name Index 109
Meloxicam (Metacam)
See Meloxicam (Veterinary—Systemic), 87
Injection, 90
Oral Suspension, 90
Metacam—
Meloxicam Injection, 90
Meloxicam Oral Suspension, 90
Methylprednisolone (Depo-Medrol; Medrol; Methysone 40; Unimed;
Vetacortyl)
See Corticosteroids (Veterinary—Systemic), 24
Acetate Injectable Suspension, 51
Tablets, 50
Methysone 40—Methylprednisolone Acetate Injectable Suspension, 51
Palaprin 65—Aspirin Tablets, 12
Palaprin 325—Aspirin Tablets, 12
Phenylbutazone (Butaject; Butapaste; Butasone 400; Butasone 1000;
Butasone Conc; Butatabs-D; Butatabs-E; Butatron Tablets; Butequine;
Buzone Concentrate Powder; Equi-Phar Phenylbutazone 1 Gram Tablets;
Equi-Phar Phenylbutazone Injection 20%; Equiphen Paste; Phenylbute
Injection 20%; Phenylbute Paste; Phenylbute Tablets 100 Mg; Phenylbute
Tablets 200 Mg; Phenylbute Tablets 1 Gram; Phenylzone Paste;
Pributazone Tablets; Pro-Bute Injection; Pro-Bute Tablets)
See Phenylbutazone (Veterinary—Systemic), 92
Injection, 97
Oral Paste, 96
Oral Powder, 96
Tablets, 97
Phenylbute Injection 20%—Phenylbutazone Injection, 97
Phenylbute Paste—Phenylbutazone Oral Paste, 96
Phenylbute Tablets 100 Mg—Phenylbutazone Tablets, 97
Phenylbute Tablets 200 Mg—Phenylbutazone Tablets, 97
Phenylbute Tablets 1 Gram—Phenylbutazone Tablets, 97
Phenylzone Paste—Phenylbutazone Oral Paste, 96
Predef 2X—Isoflupredone Acetate Injectable Suspension, 49
Ó 2004 The United States Pharmacopeial Convention, Inc.
Prednisolone (PrednisTab; Solu-Delta-Cortef; Uni-Pred 50)
See Corticosteroids (Veterinary—Systemic), 24
Acetate Injectable Suspension, 53
Sodium Succinate For Injection, 53
Tablets, 52
Prednisone (Predsone-5)
See Corticosteroids (Veterinary—Systemic), 24
Tablets, 54
PrednisTab—Prednisolone Tablets, 52
Predsone-5—Prednisone Tablets, 54
Pributazone Tablets—Phenylbutazone Tablets, 97
Pro-Bute Injection—Phenylbutazone Injection, 97
Pro-Bute Tablets —Phenylbutazone Tablets, 97
Rafter Dex—Dexamethasone Injection, 45
Rimadyl—Carprofen Injection, 21
Rimadyl Caplets—Carprofen Tablets, 21
Rimadyl Chewable Tablets—Carprofen Tablets, 21
Solu-Delta-Cortef—Prednisolone Sodium Succinate For Injection, 53
Suppressor—Flunixin Injection, 72
Tepoxalin (Zubrin)
See Tepoxalin (Veterinary—Systemic), 100
Tablets, 102
Triamcinolone (Cortalone; Triamtabs; Vetalog)
See Corticosteroids (Veterinary—Systemic), 24
Acetonide Injectable Suspension, 55
Tablets, 55
Triamtabs—Triamcinolone Tablets, 55
Uni-Dex—Dexamethasone Sodium Phosphate Injection, 47
Unimed—Methylprednisolone Acetate Injectable Suspension, 51
Uni-Pred 50—Prednisolone Acetate Injectable Suspension, 53
Vetacortyl—Methylprednisolone Acetate Injectable Suspension, 51
Vetalog—Triamcinolone Acetonide Injectable Suspension, 55
Vetrin—Aspirin Tablets, 12
Zubrin—Tepoxalin Tablets, 102
All rights reserved
110 Human Brand and Generic Name Index
Human Brand and Generic Name Index
Note: Only human dosage forms considered by USP Veterinary Medicine
Advisory Committees to be appropriate have been included in this
publication.
Includes both United States and Canadian products.
A-methaPred—Methylprednisolone Sodium Succinate For Injection, 51
Apo-ASA—Aspirin Tablets, 12
Apo-Keto—Ketoprofen Capsules, 81
Apo-Keto-E—Ketoprofen Delayed-Release Tablets, 82
Apo-Phenylbutazone—Phenylbutazone Tablets, 97
Aspirin (Apo-ASA; Aspirin Caplets; Aspirin Children’s Tablets; Aspirin
Tablets; Aspir-Low; Aspirtab; Aspirtab-Max; Bayer Children’s Aspirin;
Empirin; Extra Strength Bayer Aspirin Caplets; Extra Strength Bayer
Aspirin Tablets; Genuine Bayer Aspirin Caplets; Genuine Bayer Aspirin
Tablets; Headache Tablet; Healthprin Adult Low Strength; Healthprin Full
Strength; Healthprin Half-Dose; Norwich Aspirin; PMS-ASA; St. Joseph
Adult Chewable Aspirin)
See Aspirin (Veterinary—Systemic), 4
Tablets, 12
Aspirin Caplets—Aspirin Tablets, 12
Aspirin Children’s Tablets—Aspirin Tablets, 12
Aspirin Tablets—Aspirin Tablets, 12
Aspir-Low—Aspirin Tablets, 12
Aspirtab—Aspirin Tablets, 12
Aspirtab-Max—Aspirin Tablets, 12
Bayer Children’s Aspirin—Aspirin Tablets, 12
Butazolidin—Phenylbutazone Tablets, 97
Cortef—Hydrocortisone Tablets, 49
Decadron—Dexamethasone Tablets, 45
Dexamethasone (Decadron; Dexasone; Hexadrol)
See Corticosteroids (Veterinary—Systemic), 24
Tablets, 45
Dexasone—Dexamethasone Tablets, 45
Empirin—Aspirin Tablets, 12
Extra Strength Bayer Aspirin Caplets—Aspirin Tablets, 12
Extra Strength Bayer Aspirin Tablets—Aspirin Tablets, 12
Genuine Bayer Aspirin Caplets—Aspirin Tablets, 12
Genuine Bayer Aspirin Tablets—Aspirin Tablets, 12
Headache Tablet—Aspirin Tablets, 12
Healthprin Adult Low Strength—Aspirin Tablets, 12
Ó 2004 The United States Pharmacopeial Convention, Inc.
Healthprin Full Strength—Aspirin Tablets, 12
Healthprin Half-Dose—Aspirin Tablets, 12
Hexadrol—Dexamethasone Tablets, 45
Hydrocortisone (Cortef; Hydrocortone)
See Corticosteroids (Veterinary—Systemic), 24
Tablets, 49
Hydrocortone—Hydrocortisone Tablets, 49
Meloxicam (Mobic; Mobicox)
See Meloxicam (Veterinary—Systemic), 87
Tablets, 90
Methylprednisolone (A-methaPred; Solu-Medrol)
See Corticosteroids (Veterinary—Systemic), 24
Sodium Succinate For Injection, 51
Mobic—Meloxicam Tablets, 90
Mobicox—Meloxicam Tablets, 90
Norwich Aspirin—Aspirin Tablets, 12
Novo-Keto-EC—Ketoprofen Delayed-Release Tablets, 82
Ketoprofen (Apo-Keto; Apo-Keto-E; Novo-Keto-EC; Orudis; Orudis-E;
Orudis KT; Orudis-SR; Oruvail; Rhodis; Rhodis-EC)
See Ketoprofen (Veterinary—Systemic), 75
Capsules, 81
Delayed-Release Tablets, 82
Extended-Release Capsules, 81
Extended-Release Tablets, 82
Tablets, 81
Orudis—Ketoprofen Capsules, 81
Orudis-E—Ketoprofen Delayed-Release Tablets, 82
Orudis KT—Ketoprofen Tablets, 81
Orudis-SR—Ketoprofen Extended-Release Tablets, 82
Oruvail—Ketoprofen Extended-Release Capsules, 81
Phenylbutazone (Apo-Phenylbutazone; Butazolidin)
See Phenylbutazone (Veterinary—Systemic), 92
Tablets, 97
PMS-ASA—Aspirin Tablets, 12
Rhodis—Ketoprofen Capsules, 81
Rhodis-EC—Ketoprofen Delayed-Release Tablets, 82
Solu-Medrol—Methylprednisolone Sodium Succinate For Injection, 51
St. Joseph Adult Chewable Aspirin—Aspirin Tablets, 12
All rights reserved