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Etodolac

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

Medically reviewed by Drugs.com. Last updated on Nov 9, 2020.

Warning

Special Alerts:

[Posted 10/15/2020]

AUDIENCE: Consumer, Patient, Health Professional, Pharmacy

ISSUE: FDA is warning that use of NSAIDs around 20 weeks or later in pregnancy may cause rare but serious kidney problems in an unborn baby. This can lead to low levels of amniotic fluid surrounding the baby and possible complications.

For prescription NSAIDs, FDA is requiring changes to the prescribing information to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.

For over-the-counter (OTC) NSAIDs intended for use in adults, FDA will also update the Drug Facts labels, available at: [Web]. These labels already warn to avoid using NSAIDs during the last 3 months of pregnancy because the medicines may cause problems in the unborn child or complications during delivery. The Drug Facts labels already advise pregnant and breastfeeding women to ask a health care professional before using these medicines.

BACKGROUND:

NSAIDs

  • are a class of medicines available by prescription and OTC. They are some of the most commonly used medicines for pain and fever.

  • are used to treat medical conditions such as arthritis, menstrual cramps, headaches, colds, and the flu.

  • work by blocking the production of certain chemicals in the body that cause inflammation.

  • are available alone and combined with other medicines. Examples of NSAIDs include aspirin, ibuprofen, naproxen, diclofenac, and celecoxib.

Common side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

RECOMMENDATION:

Consumers/Patients

  • If you are pregnant, do not use NSAIDs at 20 weeks or later in pregnancy unless specifically advised to do so by your health care professional because these medicines may cause problems in your unborn baby.

  • Many OTC medicines contain NSAIDs, including those used for pain, colds, flu, and insomnia, so it is important to read the Drug Facts labels, available at: [Web], to find out if the medicines contain NSAIDs.

  • Talk to your health care professional or pharmacist if you have questions or concerns about NSAIDs or which medicines contain them.

  • Other medicines, such as acetaminophen, are available to treat pain and fever during pregnancy. Talk to your pharmacist or health care professional for help deciding which might be best.

Health Care Professionals

  • FDA recommends that health care professionals should limit prescribing NSAIDs between 20 to 30 weeks of pregnancy and avoid prescribing them after 30 weeks of pregnancy. If NSAID treatment is determined necessary, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours and discontinue the NSAID if oligohydramnios is found. FDA is warning that use of NSAIDs around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.

  • These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

  • Oligohydramnios is often, but not always, reversible with treatment discontinuation.

  • Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

  • If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. As currently described in the NSAID labels, avoid prescribing NSAIDs at 30 weeks and later in pregnancy because of the additional risk of premature closure of the fetal ductus arteriosus.

  • The above recommendations do not apply to low-dose 81 mg aspirin prescribed for certain conditions in pregnancy.

  • Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice.

For more information visit the FDA website at: [Web] and [Web].

Warning

    Cardiovascular Risk
  • Increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).1 500 502 508 Risk may occur early in treatment and may increase with duration of use.500 502 505 506 508 (See Cardiovascular Thrombotic Effects under Cautions.)

  • Contraindicated in the setting of CABG surgery.508

    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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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 information500 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; 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).

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

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 502 508

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

  • 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

  • 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

  • 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 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* 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

300 mg*

Etodolac Capsules

Tablets, film-coated

400 mg*

Etodolac Tablets

500 mg*

Etodolac Tablets

Tablets, extended-release, film-coated

400 mg*

Etodolac Extended-Release Tablets

500 mg*

Etodolac Extended-Release Tablets

600 mg*

Etodolac Extended-Release Tablets

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 9, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, 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 (http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106201.pdf)

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. http://www.ncbi.nlm.nih.gov/pubmed/16968831?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/16740558?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1473048&blobtype=pdf

8. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk; the seduction of common sense. JAMA. 2006; 296:1653-6. http://www.ncbi.nlm.nih.gov/pubmed/16968830?dopt=AbstractPlus

500. Food and Drug Administration. Drug safety communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Silver Spring, MD; 2015 Jul 9. From the FDA web site. Accessed 2016 Mar 22. http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm

501. Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013; 382:769-79. http://www.ncbi.nlm.nih.gov/pubmed/23726390?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3778977&blobtype=pdf

502. Food and Drug Administration. FDA briefing document: Joint meeting of the arthritis advisory committee and the drug safety and risk management advisory committee, February 10-11, 2014. From FDA web site http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM383180.pdf

503. Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011; 342:c7086. http://www.ncbi.nlm.nih.gov/pubmed/21224324?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3019238&blobtype=pdf

504. Gislason GH, Rasmussen JN, Abildstrom SZ et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med. 2009; 169:141-9. http://www.ncbi.nlm.nih.gov/pubmed/19171810?dopt=AbstractPlus

505. Schjerning Olsen AM, Fosbøl EL, Lindhardsen J et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011; 123:2226-35. http://www.ncbi.nlm.nih.gov/pubmed/21555710?dopt=AbstractPlus

506. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011; 8:e1001098. http://www.ncbi.nlm.nih.gov/pubmed/21980265?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3181230&blobtype=pdf

507. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; 62:e147-239. http://www.ncbi.nlm.nih.gov/pubmed/23747642?dopt=AbstractPlus

508. ANI Pharmaceuticals, Inc. Etodolac capsule prescribing information. Baudette, MN; 2015 Aug.

509. Cumberland Pharmaceuticals Inc. Caldolor (ibuprofen) injection prescribing information. Nashville, TN; 2016 Apr.

511. Olsen AM, Fosbøl EL, Lindhardsen J et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation. 2012; 126:1955-63. http://www.ncbi.nlm.nih.gov/pubmed/22965337?dopt=AbstractPlus

512. Olsen AM, Fosbøl EL, Lindhardsen J et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients--a nationwide study. PLoS One. 2013; 8:e54309.

516. Bavry AA, Khaliq A, Gong Y et al. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med. 2011; 124:614-20. http://www.ncbi.nlm.nih.gov/pubmed/21596367?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4664475&blobtype=pdf