Active Ingredient(s):
Each tablet is biconvex
and half-scored and contains either 150 or 300 mg of etodolac.
Indications: ETOGESIC®
is recommended for the management of pain and inflammation associated with
osteoarthritis in dogs.
Pharmacology: Etodolac is a pyranocarboxylic acid, chemically designated as
(}) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b] indole-1-acetic acid. The
structural formula for etodolac is shown: 47.tif The empirical formula for
etodolac is C17H21NO3. The molecular weight of the base is 287.37. It has a pKa
of 4.65 and an n-octanol:water partition coefficient of 11.4 at pH 7.4.
Etodolac is a white crystalline compound, insoluble in water but soluble in
alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol.
Etodolac is a non-narcotic, nonsteroidal anti-inflammatory drug (NSAID) with
anti-inflammatory, anti-pyretic, and analgesic activity. The mechanism of action
of etodolac, like that of other NSAIDs, is believed to be associated with the
inhibition of cyclooxygenase activity. Two unique cyclooxygenases have been
described in mammals1. The constitutive cyclooxygenase, COX-1, synthesizes
prostaglandins necessary for normal gastrointestinal and renal function. The
inducible cyclooxygenase, COX-2, generates prostaglandins involved in
inflammation. Inhibition of COX-1 is thought to be associated with
gastrointestinal and renal toxicity, while inhibition of COX-2 provides
anti-inflammatory activity. In in vitro experiments, etodolac
demonstrated more selective inhibition of COX-2 than COX-1.2 Etodolac also
inhibits macrophage chemotaxis in vivo and in vitro.3 Because of
the importance of macrophages in the inflammatory response, the
anti-inflammatory effect of etodolac could be partially mediated through
inhibition of the chemotactic ability of macrophages. Pharmacokinetics in
healthy beagle dogs: Etodolac is rapidly and almost completely absorbed from the
gastrointestinal tract following oral administration. The extent of etodolac
absorption (AUC) is not affected by the prandial status of the animal. However,
it appears that the peak concentration of the drug decreases in the presence of
food. As compared to an oral solution, the relative bioavailability of the
tablets when given with or without food is essentially 100%. Peak plasma
concentrations are usually attained within 2 hours of administration. Though the
terminal half-life increases in a nonfasted state, minimal drug accumulation
(less than 30%) is expected after repeated dosing (i.e., steady-state).
Pharmacokinetic parameters estimated in a crossover study (fed vs. fasted) in
eighteen 5-month-old beagle dogs are summarized in the following table:
Mean
Pharmacokinetic Parameters Estimated in 18 Beagle Dogs After Oral Administration
of
150 mg of Etodolac
(approximately 12-17 mg/kg)
| Pharmacokinetic
Parameter |
Tablet/Fasted |
Tablet/Nonfasted |
| Cmax (μg/mL) |
22.0±6.42 |
16.9±8.84 |
| Tmax (hours) |
1.69±0.69 |
1.08±0.46 |
| AUC0-∞ (μg.hours/mL) |
64.1±17.9 |
63.9±28.9 |
| Terminal
half-life, t1.2 (hrs) |
7.66±2.05 |
11.98±5.52 |
Pharmacokinetics in
dogs with reduced kidney function: In a study involving four beagle dogs with
induced acute renal failure, there was no observed change in drug
bioavailability after administration of 200 mg single oral etodolac doses. In a
study evaluating an additional four beagles, no changes in electrolyte, serum
albumin/total protein and creatinine concentrations were observed after single
200 mg doses of etodolac. This was not unexpected since very little etodolac is
cleared by the kidneys in normal animals. Most of etodolac and its metabolites
are eliminated via the liver and feces. In addition, etodolac is believed to
undergo enterohepatic recirculation.4
Dosage and Administration:
The recommended dose of etodolac in dogs is 10
to 15 mg/kg body weight (4.5 to 6.8 mg/lb) administered once daily. Due to
tablet sizes and scoring, dogs weighing less than 5 kg (11 lb) cannot be
accurately dosed. The effective dose and duration should be based on clinical
judgment of disease condition and patient tolerance of drug treatment. The
initial dose level should be adjusted until a satisfactory clinical response is
obtained, but should not exceed 15 mg/kg once daily. When a satisfactory
clinical response is obtained, the daily dose level should be reduced to the
minimum effective dose for longer term administration.
Contraindications: ETOGESIC® is contraindicated in animals previously
found to be hypersensitive to etodolac.
Precautions: Store at controlled room temperature, 15-30°C (59-86°F).
Cautions: Federal
(U.S.A.) law restricts this drug to use by or on the order of a licensed
veterinarian. Treatment with ETOGESIC® tablets should be terminated if signs
such as inappetence, emesis, fecal abnormalities, or anemia are observed. Dogs
treated with nonsteroidal anti-inflammatory drugs, including etodolac, should be
evaluated periodically to ensure that the drug is still necessary and well
tolerated. ETOGESIC®, as with other nonsteroidal anti-inflammatory drugs, may
exacerbate clinical signs in dogs with pre-existing or occult gastrointestinal,
hepatic or cardiovascular abnormalities, blood dyscrasias, or bleeding
disorders. As a class, cyclooxygenase inhibitory NSAIDs may be associated with
gastrointestinal and renal toxicity. Sensitivity to drug-associated adverse
effects varies with the individual patient. Patients at greatest risk for renal
toxicity are those that are dehydrated, on concomitant diuretic therapy, or
those with renal, cardiovascular, and/or hepatic dysfunction. Since many NSAIDs
possess the potential to induce gastrointestinal ulceration, concomitant use of
etodolac with other anti-inflammatory drugs, such as other NSAIDs and
corticosteroids, should be avoided or closely monitored. Studies to determine
the activity of ETOGESIC® tablets when administered concomitantly with other
protein-bound drugs have not been conducted in dogs. Drug compatibility should
be monitored closely in patients requiring adjunctive therapy. The safety of
ETOGESIC® has not been investigated in breeding, pregnant or lactating dogs or
in dogs under 12 months of age. For oral use in dogs only.
Warnings: Keep
out of reach of children. Not for human use. Consult a physician in cases of
accidental ingestion by humans. For use in dogs only. Do not use in cats. All
dogs should undergo a thorough history and physical examination before
initiation of NSAID therapy. Appropriate laboratory tests to establish
hematological and serum biochemical baseline data prior to, and periodically
during, administration of any NSAID should be considered. Owners should be
advised to observe for signs of potential drug toxicity (see Information for Dog
Owners and Adverse Reactions).
Discussion: Information for Dog Owners: ETOGESIC®, like other drugs of its
class, is not free from adverse reactions. Owners should be advised of the
potential for adverse reactions and be informed of the clinical signs associated
with drug intolerance. Adverse reactions may include decreased appetite,
vomiting, diarrhea, dark or tarry stools, increased water consumption, increased
urination, pale gums due to anemia, yellowing of gums, skin or white of the eye
due to jaundice, lethargy, incoordination, seizure, or behavioral changes.
Serious adverse reactions associated with this drug class can occur without
warning and in rare situations result in death (see Adverse Reactions). Owners
should be advised to discontinue ETOGESIC® therapy and contact their
veterinarian immediately if signs of intolerance are observed. The vast majority
of patients with drug related adverse reactions have recovered when the signs
are recognized, the drug is withdrawn, and veterinary care, if appropriate, is
initiated. Owners should be advised of the importance of periodic follow-up for
all dogs during administration of any NSAID.
Trial Data: Efficacy: A placebo-controlled, double-blinded study
demonstrated the anti-inflammatory and analgesic efficacy of ETOGESIC®
(etodolac) tablets in various breeds of dogs. In this clinical field study, dogs
diagnosed with osteoarthritis secondary to hip dysplasia showed objective
improvement in mobility as measured by force plate parameters when given
ETOGESIC® tablets at the label dosage for 8 days.
Safety: In target
animal safety studies, etodolac was well tolerated clinically when given at the
label dosage for periods as long as one year (see Cautions). Oral administration
of etodolac at a daily dosage of 10 mg/kg (4.5 mg/lb) for twelve months or 15
mg/kg (6.8 mg/lb) for six months resulted in some dogs showing a mild weight
loss, fecal abnormalities (loose, mucoid, mucosanguineous feces or diarrhea),
and hypoproteinemia. Erosions in the small intestine were observed in one of the
eight dogs receiving 15 mg/kg following six months of daily dosing. Elevated
dose levels of ETOGESIC® (etodolac), i.e. .40 mg/kg/day (18 mg/lb/day, 2.7X the
maximum daily dose), caused gastrointestinal ulceration, emesis, fecal occult
blood, and weight loss. At a dose of .80 mg/kg/day (36 mg/lb/day, 5.3X the
maximum daily dose), 6 of 8 treated dogs died or became moribund as a result of
gastrointestinal ulceration. One dog died within 3 weeks of treatment initiation
while the other 5 died after 3-9 months of daily treatment. Deaths were preceded
by clinical signs of emesis, fecal abnormalities, decreased food intake, weight
loss, and pale mucous membranes. Renal tubular nephrosis was also found in 1 dog
treated with 80 mg/kg for 12 months. Other common abnormalities observed at
elevated doses included reductions in red blood cell count, hematocrit,
hemoglobin, total protein and albumin concentrations; and increases in
fibrinogen concentration and reticulocyte, leukocyte, and platelet counts. In an
additional study which evaluated the effects of etodolac administered to 6 dogs
at the labeled dose for approximately 9.5 weeks, the incidence of stool
abnormalities (diarrhea, loose stools) was unchanged for dogs in the weeks prior
to initiation of etodolac treatment, and during the course of etodolac therapy.
Five of the dogs receiving etodolac, versus 2 of the placebo-treated dogs,
exhibited excessive bleeding during an experimental surgery. No significant
evidence of drug-related toxicity was noted on necropsy.