Drug class: Reversible COX-1/COX-2 Inhibitors

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Prototypical NSAIA; pyranocarboxylic acid derivative.^{1 2}

Uses for Etodolac

Consider potential benefits and risks of etodolac therapy as well as alternative therapies before initiating therapy with the drug.¹ Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.¹

Inflammatory Diseases

Symptomatic treatment of osteoarthritis and rheumatoid arthritis.^{1 2 3}

Management of juvenile rheumatoid arthritis in children 6–16 years of age.²

Pain

Relief of pain in adults.^{1 2}

Etodolac Dosage and Administration

General

• Consider potential benefits and risks of etodolac therapy as well as alternative therapies before initiating therapy with the drug.¹

Administration

Oral Administration

Administer orally once daily as extended-release tablets or 2 or 3 times daily as conventional capsules or tablets.^{1 2 3}

Dosage

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.¹ Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.^{1 2}

Pediatric Patients

Inflammatory Diseases

Juvenile Rheumatoid Arthritis

Oral

Adults

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

Initially, 300 mg 2 or 3 times daily, 400 mg twice daily, or 500 mg twice daily as conventional capsules or tablets.¹ Base subsequent dosage on clinical response and tolerance.¹

Alternatively, initial dosage of 400–1000 mg once daily as extended-release tablets.^{2 3} Base subsequent dosage on clinical response and tolerance.^{2 3}

Pain

Oral

1 g daily as conventional capsules or tablets given in divided doses of 200–400 mg every 6–8 hours.¹

Prescribing Limits

Adults

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

Maximum 1.2 g daily.^{2 3}

Pain

Oral

Maximum 1 g daily.¹

Cautions for Etodolac

Contraindications

• Known hypersensitivity to etodolac or any ingredient in the formulation.^{1 2 3}

• History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.^{1 2 3}

• In the setting of CABG surgery.⁵⁰⁸

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.^{500 502 508}

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information^{500 501 502} indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.⁵⁰⁰

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.^{500 502 506 508}

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.^{500 502 505 506 508}

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.⁵⁰⁸

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.⁵⁰⁵

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;^{500 508 511} absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.^{508 511}

Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs.^{6 7 8 500 501 502 503 506} FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.⁵⁰⁰

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.^{1 500 508}

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease.^{505 511 512 516} Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia.⁵⁰⁸ Contraindicated in the setting of CABG surgery.⁵⁰⁸

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.^{1 502 508} (See Specific Drugs under Interactions.)

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.^{1 2 3}

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;^{a b c d} alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)^{a b c} or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).^c

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.¹ Use with caution in patients with hypertension; monitor BP.¹

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.^{1 508 509} (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.^{1 508}

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.^{500 501 504 507 508}

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.⁵⁰⁸ (See Specific Drugs under Interactions.)

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.⁵⁰⁸

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.⁵⁰⁷

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.^{1 2 3}

Potential for overt renal decompensation.^{1 2 3} Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.^{1 2 3 5} (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.^{1 2 3} Immediate medical intervention and discontinuance for anaphylaxis.^{1 2 3}

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.^{1 2 3}

Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs.¹²⁰¹ Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).¹²⁰¹ Symptoms may resemble those of acute viral infection.¹²⁰¹ Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.¹²⁰¹ If signs or symptoms of DRESS develop, discontinue etodolac and immediately evaluate the patient.¹²⁰¹

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.¹ Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).¹

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.^{1 2 3}

Elevations of serum ALT or AST reported.^{1 2 3}

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.^{1 2 3} Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.^{1 2 3}

Hematologic Effects

Anemia reported rarely.^{1 2 3} Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.^{1 2 3}

May inhibit platelet aggregation and prolong bleeding time.^{1 2 3}

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.^{1 2 3}

May mask certain signs of infection.^{1 2 3}

Obtain CBC and chemistry profile periodically during long-term use.¹

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.^{1200 1201}

Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.¹²⁰²

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice.^{1200 1201} (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs.^{1200 1201} Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance.^{1200 1201} Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.^{1200 1201} In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.^{1200 1201} Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).^{1200 1201} Deaths associated with neonatal renal failure also reported.¹²⁰⁰ Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.¹²⁰¹ Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.¹²⁰¹

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.¹²⁰¹ In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.¹²⁰¹

Isolated occurrences of alterations in limb development observed in animal studies with etodolac; drug- or dose-response relationship not established.¹²⁰¹

Effects of etodolac on labor and delivery not known.¹²⁰¹ In animal studies, NSAIAs increased incidence of dystocia, delayed parturition, and decreased pup survival.¹²⁰¹

Lactation

Not known whether distributed into milk.^{1 2 3} Discontinue nursing or the drug.^{1 2 3}

Fertility

NSAIAs may be associated with reversible infertility in some women.¹²⁰³ Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.¹²⁰³

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.¹²⁰³

Pediatric Use

Safety and efficacy of etodolac conventional tablets or capsules not established in children.¹

Safety and efficacy of etodolac extended-release tablets not established in children <6 years of age.²

Safety and efficacy of etodolac extended-release tablets in children 6–16 years of age supported by studies (of Lodine XL extended-release tablets [no longer commercially available in the US]) in adults with rheumatoid arthritis and by safety, efficacy, and pharmacokinetic data from trials in children with juvenile rheumatoid arthritis.²

Geriatric Use

Caution advised.^{1 3} Safety similar to that in younger adults.^{1 2 3} However, geriatric patients appear to tolerate NSAIA-induced adverse effects less well than younger individuals.^{1 2}

Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.^{1 2}

Renal Impairment

Metabolites eliminated principally via the kidney.^{1 3}

Use with caution in patients with renal disease.^{1 2} Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.^{1 2 3}

Common Adverse Effects

Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI bleeding, GI perforation, nausea, peptic ulcer, vomiting, renal function abnormalities, anemia, dizziness, edema, liver function test abnormalities, headache, prolonged bleeding time, pruritus, rash, tinnitus.¹

Drug Interactions

Role, if any, of CYP enzymes in etodolac metabolism not known.^{1 2 3}

Specific Drugs

Etodolac Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration; bioavailability is about 80%.^{1 2 3} Peak plasma concentration usually attained within about 1.4 hours (conventional capsules and tablets) or 6.7 hours (extended-release tablets).^{1 2 3}

Onset

Conventional capsules or tablets provide pain relief within 30 minutes.¹

Duration

Duration of pain relief averages 4–5 or 5–6 hours following administration of a 200- or 400-mg dose of etodolac (conventional capsules or tablets), respectively.¹

Food

Food delays time to reach peak plasma concentration by about 2.4 hours but does not affect extent of absorption following administration as conventional capsules or tablets.¹

Food increases peak plasma concentration but does not affect extent of absorption following administration as extended-release tablets.^{2 3}

Distribution

Plasma Protein Binding

>99% (principally albumin).^{1 2 3}

Elimination

Metabolism

Extensively metabolized; metabolites do not contribute substantially to effects of drug.^{1 2 3}

Elimination Route

Excreted in urine (72%) mainly as metabolites and in feces (16%).^{1 2 3}

Half-life

Conventional capsules and tablets: 6.4 hours¹

Extended-release tablets: 8.4 hours in adults;^{2 3} 12.1 hours in pediatric patients.²

Special Populations

In geriatric patients, no age-related effect on half-life.^{1 2 3}

In patients with compensated hepatic cirrhosis, disposition of total and unbound etodolac not altered.^{1 2} Not studied in patients with severe hepatic failure.²

In patients with mild to moderate renal impairment (Cl_cr 37–88 mL/minute), disposition of total and unbound etodolac not altered.¹

Stability

Storage

Oral

Conventional Capsules and Tablets

Light-resistant containers at 20–25°C; protect from moisture.¹

Extended-release Tablets

25°C (may be exposed to 15–30°C); protect from excessive heat and humidity.³

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.^{1 2 3}

• Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.^{1 2 3}

Advice to Patients

• Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.¹

• Risk of serious cardiovascular events (e.g., MI, stroke).^{1 500 508}

• Risk of GI bleeding and ulceration.^{1 2 3}

• Risk of serious skin reactions, DRESS, and anaphylactoid and other sensitivity reactions.^{1 2 3 1201}

• Risk of hepatotoxicity.^{1 2 3}

• Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.^{1 500 508}

• Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.^{1 2 3}

• Advise patients to stop taking etodolac immediately if they develop any type of rash or fever and to promptly contact their clinician.¹²⁰¹ Importance of seeking immediate medical attention if an anaphylactic reaction occurs.^{1 2 3}

• Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.^{1 2 3}

• Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.⁵⁰⁸

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 2 3}

• Importance of avoiding NSAIA use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; importance of avoiding NSAIAs beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours’ duration between about 20 and 30 weeks’ gestation.^{1200 1201}

• Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.¹²⁰³

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 2 3}

• Importance of informing patients of other important precautionary information.^{1 2 3} (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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