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Flurbiprofen

Class: Other Nonsteroidal Anti-inflammatory Agents
- NSAIAs
- NSAIDs
VA Class: MS120
Chemical Name: 2-Fluoro-α-methyl-[1-1′-biphenyl]-acetic acid sodium salt dihydrate
Molecular Formula: C15H13FO2
CAS Number: 56767-76-1

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 f 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 f Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.1 f Geriatric individuals are at greater risk for serious GI events.1 f (See GI Effects under Cautions.)

Introduction

Prototypical NSAIA;1 2 3 6 7 propionic acid derivative.7

Uses for Flurbiprofen

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 flurbiprofen therapy as well as alternative therapies before initiating therapy with the drug.1 f Use lowest possible effective dosage and shortest duration of therapy consistent with patient’s treatment goals.1 f

Inflammatory Diseases

Symptomatic treatment of rheumatoid arthritis and osteoarthritis.1 2 3 4 5 6 7 10

Also has been used for the management of ankylosing spondylitis.2 6 8 a b

Flurbiprofen Dosage and Administration

General

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

Administration

Oral Administration

Administer orally 2–4 times daily.1 13 14

Administration with food or antacids may alter rate but not extent of absorption.1 3 13 g

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 f Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.1 f

Adults

Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis
Oral

200–300 mg daily given in 2–4 divided doses.1 3 Similar efficacy whether the total daily dosage of flurbiprofen is administered in 2, 3, or 4 divided doses.2 9

Prescribing Limits

Adults

Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis
Oral

Maximum 100 mg in a single dose.1 3

Special Populations

Renal Impairment

Mild renal impairment: Dosage adjustment not required.1

Moderate or severe renal impairment: Dosage reduction may be necessary.1

Hepatic Impairment

Dosage reduction may be necessary.1 3 15

Geriatric Patients

Use with caution and at the lowest effective dosage for the shortest possible duration.1 f

Cautions for Flurbiprofen

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 flurbiprofen or any ingredient in the formulation.1 15 f

  • History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.1 f

  • 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.505 508

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.19 20 21 23 500 501 502 503 506 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 f

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 16 502 508 f (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 15 f h i

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

Hypertension

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

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

Heart Failure and Edema

Fluid retention and edema reported.1 508 f

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 f

Potential for overt renal decompensation.1 f 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 18 f (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.1 f

Immediate medical intervention and discontinuance for anaphylaxis.1 f

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps);1 f caution in patients with asthma.1 f

Dermatologic Reactions

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

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.1 f

Elevations of serum ALT or AST reported.1 f

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

Hematologic Effects

Anemia reported rarely.1 Determine hemoglobin concentration or hematocrit periodically in patients receiving long-term therapy even if signs or symptoms of anemia do not occur.1

May inhibit platelet aggregation and prolong bleeding time.1

Ocular Effects

Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.1

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.1 f

May mask certain signs of infection.1 f

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

Specific Populations

Pregnancy

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

Lactation

Distributed into milk.1 13 15 c d Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Use with caution in patients ≥65 years of age.1 f Geriatric patients appear to tolerate NSAIA therapy less well (e.g., possible higher incidence of adverse GI effects, greater risk of developing renal decompensation) than younger individuals.1 f Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.1 f

Renal Impairment

Metabolites eliminated principally via the kidney.1 3 Use not recommended in patients with advanced renal disease.1 If flurbiprofen must be used, closely monitor renal function.1

Common Adverse Effects

Edema, abdominal pain, constipation, diarrhea, dyspepsia/heartburn, flatulence, GI bleeding, nausea, vomiting, elevated liver enzymes, body weight changes, headache, nervousness, CNS stimulation (e.g., anxiety, insomnia, increased reflexes, tremor), CNS inhibition (e.g., amnesia, asthenia, depression, malaise, somnolence), rhinitis, vision changes, dizziness/vertigo, tinnitus, urinary tract infection, rash.1 f

Interactions for Flurbiprofen

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to ACE inhibitor possible1 f

Possible deterioration of renal function in individuals with renal impairment1 f

Monitor BP1 f

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonist possible22

Possible deterioration of renal function in individuals with renal impairment22

Monitor BP22

Antacids (aluminum- and magnesium-containing)

Decrease in rate but not extent of flurbiprofen absorption observed in geriatric patients but not in younger adults1 g

Anticoagulants (e.g., warfarin)

Possible bleeding complications1 f

Caution advised1 f

Antidiabetic agents

Slight reduction in blood glucose concentrations (without signs or symptoms of hypoglycemia)1

Aspirin

Increased risk of GI ulceration or other complications 1

Possible decreased serum flurbiprofen concentrations 1 13 14

No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs1 16 502 508

Concomitant use not recommended1

β-Adrenergic blocking agents (e.g., atenolol, propranolol)

Potential pharmacologic interaction (reduced antihypertensive effect)1

Pharmacokinetic interaction unlikely1

Monitor BP1

Digoxin

Pharmacokinetic interaction unlikely1

Diuretics (furosemide and thiazides)

Reduced natriuretic effects possible1 f

Monitor for diuretic efficacy and renal failure1 f

Histamine H2-receptor antagonists (cimetidine, ranitidine)

Cimetidine: Small increase in AUC of flurbiprofen, but clinically important pharmacokinetic interaction unlikely1

Ranitidine: Pharmacokinetic interaction unlikely 1

Lithium

Increased plasma lithium concentrations1 f

Monitor for lithium toxicity1 f

Methotrexate

Possible toxicity associated with increased plasma methotrexate concentrations during concomitant NSAIA use1 12 f

Pharmacokinetics of methotrexate not altered during concurrent flurbiprofen administration in one studye

Caution advised1 f

Flurbiprofen Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration.1 2 3 13 14 Peak plasma concentrations usually attained within 1.5–3 hours.1 2 m

Food

Food may alter rate but not extent of absorption.1 3 13 g

Distribution

Extent

Distribution into human body tissues and fluids not fully characterized.1

Distributed into milk in very small amounts.1 13 15 c d

Plasma Protein Binding

>99% (principally albumin).1 2 13 14

Elimination

Metabolism

Extensively metabolized.1 2 13 14 CYP2C9 plays an important role in the metabolism of flurbiprofen to its major metabolite, 4′-hydroxyflurbiprofen, which has weak anti-inflammatory activity.1 2 11

Elimination Route

Following oral dosing, approximately 70% of the flurbiprofen dose is eliminated in urine as parent drug and metabolites, with <3% excreted as unchanged drug.1 3

Half-life

Approximately 4.7 and 5.7 hours for R- and S-flurbiprofen, respectively.1

Special Populations

In geriatric patients, pharmacokinetic profile similar to that in younger adults.1

In patients with renal impairment, clearance of metabolites may be decreased.1

Not substantially removed by peritoneal dialysis.1

Stability

Storage

Oral

Tablets

20–25°C.1

Actions

  • Inhibits cyclooxygenase-1 (COX-1) and COX-2.2

  • Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.1 2 3 6 7

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 to the patient each time the drug is dispensed.1 f

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

  • Risk of GI bleeding and ulceration.1 f

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

  • Risk of hepatotoxicity.1 f

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

  • Importance of discontinuing flurbiprofen and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.1 f Importance of seeking immediate medical attention if an anaphylactic reaction occurs.1 f

  • 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 f

  • Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.1 508

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

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of informing patients of other important precautionary information.1 (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

Flurbiprofen

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg*

Flurbiprofen Tablets

100 mg*

Flurbiprofen 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.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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3. Anon. Flurbiprofen. Med Lett Drugs Ther. 1989; 31:31-2.

4. Lomen PL, Lamborn KR, Porter GH et al. Treatment of osteoarthritis of the knee. A comparison of flurbiprofen and aspirin. Am J Med. 1986; 24:(Suppl 3A)97-102.

5. Lomen PL, Turner LF, Lamborn KR et al. Flurbiprofen in the treatment of rheumatoid arthritis. A comparison with aspirin. Am J Med. 1986; 24:(Suppl 3A)89-95.

6. Buchanan WW, Kassam YB. European experience with flurbiprofen. A new analgesic/anti-inflammatory agent. Am J Med. 1986; 24:(Suppl 3A)145-52.

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8. Lomen PL, Turner LF, Lamborn KR et al. Flurbiprofen in the treatment of ankylosing spondylitis. A comparison with indomethacin. Am J Med. 1986; 24:(Suppl 3A)127-32.

9. Brown BL, Daenzer CL, Hearron MS et al. Comparison of two dosing schedules of flurbiprofen for patients with rheumatoid arthritis. Twice-daily versus four-times-a-day schedules. Am J Med. 1986; 24:(Suppl 3A)19-22.

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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. Mylan. Flurbiprofen tablets prescribing information. Morgantown, WV; 2016 May.

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b. Busson M. A long-term study of flurbiprofen in rheumatological disorders: III. Other articular conditions. J Int Med Res. 1986; 14:13-8.

c. Smith IJ, Hinson JL, Johnson VA et al. Flurbiprofen in post-partum women: plasma and breast milk disposition. J Clin Pharmacol. 1989; 29: 174-84. http://www.ncbi.nlm.nih.gov/pubmed/2715375?dopt=AbstractPlus

d. Cox SR, Forbes KK. Excretion of flurbiprofen into breast milk. Pharmacotherapy. 1987; 7: 211-5. http://www.ncbi.nlm.nih.gov/pubmed/3444752?dopt=AbstractPlus

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f. US Food and Drug Administration. Proposed NSAID Package Insert Labeling Template 1. From the FDA website (http://www.fda.gov). Accessed 10 Oct 2005.

g. Caillé G, du Souich P, Vézina M et al. Pharmacokinetic interaction between flurbiprofen and antacids in healthy volunteers. Biopharm Drug Dispos. 1989; 10: 607-15.

h. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999; 340:1888-99. http://www.ncbi.nlm.nih.gov/pubmed/10369853?dopt=AbstractPlus

i. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol. 1999; 26(suppl 56):18-24.

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l. Lanza FL, and the members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol. 1998; 93:2037-46. http://www.ncbi.nlm.nih.gov/pubmed/9820370?dopt=AbstractPlus

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