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Diflunisal

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 Drugs.com on Nov 9, 2020. Written by ASHP.

Warning

Special Alerts:

[Posted 10/15/2020]

AUDIENCE: Consumer, Patient, Health Professional, Pharmacy

ISSUE: FDA is warning that use of NSAIDs around 20 weeks or later in pregnancy may cause rare but serious kidney problems in an unborn baby. This can lead to low levels of amniotic fluid surrounding the baby and possible complications.

For prescription NSAIDs, FDA is requiring changes to the prescribing information to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.

For over-the-counter (OTC) NSAIDs intended for use in adults, FDA will also update the Drug Facts labels, available at: [Web]. These labels already warn to avoid using NSAIDs during the last 3 months of pregnancy because the medicines may cause problems in the unborn child or complications during delivery. The Drug Facts labels already advise pregnant and breastfeeding women to ask a health care professional before using these medicines.

BACKGROUND:

NSAIDs

  • are a class of medicines available by prescription and OTC. They are some of the most commonly used medicines for pain and fever.

  • are used to treat medical conditions such as arthritis, menstrual cramps, headaches, colds, and the flu.

  • work by blocking the production of certain chemicals in the body that cause inflammation.

  • are available alone and combined with other medicines. Examples of NSAIDs include aspirin, ibuprofen, naproxen, diclofenac, and celecoxib.

Common side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

RECOMMENDATION:

Consumers/Patients

  • If you are pregnant, do not use NSAIDs at 20 weeks or later in pregnancy unless specifically advised to do so by your health care professional because these medicines may cause problems in your unborn baby.

  • Many OTC medicines contain NSAIDs, including those used for pain, colds, flu, and insomnia, so it is important to read the Drug Facts labels, available at: [Web], to find out if the medicines contain NSAIDs.

  • Talk to your health care professional or pharmacist if you have questions or concerns about NSAIDs or which medicines contain them.

  • Other medicines, such as acetaminophen, are available to treat pain and fever during pregnancy. Talk to your pharmacist or health care professional for help deciding which might be best.

Health Care Professionals

  • FDA recommends that health care professionals should limit prescribing NSAIDs between 20 to 30 weeks of pregnancy and avoid prescribing them after 30 weeks of pregnancy. If NSAID treatment is determined necessary, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours and discontinue the NSAID if oligohydramnios is found. FDA is warning that use of NSAIDs around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.

  • These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

  • Oligohydramnios is often, but not always, reversible with treatment discontinuation.

  • Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

  • If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. As currently described in the NSAID labels, avoid prescribing NSAIDs at 30 weeks and later in pregnancy because of the additional risk of premature closure of the fetal ductus arteriosus.

  • The above recommendations do not apply to low-dose 81 mg aspirin prescribed for certain conditions in pregnancy.

  • Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice.

For more information visit the FDA website at: [Web] and [Web].

Warning

    Cardiovascular Risk
  • Increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke). Risk may occur early in treatment and may increase with duration of use. (See Cardiovascular Thrombotic Effects under Cautions.)

  • Contraindicated in the setting of CABG surgery.

    GI Risk
  • Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine). Serious GI events can occur at any time and may not be preceded by warning signs and symptoms. Geriatric individuals are at greater risk for serious GI events. (See GI Effects under Cautions.)

Introduction

Prototypical NSAIA; a difluorophenyl derivative of salicylic acid.

Uses for Diflunisal

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Consider potential benefits and risks of diflunisal therapy as well as alternative therapies before initiating therapy with the drug. Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.

Pain

Relief of mild to moderate pain.

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

Inflammatory Disease

Symptomatic treatment of rheumatoid arthritis and osteoarthritis.

Hereditary Transthyretin-mediated Amyloidosis

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

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

Diflunisal Dosage and Administration

General

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

Administration

Oral Administration

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

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

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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. Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.

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

Adults

Pain
Oral

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

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

Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis
Oral

500 mg–1 g daily in 2 divided doses.

Prescribing Limits

Adults

Oral

Maximum 1.5 g daily.

Special Populations

Geriatric Patients

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

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

Cautions for Diflunisal

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

  • History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.

  • In the setting of CABG surgery.

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.

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.

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.

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.

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.

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI; 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.

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. FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.

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.

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease. 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. Contraindicated in the setting of CABG surgery.

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs. (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.

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol; 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).

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events. Use with caution in patients with hypertension; monitor BP.

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur. (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema. (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.

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.

Potential for overt renal decompensation. 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. (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.

Immediate medical intervention and discontinuance for anaphylaxis.

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

Potentially life-threatening, apparent hypersensitivity syndrome reported; 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). If hypersensitivity reaction occurs, discontinue therapy and institute appropriate therapy as indicated.

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur without warning. Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.

Elevations of serum ALT or AST reported.

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results. 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.

Hematologic Effects

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

May inhibit platelet aggregation and prolong bleeding time.

Ocular Effects

Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.

May mask certain signs of infection.

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

Specific Populations

Pregnancy

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

Lactation

Distributed into milk; discontinue nursing or the drug.

Pediatric Use

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

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

Geriatric Use

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

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

Renal Impairment

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

Drug and its metabolites eliminated principally via the kidney.

Common Adverse Effects

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

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. Observe for adverse effects if used with other protein-bound drugs.

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to ACE inhibitor

Possible deterioration of renal function in individuals with renal impairment

Monitor BP

Acetaminophen

Increased plasma acetaminophen concentrations

Possible increased GI toxicity

Use concomitantly with caution; closely monitor hepatic function

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonist

Possible deterioration of renal function in individuals with renal impairment

Monitor BP

Antacids

Possible decreased plasma diflunisal concentrations

Anticoagulants (warfarin)

Possible bleeding complications and increases in PT

Monitor PT during and for several days following concomitant therapy

Adjust anticoagulant dosage as needed

Aspirin

Possible decreased plasma diflunisal concentrations

Increased risk of GI ulceration and other complications

No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs

Manufacturers state that concomitant use not recommended

Corticosteroids

Increased risk of GI ulceration

Use concomitantly with caution

Cyclosporine

Increased nephrotoxic effects of cyclosporine

Caution advised; closely monitor renal function

Diuretics (furosemide, thiazides)

Increased risk of developing renal failure

Possible reduced natriuretic effects

Increased plasma hydrochlorothiazide concentrations

Potential for decreased hyperuricemic effects of hydrochlorothiazide

Monitor for diuretic efficacy and renal failure

Lithium

Increased plasma lithium concentrations

Monitor for lithium toxicity

Methotrexate

Possible toxicity associated with increased plasma methotrexate concentrations

Use concomitantly with caution

NSAIAs

Possible additive adverse GI effects

Concomitant use not recommended

Thrombolytic agents (streptokinase)

Possible increased risk of bleeding complications

Use concomitantly with caution

Tolbutamide

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

Diflunisal Pharmacokinetics

Absorption

Bioavailability

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

Onset

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

Food

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

Distribution

Extent

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

Plasma Protein Binding

Approximately 98–99%.

Elimination

Metabolism

Metabolized in the liver to glucuronide conjugates.

Elimination Route

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

Half-life

8–12 hours.

Special Populations

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

Stability

Storage

Oral

Tablets, film-coated

<40°C; preferably 15–30°C.

Actions

  • Inhibits cyclooxygenase-1 (COX-1) and COX-2.

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

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

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

  • Risk of GI bleeding and ulceration.

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

  • Risk of hepatotoxicity.

  • Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.

  • Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.

  • Importance of discontinuing therapy and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop. Importance of seeking immediate medical attention if an anaphylactic reaction occurs.

  • 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.

  • Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of avoiding diflunisal in late pregnancy (third trimester).

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

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 2021, Selected Revisions November 9, 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.

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