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Diflunisal

Pronunciation

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
Brands: Dolobid

Warning(s)

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

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

  • 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.)

Introduction

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

Slideshow: 12 Things You Should Know About Prednisone

Pain

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

Diflunisal Dosage and Administration

General

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

Administration

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

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 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

Adults

Pain
Oral

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
Oral

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

Prescribing Limits

Adults

Oral

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

Contraindications

  • 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

  • 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.94 Several prototypical NSAIAs also have been associated with increased risk of cardiovascular events.97 98 99 Current data insufficient to assess risk associated with diflunisal.97 98 99

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

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).94

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.1 94 (See Specific Drugs under Interactions.)

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

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

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

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

Pregnancy

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

Lactation

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

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to ACE inhibitor1

Possible deterioration of renal function in individuals with renal impairment1

Monitor BP1

Acetaminophen

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

Antacids

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

Aspirin

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

Manufacturers state that concomitant use not recommended1

Corticosteroids

Increased risk of GI ulceration69 73

Use concomitantly with caution69 73

Cyclosporine

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

Lithium

Increased plasma lithium concentrations1

Monitor for lithium toxicity1

Methotrexate

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

Use concomitantly with caution1

NSAIAs

Possible additive adverse GI effects1

Concomitant use not recommended1 75

Thrombolytic agents (streptokinase)

Possible increased risk of bleeding complications28

Use concomitantly with caution 28

Tolbutamide

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

Diflunisal Pharmacokinetics

Absorption

Bioavailability

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

Onset

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

Food

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

Distribution

Extent

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

Elimination

Metabolism

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

Half-life

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

Stability

Storage

Oral

Tablets, film-coated

<40°C; preferably 15–30°C.34

Actions

  • 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 with long-term use.1

  • 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 notifying clinician if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.1

  • 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

  • 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.)

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

Diflunisal

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

250 mg*

Dolobid

Merck

500 mg*

Diflunisal Tablets

Sandoz, Teva, Watson

Dolobid

Merck

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.

Diflunisal 500MG Tablets (TEVA PHARMACEUTICALS USA): 60/$81.99 or 180/$220.98

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

References

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