Etodolac

Overview

Etodolac (EtoGesic®, Lodine®) is a nonsteroidal anti-inflammatory drug (NSAID) used in dogs for the management of pain and inflammation, particularly those associated with osteoarthritis. It is considered a second-generation NSAID, although its veterinary-labeled formulations are now uncommonly used or not widely commercially available.

In canine practice, etodolac has been used for chronic musculoskeletal pain, improved mobility, and reduction of inflammation. As with other NSAIDs, treatment decisions should balance expected analgesic benefit with potential gastrointestinal, renal, hepatic, and hematologic adverse effects.

Mechanism of Action (MOA): Etodolac inhibits cyclooxygenase (COX) enzymes responsible for prostaglandin synthesis. Etodolac is generally considered a COX-1-sparing NSAID with some preference for COX-2 inhibition in dogs. However, canine in vitro studies have produced variable results, ranging from slight COX-2 selectivity to essentially nonselective inhibition. The clinical relevance of this COX selectivity for efficacy or adverse-effect risk has not been established.

Etodolac should be used cautiously in dogs with concurrent systemic disease and is generally not considered a first-line NSAID in modern practice when newer alternatives are available.

Indications

Etodolac is primarily used in dogs for management of pain and inflammation associated with chronic orthopedic disease. It is most commonly considered when long-term anti-inflammatory therapy is needed for osteoarthritis or other degenerative musculoskeletal conditions.

• Canine osteoarthritis: Labeled for control of pain and inflammation associated with osteoarthritis in dogs.
• Chronic joint pain: In the placebo-controlled licensing field study, dogs with osteoarthritis secondary to hip dysplasia showed objective force-plate improvement in mobility after 8 days at the labeled dose.
• Musculoskeletal inflammation: Used when reduction of joint or soft tissue inflammation is clinically beneficial.
• Long-term analgesic management: May be selected for dogs requiring ongoing NSAID therapy when tolerated and appropriately monitored.
• Reduced activity due to orthopedic discomfort: Can help dogs experiencing stiffness, limping, difficulty rising, or exercise intolerance related to chronic pain.
• Other orthopedic conditions: Hip dysplasia, panosteitis, bicipital tenosynovitis, and pre- or postoperative analgesia after orthopedic surgery such as patellar-luxation repair or femoral head and neck excision.

Dosage (Reference)

Dog

Etodolac is labeled in dogs for treatment of pain and inflammation associated with osteoarthritis. Oral therapy is used for ongoing management, while the injectable form was intended as a single subcutaneous dose. Base the dose and duration on the disease and the patient tolerance of treatment; once a satisfactory response is obtained, reduce the daily dose to the minimum effective level for longer-term administration.

Cat

Etodolac is labeled for dogs only and must not be given to cats. No feline dose has been established, and the product label carries an explicit instruction not to use it in cats. There is no feline dose and no situation in which routine feline use is appropriate; a cat-licensed analgesic should be used instead.

Warnings & Precautions

Etodolac is an NSAID that should be used carefully in dogs because clinically important gastrointestinal, renal, hepatic, ocular, and hematologic adverse effects may occur. Take a thorough history and perform a physical examination before starting. Consider baseline CBC, serum chemistry including hepatic and renal values, and urinalysis – especially in geriatric dogs, dogs with chronic disease, or when prolonged treatment is likely – and repeat appropriate testing periodically during therapy.

• NSAID hypersensitivity: Contraindicated in dogs with known hypersensitivity to etodolac, aspirin, or other NSAIDs.
• Gastrointestinal disease: Use cautiously in dogs with current or previous vomiting, diarrhea, ulceration, melena, inflammatory bowel disease, or other GI disorders – and avoid it altogether in a dog with a history of gastrointestinal ulceration.
• Renal risk: Dehydrated dogs, dogs receiving diuretics, or those with preexisting renal disease may be more susceptible to kidney injury; guidance ranges from cautious use to avoiding etodolac altogether in dogs with compromised renal function.
• Hepatic disease: Use cautiously in dogs with liver dysfunction. Recheck liver enzymes in treated dogs after the first week of therapy and periodically thereafter; if liver enzymes rise, discontinue the drug.
• Cardiovascular disease: Dogs with reduced perfusion states, heart disease, or compromised circulation may have increased renal risk during NSAID therapy.
• Bleeding disorders: Use cautiously in dogs with coagulation abnormalities (e.g., von Willebrand disease) or in patients receiving anticoagulants.
• Young dogs: Safety has not been established in dogs less than 12 months of age.
• Keratoconjunctivitis sicca (KCS): Do not give etodolac to dogs that may be prone to developing keratoconjunctivitis sicca. In a series of 211 affected dogs most developed severe dry eye, and it resolved after stopping the drug in only about 10 to 15% of cases; dogs treated for less than 6 months were substantially more likely to recover. Perform a Schirmer tear test before starting etodolac and repeat it periodically during therapy; also monitor for ocular signs of KCS. Shorter treatment duration was associated with improved remission.
• Thyroid testing interference: Etodolac has had varying effects on total T4, free T4 and TSH in dogs; one study found no effect and another a fall in total and free T4 after two weeks of treatment. Interpret thyroid panels in treated dogs with caution.
• Surgery and bleeding: Although etodolac appears to affect clotting times less than some other canine NSAIDs, excessive surgical bleeding has been documented: in the target-animal safety study five treated dogs bled excessively during an experimental surgery, against two of the placebo-treated dogs.
• Do not combine NSAIDs: Concurrent use with another NSAID or corticosteroid greatly increases ulcer and toxicity risk.
• Pregnancy / lactation: Safety has not been established in breeding, pregnant or nursing dogs, and NSAIDs as a class are regarded as contraindicated in pregnancy because of an abortifacient effect, fetal cardiopulmonary and renal risk, and prolongation of pregnancy when given in the third trimester.
• Lactation and the litter: Most NSAIDs are excreted in milk, so etodolac may expose a nursing litter; use it during lactation only when the maternal benefit outweighs the potential risk to the offspring.
• Laboratory interference: Etodolac may cause a false-positive urine bilirubin result; interpret bilirubinuria cautiously in treated dogs.
• Unmasking occult disease: Because prostaglandins maintain normal homeostatic function, an NSAID can produce clinically significant illness in a patient with underlying or occult disease, unmasking a problem that had not previously been diagnosed.

Drug Interactions

Etodolac has many clinically relevant drug interactions, most commonly involving increased risk of gastrointestinal ulceration, renal injury, bleeding, or altered efficacy of concurrent medications. Careful medication review is recommended before starting therapy.

• Other NSAIDs: Concurrent use with another NSAID should be avoided because it increases the risk of gastrointestinal ulceration.
• Corticosteroids (e.g., prednisolone, dexamethasone): Concurrent corticosteroid administration may significantly increase gastrointestinal adverse effects, including ulceration.
• ACE inhibitors (e.g., enalapril, benazepril): May reduce antihypertensive effect and increase renal injury risk when combined.
• ARBs (e.g., telmisartan): May reduce antihypertensive effect and potentially worsen renal perfusion.
• Diuretics (e.g., furosemide): May reduce diuretic efficacy and increase the risk of nephrotoxicity; a dog that is already dehydrated or on a diuretic is at greatest risk of renal injury.
• Aminoglycosides (e.g., gentamicin, amikacin): Increased risk of nephrotoxicity.
• Cyclosporine / Tacrolimus: Cyclosporine: concurrent use may increase the risk of cyclosporine nephrotoxicity. Tacrolimus: concurrent use with etodolac may result in acute renal failure.
• Anticoagulants (e.g., heparin, warfarin, rivaroxaban): Increased risk of bleeding or hemorrhage.
• Clopidogrel / SSRIs: May increase bleeding tendency when used together.
• Aspirin: Increased risk of GI irritation, ulceration, and bleeding.
• Methotrexate: Potential for serious toxicity; use with caution.
• Digoxin: May increase serum digoxin concentrations and prolong half-life.
• Phenobarbital: May increase metabolism of etodolac and reduce effectiveness.
• Probenecid: May increase etodolac blood levels and prolong elimination.
• Cholestyramine: May reduce etodolac absorption and decrease clinical effect.
• Other nephrotoxic drugs: Concurrent use with agents such as cisplatin or amphotericin B may further increase renal risk.
• Bisphosphonates (e.g., alendronate): Concurrent use with a bisphosphonate such as alendronate may increase the risk of gastrointestinal ulceration and nephrotoxicity.
• Tigilanol tiglate: Because tigilanol tiglate must be given together with a glucocorticoid, NSAIDs must be avoided during that protocol.
• Sulfonamides: Etodolac may cross-react with sulfonamides in sensitive animals.
• Highly protein-bound drugs: Etodolac is highly protein bound, and concurrent use with other drugs that are also highly protein bound should be avoided or closely monitored. Commonly used protein-bound drugs include cardiac, anticonvulsant and behavioral medications.
• Switching from another NSAID: Except when switching from aspirin, evidence that a multi-day washout is required is limited; consider starting the new NSAID when the next dose of the previous one would have been due.

Side Effects & Overdose

Side Effects

Adverse effects of etodolac in dogs are similar to other NSAIDs and most commonly involve the gastrointestinal tract. Serious adverse reactions can occur without warning and may rarely be fatal; most affected dogs recover when the signs are recognized, the drug is withdrawn and appropriate veterinary care is provided.

• Vomiting / regurgitation: The primary adverse effects, reported in about 5% of dogs tested; in the placebo-controlled field study vomiting occurred in 4.3% of treated dogs versus 1.7% on placebo and regurgitation in 0.9%.
• Diarrhea or fecal abnormalities: Soft stool, mucus, melena, or other bowel changes may occur.
• Reduced appetite: Reported in fewer than 1% of treated dogs, and an early sign of intolerance: stop etodolac if a treated dog goes off its food.
• Lethargy: Reduced activity or abnormal tiredness may develop during therapy.
• Gastrointestinal ulceration: May cause abdominal pain, vomiting blood, black stool, anemia, or collapse.
• Hypoproteinemia: Reported in 2.6% of treated dogs versus none on placebo, and it can appear late – one dog developed it after 11 months of therapy. Serum protein returned to normal after the drug was discontinued.
• Kidney injury: Reported renal effects include polydipsia, polyuria, urinary incontinence, azotemia, acute renal failure, proteinuria and hematuria. Dehydration increases the risk of etodolac-associated kidney injury.
• Liver injury: Hepatotoxicity is possible but is not a well-documented problem in dogs. Abnormal liver function tests, elevated hepatic enzymes, icterus and acute hepatitis have been reported after approval, and etodolac is one of the drugs associated with rare idiosyncratic reactions resulting in hepatic dysfunction or failure in dogs.
• Keratoconjunctivitis sicca (dry eye): Etodolac-associated keratoconjunctivitis sicca in dogs can be severe and frequently persists after withdrawal: resolution occurred in only about 10 to 15% of cases, and was more likely when the treatment course was short.
• Behavioral changes: Reported neurological and behavioral effects include ataxia, paresis, aggression, sedation, hyperactivity, disorientation, hyperesthesia, vestibular signs and seizures.
• Injection site reactions: Pain or localized tissue irritation may occur with injectable use.
• Skin and immune reactions: Urticaria was reported in 0.9% of dogs in the field study and in none of the placebo-treated dogs; pruritus, dermatitis, edema and alopecia have also been reported after approval. Reported cardiovascular and respiratory effects are tachycardia and dyspnea.
• Further gastrointestinal reports: Gastroenteritis and elevated pancreatic enzymes have also been reported after approval.
• Blood: Hematological effects reported after approval include anemia, hemolytic anemia, thrombocytopenia and prolonged bleeding time – not all of which are explained by gastrointestinal blood loss.
• Weight loss and soft stools at the labeled dose: Mild weight loss, loose or mucoid feces and hypoproteinemia can occur at the labeled dose during long-term therapy; in the safety study small-intestinal erosions were found in one of eight dogs given 15 mg/kg for six months.
• Serious reactions without warning: Serious adverse reactions in this drug class can occur without warning and in rare situations have resulted in death; the vast majority of affected dogs recover once the signs are recognized, the drug is withdrawn and veterinary care is given. Owners should be told which signs to look for before the first dose.
• When to stop the drug: Stop etodolac and reassess if inappetence, vomiting, abnormal feces or anemia appear.

Overdose

Etodolac overdose can produce severe gastrointestinal and renal toxicity. In repeated-dose safety studies, 40 mg/kg/day (2.7 times the labeled dose) caused gastrointestinal ulceration, emesis, fecal occult blood and weight loss, and 80 mg/kg/day (5.3 times the labeled dose) caused 6 of 8 dogs to die or become moribund from gastrointestinal ulceration. These findings were not from single-dose overdoses.

• Early GI signs: Vomiting, diarrhea, drooling, anorexia, abdominal pain, or melena.
• Ulceration / GI bleeding: Repeated or high overdoses may lead to gastric ulceration, blood loss, weakness, or shock.
• Renal toxicity: Acute kidney injury, reduced urine production, hyperkalemia, or worsening dehydration may occur.
• Neurologic signs: With very large doses, ataxia, seizures, CNS depression and coma may occur; collapse may also occur.
• Weight loss: May occur with repeated overdose exposure.
• Management: No specific antidote exists. Induce emesis only if ingestion was within about 2 hours and the dog is not already vomiting or at risk of aspiration, then give activated charcoal 1-2 g/kg with a cathartic. Because etodolac undergoes enterohepatic recirculation, repeat the charcoal without a cathartic every 6 to 8 hours for two further doses. Give intravenous fluids at twice maintenance where renal involvement is known or suspected, and use gastroprotectants.
• Hospitalization: Hospitalize after a high ingested dose, where there is potential for renal toxicosis, or for serious signs such as frequent vomiting, bloody vomitus, melena, anemia or evidence of renal involvement; mild signs after a low ingested dose may be managed as an outpatient.
• Monitoring after an overdose: Check urea and creatinine daily for several days – the full extent of renal damage may not be evident immediately – and recheck 2 to 3 days after discharge. Check packed cell volume and total solids every 12 to 24 hours while hospitalized and again 2 to 3 days after discharge, because gastrointestinal bleeding may not develop for several days.
• Prognosis and complications: Gastrointestinal upset or ulceration usually resolves with appropriate treatment, renal effects are generally reversible when treated early and aggressively, and acute liver injury generally resolves after withdrawal and symptomatic care. Serious complications include perforation of a gastrointestinal ulcer with peritonitis, which may require surgery, and irreversible acute or chronic renal failure.
• Poison control: For a known or suspected overdose, consult a 24-hour veterinary poison control centre.
• Duration of treatment: The duration of treatment depends on the dose ingested and the half-life of the drug. Etodolac’s elimination half-life in dogs is about 8 hours fasted and 12 hours non-fasted.

Key Notes

Practical clinical points that may help optimize the safe and effective use of etodolac in dogs:

• Older-generation option: Etodolac is uncommonly used today: the veterinary-approved dosage forms are no longer commercially available, and other NSAIDs have largely replaced it.
• Best use case: Etodolac is indicated for canine osteoarthritis; dogs on continuing treatment should be reassessed periodically to confirm that it is still necessary and well tolerated.
• Mobility matters: Judge the response by objective improvement in mobility – willingness to rise, climb stairs, jump, run and exercise.
• Use multimodal plans: Use etodolac within a multimodal plan that includes weight control, physical therapy and dietary omega-3 supplementation.
• Lowest effective strategy: Once stable comfort is achieved, some patients can be maintained on carefully individualized minimum effective dosing plans.
• Senior patient attention: Give particular attention to baseline examination and laboratory testing in geriatric dogs and in dogs with chronic disease.
• Owner observation is valuable: Owner-observed changes in limping, activity or exercise, willingness to stand, climb stairs, jump or run, and joint stiffness can help judge whether treatment is working.
• Recheck early: Recheck liver enzymes in treated dogs after the first week of therapy, and reassess the continuing need for and tolerance of treatment periodically thereafter.
• Not for cats: Etodolac is labeled for dogs only and must not be given to cats; a cat-licensed analgesic should be used instead.
• Pharmacokinetics: Etodolac is rapidly and almost completely absorbed, with peak concentrations 1 to 2 hours after dosing. The elimination half-life is about 8 hours in a fasted dog and about 12 hours in a fed dog (reported range 7.6 to 14 hours), which supports once-daily dosing, and the drug is highly bound to serum proteins.
• Elimination: The kidneys clear very little etodolac: the drug and its metabolites are eliminated by the liver and in the feces, with extensive enterohepatic recirculation. This is why the half-life lengthens with food in the gut and why repeated activated charcoal is used after an overdose.
• Half-life and dosing interval: Serum half-life is not necessarily a reliable predictor of the duration of efficacy, possibly because etodolac is highly protein bound.
• Food and absorption: Feeding does not change the total amount of etodolac absorbed – relative bioavailability with or without food is essentially 100% – although the peak concentration is lower with food. Giving the tablet with food to reduce stomach upset therefore does not reduce the dose delivered.
• Monitoring schedule: Before starting: physical examination, CBC, serum chemistry including liver enzymes and renal values, urinalysis, and a Schirmer tear test – especially in geriatric dogs or dogs with chronic disease. After one week: recheck liver enzymes. During long-term therapy: repeat CBC, chemistry, urinalysis and tear testing on an ongoing basis.
• Storage: Store tablets in a tightly sealed container protected from light at 15–30°C (59–86°F). Store the injection at or below 25°C (77°F).
• Racing and competition: Etodolac is an ARCI class 4 substance, so treatment may make a dog ineligible for regulated racing or competition; check the rules of the governing body before dispensing. No withdrawal times have been established.
• Availability: Etodolac remains listed in the FDA Green Book of approved animal drugs, but the veterinary-labeled products are no longer commercially available in the United States. The human-labeled products are listed as distinct formulations: immediate-release tablets, extended-release tablets and capsules.