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
- 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
Symptomatic treatment of rheumatoid arthritis1 17 18 32 36 and osteoarthritis.1 12
Diflunisal Dosage and Administration
Consider potential benefits and risks of diflunisal therapy as well as alternative therapies before initiating therapy with the drug.1
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
Osteoarthritis or Rheumatoid ArthritisOral
500 mg–1 g daily in 2 divided doses.1 75
Maximum 1.5 g daily.1 75 b
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.)
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
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.)
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
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
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
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
Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.1
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
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
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 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
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
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
Reduced BP response to ACE inhibitor1
Possible deterioration of renal function in individuals with renal impairment1
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
Possible decreased plasma diflunisal concentrations1
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
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
Excreted in urine (90%) mainly as glucuronide conjugates and in feces (<5%).1 2 5 8
8–12 hours.1 7
In patients with severe renal impairment (i.e., Clcr<2 mL/minute), terminal half-life is approximately 68–138 hours.7
<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
AHFS DI Essentials. © Copyright 2018, Selected Revisions February 7, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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. [PubMed 6988202]
3. Hannah J, Ruyle WV, Jones H et al. Discovery of diflunisal. Br J Clin Pharmacol. 1977; 4(Suppl):7S-13S. [PubMed 328036]
4. Stone CA, Van Arman CG, Lotti VJ et al. Pharmacology and toxicology of diflunisal. Br J Clin Pharmacol. 1977; 4(Suppl):19S-29S. [PubMed 301744]
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. [PubMed 427004]
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. [PubMed 328032]
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. [PubMed 7068938]
10. Van Winzum C, Rodda B. Diflunisal: efficacy in post-operative pain. Br J Clin Pharmacol. 1977; 4(Suppl):39S-43S. [PubMed 328033]
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. [PubMed 6750171]
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. [PubMed 308826]
15. Upadhyay HP, Gupta SK. Diflunisal (Dolobid) overdose. Br Med J. 1978; 2:640. [PubMed 698637]
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. [PubMed 6996072]
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. [PubMed 7024866]
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. [PubMed 6988717]
21. Ferreira SH, Lorenzetti BB, Correa FMA. Central and peripheral antianalgesic action of aspirin-like drugs. Eur J Pharmacol. 1978; 53:39-48. [PubMed 310771]
22. Atkinson DC, Collier HOJ. Salicylates: molecular mechanism of therapeutic action. Adv Pharmacol Chemother. 1980; 17:233-88. [PubMed 7004141]
23. Bernheim HA, Block LH, Atkins E. Fever: pathogenesis, pathophysiology, and purpose. Ann Intern Med. 1979; 91:261-70. [PubMed 223485]
24. Dresse A, Fischer P, Gerard MA et al. Uricosuric properties of diflunisal in man. Br J Clin Pharmacol. 1979; 7:267-72. [PubMed 427003]
25. Miller TA, Jacobson ED. Gastrointestinal cytoprotection by prostaglandins. Gut. 1979; 20:875-87. [PubMed 391656]
26. Robert A. Cytoprotection by prostaglandins. Gastroenterology. 1979; 77:761-7. [PubMed 38173]
27. Willkens RF. The use of nonsteroidal anti-inflammatory agents. JAMA. 1978; 240:1632-5. [PubMed 691156]
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. [PubMed 11840435]
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. [PubMed 359247]
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. [PubMed 6377249]
38. Wolf RE. Nonsteroidal anti-inflammatory drugs. Arch Intern Med. 1984; 144:1658-60. [PubMed 6235791]
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. [PubMed 6363936]
42. Adams DH, Michael J, Bacon PA et al. Non-steroidal anti-inflammatory drugs and renal failure. Lancet. 1986; 1:57-9. [PubMed 2867313]
43. Henrich WL. Nephrotoxicity of nonsteroidal anti-inflammatory agents. Am J Kidney Dis. 1983; 2:478-84. [PubMed 6823966]
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. [PubMed 645744]
45. Corwin HL, Bonventre JV. Renal insufficiency associated with nonsteroidal anti-inflammatory agents. Am J Kidney Dis. 1984; 4:147-52. [PubMed 6475945]
46. Settipane GA. Adverse reactions to aspirin and other drugs. Arch Intern Med. 1981; 141:328-32. [PubMed 7008734]
47. Weinberger M. Analgesic sensitivity in children with asthma. Pediatrics. 1978; 62(Suppl):910-5. [PubMed 103067]
48. Settipane GA. Aspirin and allergic diseases: a review. Am J Med. 1983; 74(Suppl):102-9. [PubMed 6344621]
49. VanArsdel PP Jr. Aspirin idiosyncracy and tolerance. J Allergy Clin Immunol. 1984; 73:431-3. [PubMed 6423718]
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. [PubMed 6436354]
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. [PubMed 7054250]
53. Cook DJ, Achong MR, Murphy FR. Three cases of diflunisal hypersensitivity. CMAJ. 1988; 138:1029-30. [PubMed 2967101]
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. [PubMed 2868265]
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. [PubMed 3978662]
58. Singh RR, Malaviya AN, Pandey JN et al. Fatal interaction between methotrexate and naproxen. Lancet. 1986; 1:1390. [PubMed 2872507]
59. Day RO, Graham GG, Champion GD et al. Anti-rheumatic drug interactions. Clin Rheum Dis. 1984; 10:251-75. [PubMed 6150784]
60. Daly HM, Scott GL, Boyle J et al. Methotrexate toxicity precipitated by azapropazone. Br J Dermatol. 1986; 114:733-5. [PubMed 3718865]
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. [PubMed 2872506]
63. Searle. Cytotec (misoprostol) prescribing information. Skokie, IL; 1989 Jan.
64. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2000; 42:57-64. [PubMed 10887424]
65. Soll AH, Weinstein WM, Kurata J et al. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med. 1991; 114:307-19. [PubMed 1987878]
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. [PubMed 7907735]
71. Hollander D. Gastrointestinal complications of nonsteroidal anti-inflammatory drugs: prophylactic and therapeutic strategies. Am J Med. 1994; 96:274-81. [PubMed 8154516]
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. [PubMed 8475935]
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. [PubMed 2012355]
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. [PubMed 7711609]
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. [PubMed 9929039]
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. [PubMed 8967954]
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. [PubMed 9990677]
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. [PubMed 10369853]
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. [PubMed 9820370]
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. [PubMed 11794217]
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. [PubMed 8757015]
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. [PubMed 9787743]
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. [PubMed 10192221]
90. Stewart WF, Kawas C, Corrada M et al. Risk of Alzheimer’s disease and duration of NSAID use. Neurology. 1997; 48:626-32. [PubMed 9065537]
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. [PubMed 12501222]
93. Graham DY. NSAIDs, Helicobacter pylori, and Pandora’s box. N Engl J Med. 2002; 347:2162-4. [PubMed 12501230]
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. [PubMed 16968831]
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. [PubMed 16740558]
99. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk; the seduction of common sense. JAMA. 2006; 296:1653-6. [PubMed 16968830]
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: .
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. [PubMed 23726390]
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. [PubMed 21224324]
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. [PubMed 19171810]
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. [PubMed 21555710]
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. [PubMed 21980265]
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. [PubMed 23747642]
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. [PubMed 22965337]
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. [PubMed 21596367]
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