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 2017, Selected Revisions February 7, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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