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Etodolac

Pronunciation

Class: Other Nonsteroidal Anti-inflammatory Agents
VA Class: MS102
Molecular Formula: C17H21N03
CAS Number: 41340-25-4

Warning(s)

  • Cardiovascular Risk
  • Possible increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).1 Risk may increase with duration of use.1 Individuals with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.1 (See Cardiovascular Effects under Cautions.)

  • Contraindicated for the treatment of pain in the setting of CABG surgery.1

  • GI Risk
  • Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).1 Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.1 Geriatric individuals are at greater risk for serious GI events.1 (See GI Effects under Cautions.)

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

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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
Dosage Based on Child’s Body Weight2

Weight (kg)

Dosage (as extended-release tablets)

20–30

400 mg once daily

31–45

600 mg once daily

46–60

800 mg once daily

>60

1 g once daily

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

  • Treatment of perioperative pain in the setting of CABG surgery.1

Warnings/Precautions

Warnings

Cardiovascular Effects

Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e.g., MI, stroke) in certain situations.1 4 Several prototypical NSAIAs also have been associated with increased risk of cardiovascular events.6 7 8 Current data insufficient to assess risk associated with etodolac.6 7 8

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events), and at the lowest effective dosage for the shortest duration necessary.1

Short-term use to relieve acute pain, especially at low dosages, does not appear to be associated with increased risk of serious cardiovascular events (except immediately following CABG surgery).4

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

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 certain diuretics may occur.1 (See Specific Drugs under Interactions.)

Fluid retention and edema reported.1 Caution in patients with fluid retention or heart failure.1

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; alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole) or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).

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

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

Category C.1 2 3 Avoid use in third trimester because of possible premature closure of the ductus arteriosus.1 2 3

Lactation

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

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

Interactions for Etodolac

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

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to ACE inhibitor1 2 3

Possible deterioration of renal function in individuals with renal impairment5

Monitor BP1 2

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonist5

Possible deterioration of renal function in individuals with renal impairment5

Monitor BP5

Antacids

Decreased peak plasma etodolac concentration; no effect on extent of etodolac absorption1 2 3

Aspirin

Increased risk of GI ulceration and other complications1

No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs1

Manufacturer states that concomitant use not recommended1 2 3

Cyclosporine

Possible increase in serum cyclosporine concentrations; possible increase in nephrotoxic effects of cyclosporine1 2 3

Monitor for cyclosporine toxicity1 2 3

Digoxin

Possible increase in plasma digoxin concentrations1 2 3

Monitor plasma digoxin concentrations1 2 3

Diuretics (furosemide, thiazides)

Reduced natriuretic effects1 2 3

Monitor for diuretic efficacy and renal failure1

Glyburide

Pharmacokinetic interaction unlikely1 2 3

Lithium

Increased plasma lithium concentrations1 2 3

Monitor for lithium toxicity1 2 3

Methotrexate

Pharmacokinetics of methotrexate not altered2 3

Caution advised2 3

Phenytoin

Pharmacokinetic interaction unlikely1 2 3

Warfarin

Reports of bleeding complications and increases in PT1 2 3

Caution advised1 2 3

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 (Clcr 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 with long-term use.1

  • Risk of GI bleeding and ulceration.1 2 3

  • Risk of serious skin reactions.1 Risk of anaphylactoid and other sensitivity reactions.1 2 3

  • Risk of hepatotoxicity.1 2 3

  • Importance of notifying clinician if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.1

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

  • Importance of discontinuing etodolac and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.1 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

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 3 Importance of avoiding etodolac in late pregnancy (third trimester).1 2 3

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Etodolac

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

200 mg*

Etodolac Capsules

Apotex

300 mg*

Etodolac Capsules

Apotex, Taro, Teva

Tablets, film-coated

400 mg*

Etodolac Tablets

Actavis, Apotex, Sandoz, Taro, Teva

500 mg*

Etodolac Tablets

Actavis, Apotex, Par, Sandoz, Taro, Teva

Tablets, extended-release, film-coated

400 mg*

Etodolac Extended-Release Tablets

Andrx, Sandoz, Taro, Teva

500 mg*

Etodolac Extended-Release Tablets

Taro, Teva

600 mg*

Etodolac Extended-Release Tablets

Taro, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Etodolac 300MG Capsules (TARO): 60/$35.99 or 180/$85.97

Etodolac 400MG Tablets (ACTAVIS ELIZABETH): 60/$38.99 or 180/$100.98

Etodolac 500MG Tablets (APOTEX): 60/$75.99 or 180/$205.97

Etodolac CR 400MG 24-hr Tablets (TEVA PHARMACEUTICALS USA): 30/$35.99 or 90/$97.97

Etodolac CR 500MG 24-hr Tablets (TEVA PHARMACEUTICALS USA): 30/$36.99 or 90/$101.97

Etodolac CR 600MG 24-hr Tablets (TEVA PHARMACEUTICALS USA): 30/$68.99 or 90/$189.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Wyeth. Lodine (etodolac capsules and tablets) prescribing information. Philadelphia, PA; 2006 Apr.

2. Wyeth. LodineXL (etodolac extended-release tablets) prescribing information. Philadelphia, PA; 2003 Oct.

3. Taro Pharmaceutical Industries. Etodolac extended-release tablets prescribing information. Haifa Bay, Israel; 2003 Feb.

4. Jenkins JK and Seligman PJ. Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6. From FDA website ()

5. Merck & Co. Clinoril (sulindac) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.

6. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006; 296: 1633-44. [PubMed 16968831]

7. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006; 332: 1302-5. [PubMed 16740558]

8. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk; the seduction of common sense. JAMA. 2006; 296:1653-6. [PubMed 16968830]

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