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Class: Other Nonsteroidal Anti-inflammatory Agents
Chemical Name: 2′,4′-Difluoro-4- hydroxy-[1,1′-biphenyl]-3-carboxylic acid
Molecular Formula: C13H8F2O3
CAS Number: 22494-42-4

Medically reviewed by Last updated on Mar 2, 2020.


    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.)


Prototypical NSAIA; a difluorophenyl derivative of salicylic acid.1 2 3

Uses for Diflunisal

Consider potential benefits and risks of diflunisal 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


Relief of mild to moderate pain.1 2

Symptomatic relief of postoperative,2 9 10 postpartum, and orthopedic pain (e.g., musculoskeletal sprains or strains) and visceral pain associated with cancer.2

Inflammatory Disease

Symptomatic treatment of rheumatoid arthritis1 17 18 32 36 and osteoarthritis.1 12

Hereditary Transthyretin-mediated Amyloidosis

Has been used in the treatment of polyneuropathy in patients with hereditary transthyretin-mediated amyloidosis.101 102 103 104

Binds to and stabilizes the disease-causing protein (transthyretin), reducing progression of neurologic impairment; however, safety of prolonged use (>2 years) not known.101 102 103 104 105

Diflunisal Dosage and Administration


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


Oral Administration

Administer orally.1 75 If GI disturbances occur, administer with meals or milk.1 75

Do not break, crush, or chew diflunisal tablets.1 75 Swallow intact.1 75


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

Exhibits concentration-dependent pharmacokinetics.1 75 Plasma diflunisal concentrations increase more than proportionally with increasing and/or multiple doses; use caution when adjusting doses.1 75



Mild to moderate pain: Initially, 1 g, followed by 500 mg every 12 hours.1 75 Some patients may require 500 mg every 8 hours.1 75

Patients with lower dosage requirements (less severe pain, heightened response, low body weight): Initially, 500 mg, followed by 250 mg every 8–12 hours.1

Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis

500 mg–1 g daily in 2 divided doses.1 75

Prescribing Limits



Maximum 1.5 g daily.1 75 b

Special Populations

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function.1

Initially, 500 mg, followed by 250 mg every 8–12 hours.1

Cautions for Diflunisal


  • Known hypersensitivity to diflunisal or any ingredient in the formulation.1

  • History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.1 48 49 50 51 52

  • In the setting of CABG surgery.508



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.97 98 99 100 500 501 502 503 506 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 94 502 508 (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 82 84 91

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;29 64 82 83 alternatively, consider concomitant use of a proton-pump inhibitor (e.g., lansoprazole, omeprazole) or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).29 64 82


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

Potential for overt renal decompensation.1 38 40 41 42 43 44 45 Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in patients with volume depletion, in geriatric patients, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.1 39 41 (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.1

Immediate medical intervention and discontinuance for anaphylaxis.1

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

Potentially life-threatening, apparent hypersensitivity syndrome reported;1 53 includes constitutional manifestations (e.g., fever, chills) and dermatologic effects (e.g., rash), and also may involve major organs (e.g., liver function abnormalities, jaundice, leukopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal impairment) and include less specific findings (e.g., adenitis, arthralgia, myalgia, arthritis, malaise, anorexia, disorientation).1 53 If hypersensitivity reaction occurs, discontinue therapy and institute appropriate therapy as indicated.1 53

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) 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

Elevations of serum ALT or AST reported.1

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 or if liver function test abnormalities persist or worsen.1

Hematologic Effects

Anemia reported rarely.1 Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia 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

May mask certain signs of infection.1

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

Specific Populations


Category C.1 Avoid use in third trimester because of possible premature closure of the ductus arteriosus.1 75


Distributed into milk; discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1

Use in children with varicella infections or influenza-type illnesses may be associated with an increased risk of developing Reye’s syndrome.1

Geriatric Use

Geriatric patients appear to tolerate GI ulceration and bleeding less well than other individuals.1 Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.1

Select dosage with caution because of age-related decreases in renal function.1 May be useful to monitor renal function.1

Renal Impairment

Use with caution in patients with renal impairment.1 Use not recommended in patients with severe renal impairment; close monitoring of renal function if used.1

Drug and its metabolites eliminated principally via the kidney.1

Common Adverse Effects

Nausea, vomiting, dyspepsia, GI pain, diarrhea, constipation, flatulence, somnolence, insomnia, dizziness, tinnitus, rash, headache, fatigue/tiredness.1

Interactions for Diflunisal

Protein-bound Drugs

Potential for diflunisal to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs.1 2 5 Observe for adverse effects if used with other protein-bound drugs.b

Specific Drugs




ACE inhibitors

Reduced BP response to ACE inhibitor1

Possible deterioration of renal function in individuals with renal impairment1

Monitor BP1


Increased plasma acetaminophen concentrations1

Possible increased GI toxicity1

Use concomitantly with caution; closely monitor hepatic function1

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonist1

Possible deterioration of renal function in individuals with renal impairment1

Monitor BP1


Possible decreased plasma diflunisal concentrations1

Anticoagulants (warfarin)

Possible bleeding complications and increases in PT1

Monitor PT during and for several days following concomitant therapy1

Adjust anticoagulant dosage as needed1


Possible decreased plasma diflunisal concentrations1 5

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 NSAIAs94 502 508

Manufacturers state that concomitant use not recommended1


Increased risk of GI ulceration69 73

Use concomitantly with caution69 73


Increased nephrotoxic effects of cyclosporine1

Caution advised; closely monitor renal function1

Diuretics (furosemide, thiazides)

Increased risk of developing renal failure1

Possible reduced natriuretic effects1

Increased plasma hydrochlorothiazide concentrations 1

Potential for decreased hyperuricemic effects of hydrochlorothiazide1

Monitor for diuretic efficacy and renal failure1


Increased plasma lithium concentrations1

Monitor for lithium toxicity1


Possible toxicity associated with increased plasma methotrexate concentrations56 57 58 59 60 61 62

Use concomitantly with caution1


Possible additive adverse GI effects1

Concomitant use not recommended1 75

Thrombolytic agents (streptokinase)

Possible increased risk of bleeding complications28

Use concomitantly with caution 28


Concomitant use does not appear to affect the hypoglycemic response or plasma tolbutamide concentrations1

Diflunisal Pharmacokinetics



Well absorbed following oral administration; peak plasma concentrations usually attained within 2–3 hours.1 2 5


Analgesic effect occurs within 1 hour; maximum analgesic effect occurs within 2–3 hours.1


Food slightly decreases the rate but not the extent of absorption.5



Distributed into CSF and crosses the placenta in small amounts in animals.1 Distributed into human milk.1

Plasma Protein Binding

Approximately 98–99%.1 2 5



Metabolized in the liver to glucuronide conjugates.1 2 8

Elimination Route

Excreted in urine (90%) mainly as glucuronide conjugates and in feces (<5%).1 2 5 8


8–12 hours.1 7

Special Populations

In patients with severe renal impairment (i.e., Clcr <2 mL/minute), terminal half-life is approximately 68–138 hours.7




Tablets, film-coated

<40°C; preferably 15–30°C.34


  • Inhibits cyclooxygenase-1 (COX-1) and COX-2.76 77 78 79 80 81

  • Pharmacologic actions similar to those of other prototypical NSAIAs;2 5 exhibits anti-inflammatory, analgesic, and antipyretic activity.1 2

Advice to Patients

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

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

  • Risk of GI bleeding and ulceration.1

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

  • Risk of hepatotoxicity.1

  • 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

  • Importance of discontinuing therapy 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

  • 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

  • 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 Importance of avoiding diflunisal 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.)


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



Dosage Forms


Brand Names



Tablets, film-coated

500 mg*

Diflunisal Tablets

AHFS DI Essentials™. © Copyright 2020, Selected Revisions March 2, 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.


1. Merck & Co. Dolobid (diflunisal) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.

2. Brogden RN, Heel RC, Pakes GE et al. Diflunisal: a review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis. Drugs. 1980; 19:84-106.

3. Hannah J, Ruyle WV, Jones H et al. Discovery of diflunisal. Br J Clin Pharmacol. 1977; 4(Suppl):7S-13S.

4. Stone CA, Van Arman CG, Lotti VJ et al. Pharmacology and toxicology of diflunisal. Br J Clin Pharmacol. 1977; 4(Suppl):19S-29S.

5. Davies RO. Review of the animal and clinical pharmacology of diflunisal. Pharmacotherapy. 1983; 3(Suppl):9S-22S.

6. Green D, Davies RO, Holmes GI et al. Effects of diflunisal on platelet function and fecal blood loss. Pharmacotherapy. 1983; 3(Suppl):65S-9S.

7. Verbeeck R, Tjandramaga TB, Mullie A et al. Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency. Br J Clin Pharmacol. 1979; 7:273-82.

8. Tempero KF, Cirillo VJ, Steelman SL. Diflunisal: a review of pharmacokinetic and pharmacodynamic properties, drug interactions, and special tolerability studies in humans. Br J Clin Pharmacol. 1977; 4(Suppl):31S-6S.

9. Forbes JA, Calderazzo JP, Bowser MW et al. A 12-hour evaluation of the analgesic efficacy of diflunisal, aspirin, and placebo in postoperative dental pain. J Clin Pharmacol. 1982; 22:89-96.

10. Van Winzum C, Rodda B. Diflunisal: efficacy in post-operative pain. Br J Clin Pharmacol. 1977; 4(Suppl):39S-43S.

11. Forbes JA, Beaver WT, White EH et al. Diflunisal: a new oral analgesic with an unusually long duration of action. JAMA. 1982; 248:2139-42.

12. Umbenhauer ER. Diflunisal in the treatment of the pain of osteoarthritis. Pharmacotherapy. 1983; 3(Suppl):55S-60S.

13. Rider JA. Comparison of fecal blood loss after use of aspirin and diflunisal. Pharmacotherapy. 1983; 3(Suppl):61S-4S.

14. Dieppe PA, Doyle DV, Burry HC. Renal damage during treatment with antirheumatic drugs. Br Med J. 1978; 2:664.

15. Upadhyay HP, Gupta SK. Diflunisal (Dolobid) overdose. Br Med J. 1978; 2:640.

16. Flower RJ, Moncada S, Vane JR. Drug therapy of inflammation: analgesic-antipyretics and anti-inflammatory agents; drugs employed in the treatment of gout. In: Gilman AG, Goodman L, Gilman A, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 6th ed. New York: Macmillan Publishing Company; 1980:682-93.

17. DeSilva M, Hazleman BL, Dippy JE. Diflunisal and aspirin: a comparative study in rheumatoid arthritis. Rheumatol Rehabil. 1980; 19:126-30.

18. Palmer DG, Ferry DG, Gibbins BL et al. Ibuprofen and diflunisal in rheumatoid arthritis: a double-blind comparative trial. N Z Med J. 1981; 94:45-7.

19. The United States pharmacopeia, 25th rev, and The national formulary, 20th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 2002: 567.

20. Simon LS, Mills JA. Nonsteroidal anti-inflammatory drugs. N Engl J Med. 1980; 302:1179-85.

21. Ferreira SH, Lorenzetti BB, Correa FMA. Central and peripheral antianalgesic action of aspirin-like drugs. Eur J Pharmacol. 1978; 53:39-48.

22. Atkinson DC, Collier HOJ. Salicylates: molecular mechanism of therapeutic action. Adv Pharmacol Chemother. 1980; 17:233-88.

23. Bernheim HA, Block LH, Atkins E. Fever: pathogenesis, pathophysiology, and purpose. Ann Intern Med. 1979; 91:261-70.

24. Dresse A, Fischer P, Gerard MA et al. Uricosuric properties of diflunisal in man. Br J Clin Pharmacol. 1979; 7:267-72.

25. Miller TA, Jacobson ED. Gastrointestinal cytoprotection by prostaglandins. Gut. 1979; 20:875-87.

26. Robert A. Cytoprotection by prostaglandins. Gastroenterology. 1979; 77:761-7.

27. Willkens RF. The use of nonsteroidal anti-inflammatory agents. JAMA. 1978; 240:1632-5.

28. Hoechst-Roussel. Streptase prescribing information. Somerville, NJ; 1980 Aug.

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

30. Hart FD. Rheumatic disorders. In: Avery GS, ed. Drug treatment: principles and practice of clinical pharmacology and therapeutics. 2nd ed. New York: ADIS Press; 1980:861-2.

31. De Vroey P. A double-blind comparison of diflunisal and aspirin in the treatment of post-operative pain after episiotomy. Curr Med Res Opin. 1978; 5:544-7.

32. Merck, Sharp & Dohme. Dolobid (diflunisal)—an anti-inflammatory analgesic. West Point, PA. 1983 Aug.

33. Dal Pino E (Merck, Sharp & Dohme, West Point, PA): Personal communication; 1984 Feb 24.

34. USP DI. Vol. 1: 1984 Drug information for the health care provider. Rockville, MD: The United States Pharmacopeial Convention, Inc; 2002: 430-1.

35. Gosselin RE, Hodge HC, Smith RP et al. Clinical toxicology of commercial products: acute poisoning. 5th ed. Baltimore: The Williams & Wilkins Co; 1984:I-10.

36. Turner RA, Whipple JP, Shackleford RW. Diflunisal 500–700 mg versus aspirin 2600–3900 mg in the treatment of rheumatoid arthritis. Pharmacotherapy. 1984; 4:151-7.

38. Wolf RE. Nonsteroidal anti-inflammatory drugs. Arch Intern Med. 1984; 144:1658-60.

39. Robinson DR. Prostaglandins and the mechanism of action of anti-inflammatory drugs. Am J Med. 1983; 10:26-31.

40. O’Brien WM. Pharmacology of nonsteroidal anti-inflammatory drugs: practical review for clinicians. Am J Med. 1983; 10:32-9.

41. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med. 1984; 310:563-72.

42. Adams DH, Michael J, Bacon PA et al. Non-steroidal anti-inflammatory drugs and renal failure. Lancet. 1986; 1:57-9.

43. Henrich WL. Nephrotoxicity of nonsteroidal anti-inflammatory agents. Am J Kidney Dis. 1983; 2:478-84.

44. Kimberly RP, Bowden RE, Keiser HR et al. Reduction of renal function by newer nonsteroidal anti-inflammatory drugs. Am J Med. 1978; 64:804-7.

45. Corwin HL, Bonventre JV. Renal insufficiency associated with nonsteroidal anti-inflammatory agents. Am J Kidney Dis. 1984; 4:147-52.

46. Settipane GA. Adverse reactions to aspirin and other drugs. Arch Intern Med. 1981; 141:328-32.

47. Weinberger M. Analgesic sensitivity in children with asthma. Pediatrics. 1978; 62(Suppl):910-5.

48. Settipane GA. Aspirin and allergic diseases: a review. Am J Med. 1983; 74(Suppl):102-9.

49. VanArsdel PP Jr. Aspirin idiosyncracy and tolerance. J Allergy Clin Immunol. 1984; 73:431-3.

50. Stevenson DD. Diagnosis, prevention, and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol. 1984; 74(4 Part 2):617-22.

51. Stevenson DD, Mathison DA. Aspirin sensitivity in asthmatics: when may this drug be safe? Postgrad Med. 1985; 78:111-3,116-9. (IDIS 205854)

52. Pleskow WW, Stevenson DD, Mathison DA et al. Aspirin desensitization in aspirin-sensitive asthmatic patients: clinical manifestations and characterization of the refractory period. J Allergy Clin Immunol. 1982; 69(1 Part 1):11-9.

53. Cook DJ, Achong MR, Murphy FR. Three cases of diflunisal hypersensitivity. CMAJ. 1988; 138:1029-30.

54. Food and Drug Administration. Labeling revisions for NSAIDs. FDA Drug Bull. 1989; 19:3-4.

55. Palmer JF. Letter sent to Berger ET of Merck Sharp & Dohme regarding labeling revisions about gastrointestinal adverse reactions to Dolobid (diflunisal). Rockville, MD: Food and Drug Administration, Division of Oncology and Radiopharmaceutical Drug Products; 1988 Sep.

56. Thyss A, Milano G, Kubar J et al. Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet. 1986; 1:256-8.

57. Ellison NM, Servi RJ. Acute renal failure and death following sequential intermediate-dose methotrexate and 5-FU: a possible adverse effect due to concomitant indomethacin administration. Cancer Treat Rep. 1985; 69:342-3.

58. Singh RR, Malaviya AN, Pandey JN et al. Fatal interaction between methotrexate and naproxen. Lancet. 1986; 1:1390.

59. Day RO, Graham GG, Champion GD et al. Anti-rheumatic drug interactions. Clin Rheum Dis. 1984; 10:251-75.

60. Daly HM, Scott GL, Boyle J et al. Methotrexate toxicity precipitated by azapropazone. Br J Dermatol. 1986; 114:733-5.

61. Hansten PD, Horn JR. Methotrexate interactions: ketoprofen (Orudis). Drug Interact Newsl. 1986; 6(Updates):U5-6.

62. Maiche AG. Acute renal failure due to concomitant action of methotrexate and indomethacin. Lancet. 1986; 1:1390.

63. Searle. Cytotec (misoprostol) prescribing information. Skokie, IL; 1989 Jan.

64. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2000; 42:57-64.

65. Soll AH, Weinstein WM, Kurata J et al. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med. 1991; 114:307-19.

67. Ciba Geigy, Ardsley, NY: Personal communication on diclofenac 28:08.04.

68. Reviewers’ comments (personal observation) on diclofenac 28:08.04.

69. Corticosteroid interactions: nonsteroidal anti-inflammatory drugs (NSAIDs). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:562.

70. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994; 343:769-72.

71. Hollander D. Gastrointestinal complications of nonsteroidal anti-inflammatory drugs: prophylactic and therapeutic strategies. Am J Med. 1994; 96:274-81.

72. Schubert TT, Bologna SD, Yawer N et al. Ulcer risk factors: interaction between Helicobacter pylori infection, nonsteroidal use, and age. Am J Med. 1993; 94:413-7.

73. Piper JM, Ray WA, Daugherty JR et al. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1991; 114:735-40.

74. Bateman DN, Kennedy JG. Non-steroidal anti-inflammatory drugs and elderly patients: the medicine may be worse than the disease. BMJ. 1995; 310:817-8.

75. West Point Pharma. Diflunisal tablets, USP, prescribing information. West Point, PA; 1995 Oct.

76. Hawkey CJ. COX-2 inhibitors. Lancet. 1999; 353:307-14.

77. Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996; 384:644-8.

78. Riendeau D, Charleson S, Cromlish W et al. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Phsiol Pharmacol. 1997; 75:1088-95.

79. DeWitt DL, Bhattacharyya D, Lecomte M et al. The differential susceptibility of prostaglandin endoperoxide H synthases-1 and -2 to nonsteroidal anti-inflammatory drugs: aspirin derivatives as selective inhibitors. Med Chem Res. 1995; 5:325-43.

80. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenase— a review. Prostaglandins Other Lipid Mediators. 1998; 56:341-61.

81. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med. 1999; 106(Suppl 5B):37-42S.

82. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999; 340:1888-99.

83. 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.

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

85. in’t Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med. 2001; 345:1515-21.

86. Breitner JCS, Zandi PP. Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer’s disease? N Engl J Med. 2001; 345:1567-8. Editorial.

87. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology. 1996; 47:425-32.

88. Beard CM, Waring SC, O’sBrien PC et al. Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease : a case-control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin Proc. 1998; 73:951-5.

89. in’t Veld BA, Launer LJ, Hoes AW et al. NSAIDs and incident Alzheimer’s disease: the Rotterdam Study. Neurobiol Aging. 1998; 19:607-11.

90. Stewart WF, Kawas C, Corrada M et al. Risk of Alzheimer’s disease and duration of NSAID use. Neurology. 1997; 48:626-32.

91. Pharmacia. Daypro (oxaprozin) caplets prescribing information. Chicago, IL; 2002 May.

92. Chan FKL, Hung LCT, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002; 347:2104-10.

93. Graham DY. NSAIDs, Helicobacter pylori, and Pandora’s box. N Engl J Med. 2002; 347:2162-4.

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

95. Cush JJ. The safety of COX-2 inhibitors: deliberations from the February 16-18, 2005, FDA meeting. From the American College of Rheumatology website ( Accessed 2005 Oct 12.

96. 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.

97. 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.

98. 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.

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

100. 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:

101. Ando Y, Coelho T, Berk JL et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013; 8:31.

102. Berk JL, Suhr OB, Obici L et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013; 310:2658-67.

103. Sekijima Y, Tojo K, Morita H et al. Safety and efficacy of long-term diflunisal administration in hereditary transthyretin (ATTR) amyloidosis. Amyloid. 2015; 22:79-83.

104. Hawkins PN, Ando Y, Dispenzeri A et al. Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015; 47:625-38.

105. Sekijima Y, Dendle MA, Kelly JW. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid. 2006; 13:236-49.

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.

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.

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

503. Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011; 342:c7086.

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.

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.

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.

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.

508. Rising Pharmaceuticals, Inc. Diflunisal tablets prescribing information. Allendale, NJ; 2016 May.

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

b. AHFS drug information 2006. McEvoy GK, ed. Diflunisal. Bethesda, MD: American Society of Health-System Pharmacists; 2006:2022-2026.

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.

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.