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Diflunisal (Monograph)

Drug class: Reversible COX-1/COX-2 Inhibitors

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Warning

    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.)

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

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

Hereditary Transthyretin-mediated Amyloidosis

Has been used in the treatment of polyneuropathy in patients with hereditary transthyretin-mediated amyloidosis† [off-label].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

General

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

Detailed Diflunisal dosage information

Cautions for Diflunisal

Contraindications

Warnings/Precautions

Warnings

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

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 fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs.1201 Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).1201 Symptoms may resemble those of acute viral infection.1201 Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.1201 If signs or symptoms of DRESS develop, discontinue diflunisal and immediately evaluate the patient.1201

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

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.1200 1201

Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.1202

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice.1200 1201 (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs.1200 1201 Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance.1200 1201 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1200 1201 In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.1200 1201 Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).1200 1201 Deaths associated with neonatal renal failure also reported.1200 Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1201 Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.1201

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.1201 In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.1201

Diflunisal was maternotoxic, embryotoxic, and teratogenic in animal studies.1201

Effects of diflunisal on labor and delivery not known.1201 In animal studies, NSAIAs increased incidence of dystocia, delayed parturition, and decreased pup survival.1201

Lactation

Distributed into milk; discontinue nursing or the drug.1

Fertility

NSAIAs may be associated with reversible infertility in some women.1203 Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.1203

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.1203

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

Drug Interactions

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 502 508

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

Pemetrexed

Possible increased risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity1203

Short half-life NSAIAs (e. g., diclofenac, indomethacin): Avoid administration beginning 2 days before and continuing through 2 days after pemetrexed administration1203

Longer half-life NSAIAs (e.g., meloxicam, nabumetone): In the absence of data, avoid administration beginning at least 5 days before and continuing through 2 days after pemetrexed administration1203

Patients with Clcr 45–79 mL/minute: Monitor for myelosuppression, renal toxicity, and GI toxicity1203

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 drug interactions (more detail)

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

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

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

Diflunisal

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

500 mg*

Diflunisal Tablets

AHFS DI Essentials™. © Copyright 2025, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

References

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