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Flurbiprofen

Pronunciation

Class: Other Nonsteroidal Anti-inflammatory Agents
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
Brands: Ansaid

Warning(s)

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

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

  • 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

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

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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

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

  • 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

  • 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 cardiovascular events (e.g., MI, stroke) in certain situations.1 16 f Several prototypical NSAIAs also have been associated with increased risk of cardiovascular events.19 20 21 Current data insufficient to assess risk associated with flurbiprofen.19 20 21

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

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).1 16 f

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.1 16 f (See Specific Drugs under Interactions.)

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

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

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

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

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

  • 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 with long-term use.1 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 notifying clinician if signs or symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.1 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

  • 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.

* 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*

Ansaid

Pfizer

Flurbiprofen Tablets

Caraco, Mylan, Pliva, Sandoz, Teva

100 mg*

Ansaid

Pfizer

Flurbiprofen Tablets

Caraco, Mylan, Pliva, Sandoz, 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.

Flurbiprofen 100MG Tablets (TEVA PHARMACEUTICALS USA): 60/$21.99 or 180/$52.99

Flurbiprofen 50MG Tablets (MYLAN): 60/$18.99 or 180/$51.97

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

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

References

1. Pharmacia & Upjohn Company. Ansaid (flurbiprofen) tablets prescribing information. Kalamazoo, MI; 2006 Mar.

2. Brogden RN, Heel RC, Speight TM et al. Flurbiprofen: a review of its pharmacological properties and therapeutic use in rheumatic diseases. Drugs. 1979; 18:417-38. (IDIS 106659)

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.

7. Marsh CC, Schuna AA, Sundstrom WR. A review of selected investigational nonsteroidal anti-inflammatory drugs of the 1980s. Pharmacotherapy. 1986; 6:10-25. (IDIS 394812)

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.

10. Atkinson MH, Buchanan WW, Fitzgerald AA et al. A comparison of flurbiprofen and naproxen in the treatment of rheumatoid arthritis: a Canadian multi-centre study. Curr Med Res Opin. 1990; 12:76-85.

11. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998; 45:525-38. (IDIS 409207)

12. Frenia ML, Long KS. Methotrexate and nonsteroidal anti-inflammatory drug interactions. Ann Pharmacother. 1992; 26:234-7. (IDIS 291616)

13. Davies NM. Clinical pharmacokinetics of flurbiprofen and its enantiomers. Clin Pharmacokinet. 1995; 28:100-14.

14. Kaiser DG, Brooks CD, Lomen PL. Pharmacokinetics of flurbiprofen. Am J Med. 1986; 24:(Suppl 3A)10-13.

15. Pharmacia, Kalamazoo, MI: Personal communication.

16. Food and Drug Administration. Analysis and recommendations for agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6.

17. Cush JJ. The safety of COX-2 inhibitors: deliberations from the February 16-18, 2005, FDA meeting. From the American College of Rheumatology website (http://www.rheumatology.org). Accessed 2005 Oct 12 .

18. Novartis Pharmaceuticals. Diovan (valsartan) capsules prescribing information. (dated 1997 Apr). In: Physicians’ desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:2013-5.

19. 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]

20. 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]

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

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

23. Chou R, Helfand M, Peterson K et al. Comparative effectiveness and safety of analgesics for osteoarthritis. Comparative effectiveness review no. 4. (Prepared by the Oregon evidence-based practice center under contract no. 290-02-0024.) . Rockville, MD: Agency for Healthcare Research and Quality. 2006 Sep. Available at: .

a. Lomen PL, Turner LF, Lamborn KR et al. Flurbiprofen in the treatment of ankylosing spondylitis. A comparison with phenylbutazone. Am J Med. 1986; 24:(Suppl 3A)120-6.

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. [PubMed 2715375]

d. Cox SR, Forbes KK. Excretion of flurbiprofen into breast milk. Pharmacotherapy. 1987; 7: 211-5. [PubMed 3444752]

e. Skeith KJ, Russell AS, Jamali F et al. Lack of significant interaction between low dose methotrexate and ibuprofen or flurbiprofen in patients with arthritis. J Rheumatol. 1990; 17: 1008-10. [PubMed 2213774]

f. US Food and Drug Administration. Proposed NSAID Package Insert Labeling Template 1. From the FDA website (). 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. [IDIS 426864] [PubMed 10369853]

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

j. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2000; 42:57-64. [PubMed 10887424]

k. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum. 2002;46:328-46.

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. [IDIS 417402] [PubMed 9820370]

m. AHFS Drug Information 2007. McEvoy GK, ed. Flurbiprofen sodium. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2058-9.

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