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diflunisal 500 mg tablet

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Uses

Diflunisal is used for the acute or long-term relief of mild to moderate pain. Diflunisal is also used for anti-inflammatory and analgesic effects in the symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis. Diflunisal is not recommended for use as an antipyretic agent.

The potential benefits and risks of diflunisal therapy as well as alternative therapies should be considered prior to initiating diflunisal therapy. The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.

Pain

Diflunisal is used for symptomatic relief of postoperative (including that associated with dental surgery), postpartum, and orthopedic (including musculoskeletal sprains or strains) pain and visceral pain associated with cancer. When used to relieve mild to moderate acute pain, a single 500-mg dose of diflunisal has been reported to be as effective as a single 650-mg dose of aspirin, a 600- or 650-mg dose of acetaminophen, or a 650-mg dose of acetaminophen with 100 mg of propoxyphene napsylate. A single 1-g dose of diflunisal has been reported to be as effective as a single 600-mg dose of acetaminophen with 60 mg of codeine. Diflunisal dosages of 500 mg twice daily have been reported to be as effective as 50 mg of oral pentazocine 4 times daily or as 200 mg of oxyphenbutazone 3 times daily. When used to relieve oral surgery pain, 250-mg, 500-mg, or 1-g doses of diflunisal appear to be more effective than 650-mg doses of aspirin. In the treatment of episiotomy pain in one study, the analgesic effect of 500-mg doses of diflunisal has been reported to be greater than that of 600-mg doses of aspirin. Diflunisal has a longer duration of analgesic activity than many other similar analgesics (e.g., aspirin); however, the onset of diflunisal's analgesic activity may be delayed. In several studies, 500-mg and 1-g doses of diflunisal have produced symptomatic relief for up to 12 hours in most patients with postoperative pain. Initiating therapy with a 1-g loading dose of diflunisal results in an initial analgesic effect that has a more rapid onset, a shorter time to peak, and a greater intensity at peak than that associated with an initial 500-mg dose.

Inflammatory Disease

Rheumatoid Arthritis and Osteoarthritis

When used in the symptomatic treatment of rheumatoid arthritis, diflunisal has relieved pain and stiffness, reduced joint tenderness, and improved mobility and grip strength. In the symptomatic treatment of osteoarthritis, diflunisal has relieved pain and stiffness and has increased range of motion and functional activity. Diflunisal appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process. Most clinical studies have shown that the anti-inflammatory and analgesic effects of usual dosages of diflunisal in the management of rheumatoid arthritis or osteoarthritis are about equal to those of usual dosages of salicylates, ibuprofen, or naproxen. In controlled clinical studies of 8-12 weeks' duration in patients with rheumatoid arthritis or osteoarthritis, 500 mg to 1 g of diflunisal daily was as effective as 2-4 g of aspirin daily.

Patient response to oral NSAIAs is variable; patients who do not respond to or cannot tolerate one NSAIA might be successfully treated with a different agent. However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs.(See Cautions: Precautions and Contraindications.)

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction. Disease modifying antirheumatic drugs (DMARDs) (e.g., azathioprine, cyclosporine, etanercept, oral or injectable gold compounds, hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, penicillamine, sulfasalazine) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy. DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs. NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued. For further information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.)

The addition of diflunisal to a regimen of gold compounds has resulted in increased symptomatic relief in some patients with rheumatoid arthritis but has not reversed the underlying disease process. Diflunisal and gold compounds may be used concomitantly at their usual dosage levels.

Other Uses

Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease among patients who received an NSAIA for 2 years or longer. Similar findings have been reported from some other, but not all, observational studies.

Dosage and Administration

Administration

The potential benefits and risks of diflunisal therapy as well as alternative therapies should be considered prior to initiating diflunisal therapy.

Diflunisal is administered orally and may be given with water, milk, or food. Diflunisal tablets should be swallowed intact and should not be crushed or chewed.

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed. Dosage of diflunisal must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.

When adjusting diflunisal dosage, it should be remembered that the drug exhibits concentration-dependent pharmacokinetics, and plasma diflunisal concentrations increase more than proportionally with increasing and/or multiple doses. Maintenance dosages of diflunisal should not exceed 1.5 g daily.

Pain

For the relief of mild to moderate pain in adults, diflunisal therapy usually is initiated with a loading dose of 1 g followed by a maintenance dosage of 500 mg every 12 hours; some patients may require a maintenance dosage of 500 mg every 8 hours. Patients with lower dosage requirements (e.g., those with less severe pain, heightened response, low body weight, or advanced age) may receive an initial 500-mg loading dose followed by a maintenance dosage of 250 mg every 8-12 hours. If an initial loading dose is not used, patients receiving diflunisal should be observed and their response to therapy evaluated for 2-3 days following initiation of therapy.

Rheumatoid Arthritis and Osteoarthritis

For the symptomatic treatment of acute or chronic rheumatoid arthritis or osteoarthritis in adults, a diflunisal dosage of 500 mg to 1 g daily, given in 2 divided doses, has been suggested. Dosage of diflunisal should be adjusted according to the patient's response and tolerance.

Cautions

Adverse reactions to diflunisal are usually mild and mainly involve the GI tract.

Cardiovascular Effects

Peripheral edema, palpitations, and chest pain have been reported in patients receiving diflunisal.

Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease. Use of NSAIAs also is associated with an increased risk of heart failure.

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study. Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied. Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use. Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, 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.

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment. Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years). Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased. Therefore, NSAIAs are contraindicated in the setting of CABG surgery.

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs. However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another. Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time. (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality. Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure. In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure. Fluid retention and edema also have been observed in some patients receiving NSAIAs.

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of cardiovascular effects associated with NSAIAs.

GI Effects

Peptic ulceration and GI bleeding have occurred in patients receiving diflunisal and rarely have been fatal. GI bleeding is associated with increased morbidity and mortality in patients acutely ill with other conditions, geriatric patients, and patients with hemorrhagic disorders.

Adverse GI effects of diflunisal occurring in 3-9% of patients include nausea, dyspepsia, GI pain, and diarrhea. Vomiting, constipation, stomatitis, and flatulence occur less frequently. GI perforation, gastritis, anorexia, and eructation have also been reported. In general, usual dosages of diflunisal reportedly produce fewer adverse GI effects than usual anti-inflammatory dosages of aspirin. In one study in healthy adults, GI bleeding as determined by fecal blood loss was less in patients receiving 2 g of diflunisal daily (higher than recommended dosage) than in those receiving 2.6 g of aspirin daily. In one study in patients with osteoarthritis receiving prolonged therapy with aspirin or diflunisal, endoscopic examination revealed a lower frequency of gastric erosion in diflunisal-treated patients.

Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms. Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic. Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up. In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur. If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects. In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year. Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event. However, short-term therapy is not without risk. High dosages of any NSAIA probably are associated with increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs. Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors. In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status. Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis. In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy. Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy. In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest. In addition, efficacy of usual dosages of H2-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established. Therefore, most clinicians do not recommend use of H2-receptor antagonists for the prevention of NSAIA-associated ulcers. Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs. However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori-negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk. Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.

Nervous System Effects

Headache occurs in 3-9% of patients receiving diflunisal. Other adverse nervous system effects including somnolence or insomnia, fatigue, tiredness, dizziness, vertigo, nervousness, and asthenia occur less frequently. Mental depression, paresthesia, and malaise have also been reported, but a causal relationship to diflunisal has not been established.

Renal Effects

Dysuria, interstitial nephritis, and renal impairment (including renal failure) have been reported in patients receiving diflunisal. Nephrotic syndrome also has been reported but not directly attributed to the drug.

Long-term administration of NSAIAs has resulted in renal papillary necrosis and other renal injury. Administration of high dosages of diflunisal in rats and dogs occasionally has caused renal papillary edema. Papillary necrosis has occurred following prolonged administration of the drug in mice. In one study in humans, urinary excretion of N-acetyl-glucosaminidase (NAG) increased in patients receiving aspirin or diflunisal dosages of 2-3 g or 500-750 mg daily, respectively; however, the effect was greater in aspirin-treated individuals. Increases in urinary protein or serum creatinine concentration were not observed in these patients. Further study is needed to determine the extent of renal toxicity of diflunisal in humans.

Hepatic Effects

Severe hepatic reactions, including cholestasis and/or jaundice, have occurred during diflunisal therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIAs.

Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with NSAIAs; meaningful (3 times the upper limit of normal) elevations of serum ALT (SGPT) or AST (SGOT) concentration have occurred in less than 1% of patients receiving NSAIAs in controlled clinical studies. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Diflunisal should be discontinued if signs or symptoms of a severe hepatic reaction occur.(See Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

Rash occurs in 3-9% of patients treated with diflunisal. Other adverse dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, pruritus, sweating, and dryness of mucous membranes occur less frequently.

A potentially life-threatening, apparent hypersensitivity syndrome has been associated with diflunisal use. This multisystem syndrome includes constitutional manifestations (e.g., fever, chills) and dermatologic effects (e.g., rash). The syndrome also may involve major organs, with manifestations such as liver function abnormalities, jaundice, leukopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, and renal impairment (including failure), and less specific findings such as adenitis, arthralgia, myalgia, arthritis, malaise, anorexia, and disorientation. Other hypersensitivity reactions have included vasculitis, angioedema, flushing, and acute anaphylaxis with bronchospasm. If evidence of a hypersensitivity reaction occurs during diflunisal therapy, the drug should be discontinued and appropriate therapy instituted as necessary.

Other Adverse Effects

Patients receiving diflunisal have experienced tinnitus. Hearing loss also has been reported in patients receiving diflunisal. Although a causal relationship to diflunisal has not been established, fulminant necrotizing fasciitis, which may be fatal and is usually associated with group A β-hemolytic streptococcal infection, has been reported rarely in patients receiving NSAIAs, including diflunisal.

Agranulocytosis, thrombocytopenia, and hemolytic anemia have occurred rarely in patients receiving diflunisal. Although a causal relationship to diflunisal has not been established, dyspnea, syncope, transient visual disturbances, muscle cramps, fever, hypersensitivity reactions, and anaphylaxis with bronchospasm have been reported. In addition, the manufacturer states that adverse effects reported with other NSAIAs, but not reported to date with diflunisal, should be considered potential adverse effects of the drug.

Precautions and Contraindications

Patients should be advised that diflunisal, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur. Patients also should be informed that, while NSAIAs may be commonly employed for conditions that are less serious, NSAIA therapy often is considered essential for the management of some diseases, and the drugs have a major role in the management of pain. Clinicians may wish to discuss with their patients the potential risks and likely benefits of NSAIA therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without an NSAIA may represent an acceptable alternative to both the patient and clinician.

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events. (See Cautions: Cardiovascular Effects.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed. Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease. Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy. Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs. Diflunisal should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if diflunisal is used in such patients, the patient should be monitored for cardiac ischemia.

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs. Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving diflunisal should be advised not to take aspirin.

Use of NSAIAs, including diflunisal, can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events. Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents. NSAIAs, including diflunisal, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation of diflunisal therapy and throughout therapy.

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that diflunisal should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if diflunisal is used in such patients, the patient should be monitored for worsening heart failure. Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure. Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema. Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists). (See Drug Interactions.)

The risk of potentially serious adverse GI effects should be considered in patients receiving diflunisal, particularly in patients receiving chronic therapy with the drug.(See Cautions: GI Effects.) Diflunisal should be used with caution in patients with a history of upper or lower GI disease. Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.

Diflunisal should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration, and such patients should receive an appropriate ulcer preventive regimen. All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely for signs and symptoms of ulcer perforation or severe GI bleeding. To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed. For patients who are at high risk, alternative therapy other than an NSAIA should be considered.

Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving diflunisal should be evaluated for evidence of the development of a more severe hepatic reaction. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) have occurred during therapy with NSAIAs. Although such reactions are rare, diflunisal should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).(See Cautions: Hepatic Effects.)

Diflunisal should be used with caution in patients who may be adversely affected by a prolongation of bleeding time since, at relatively high dosages, the drug inhibits platelet function. If signs and/or symptoms of anemia occur during therapy with diflunisal, hemoglobin concentration and hematocrit should be determined.

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion. Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II antagonist concomitantly; and geriatric patients. Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs. Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy. Some clinicians recommend that renal function be monitored periodically in patients receiving long-term NSAIA therapy.

Diflunisal has not been evaluated in patients with severe renal impairment, and the manufacturer states that use of the drug is not recommended in patients with advanced renal disease. If diflunisal is used in patients with severe renal impairment, close monitoring is recommended.

Anaphylactoid reactions and other hypersensitivity reactions have been reported in patients receiving diflunisal. Patients receiving diflunisal should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving diflunisal. These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur. Diflunisal should be discontinued at the first appearance of rash or any other sign of hypersensitivity.

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.

Diflunisal is not a substitute for corticosteroid therapy, and the drug is not effective in the management of adrenal insufficiency. Abrupt withdrawal of corticosteroids may exacerbate corticosteroid-responsive conditions. If corticosteroid therapy is to be discontinued after prolonged therapy, the dosage should be tapered gradually.

Because NSAIAs have caused adverse ocular effects, patients who experience ocular disturbances during diflunisal therapy should have an ophthalmologic examination.

The possibility that the antipyretic effect of diflunisal may mask the usual signs and symptoms of infection should be considered, especially when the drug is administered in high dosages or for prolonged periods.

The manufacturers state that diflunisal is contraindicated in patients with known hypersensitivity to the drug. In addition, NSAIAs, including diflunisal, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients. Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, diflunisal should be used with caution in patients with asthma. In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad. For further discussion of cross-sensitivity of NSAIAs,

Diflunisal is contraindicated in the setting of CABG surgery.

Pediatric Precautions

Safety and efficacy of diflunisal in children have not been established. Use of the drug in children younger than 12 years of age is not recommended. Because diflunisal is a derivative of salicylic acid, the possibility that diflunisal may be associated with an increased risk of developing Reye's syndrome in children with varicella infections or influenza-type illnesses cannot be excluded.

Geriatric Precautions

Diflunisal should be used with caution in geriatric individuals 65 years of age or older since increasing age may be associated with increased risk of adverse reactions. Geriatric individuals appear to tolerate GI ulceration or bleeding less well than other individuals, and many of the spontaneous reports of fatal adverse GI effects in patients receiving diflunisal involved geriatric individuals.(See Cautions: GI Effects.) Diflunisal is eliminated mainly by the kidney and individuals with renal impairment may be at increased risk of toxic reactions to the drug. Because geriatric patients frequently have decreased renal function, particular attention should be paid to diflunisal dosage and it may be useful to monitor renal function in these patients.

Mutagenicity and Carcinogenicity

Animal studies have not revealed evidence of a mutagenic effect. In long-term studies in rats or mice, diflunisal dosages up to 40 or 80 mg/kg daily, respectively, did not affect the type or frequency of neoplasia.

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, diflunisal has been shown to be maternotoxic, embryotoxic, and teratogenic in rabbits when given in dosages of 60 mg/kg daily; evidence of teratogenicity also has been observed in rabbits at dosages of 40-50 mg/kg daily. Administration of the drug to rats increased the average length of gestation, probably as a result of inhibition of prostaglandin synthesis by the drug. Similar prolongation of gestation has occurred with other NSAIAs. NSAIAs also have caused dystocia and prolongation of labor in animals. Diflunisal should not be used during the third trimester of pregnancy, since inhibitors of prostaglandin synthesis may have adverse effects on the fetus, including effects on the cardiovascular system (e.g., premature closure or constriction of the ductus arteriosus, degenerative myocardial changes, tricuspid incompetence, postnatal nonclosure of the ductus arteriosus [which may be resistant to medical management]), platelets (e.g., bleeding), renal function, (e.g., renal failure with or without oligohydramnios, renal injury/dysgenesis [which may result in prolonged or permanent renal failure]), and GI system (e.g., bleeding, perforation, increased risk of necrotizing enterocolitis). Other adverse effects associated with such use have included pulmonary hypertension and intracranial bleeding. The drug should be used during the first or second trimester of pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

Reproduction studies in rats using diflunisal dosages up to 50 mg/kg daily have not revealed evidence of impaired fertility.

Lactation

Diflunisal is distributed into milk. Because of the potential for serious adverse reactions from diflunisal in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Protein-bound Drugs

Because diflunisal is highly protein bound, it theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as oral anticoagulants, salicylates, and sulfonylureas. Patients receiving diflunisal with any of these drugs should be observed for adverse effects.

Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

There is some evidence that concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists may reduce the blood pressure response to the antihypertensive agent.

Anticoagulants and Thrombolytic Agents

The effects of warfarin and NSAIAs on GI bleeding are synergistic. Concomitant use of diflunisal and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.

Administration of diflunisal with warfarin results in prolonged prothrombin times in some individuals. When diflunisal is administered with oral anticoagulants, prothrombin time should be closely monitored during and for several days following concomitant therapy. Dosage adjustment of oral anticoagulants also may be required. In addition, because diflunisal may cause GI bleeding and may inhibit platelet aggregation, the drug should be used with caution in patients receiving any anticoagulant or thrombolytic agent (e.g., streptokinase).

Antidiabetic Agents

Diflunisal does not appear to substantially affect the hypoglycemic response (as determined by fasting blood glucose) to tolbutamide in patients with diabetes mellitus. Diflunisal also reportedly does not substantially affect plasma concentrations of tolbutamide.

Antacids

Concomitant administration of diflunisal and antacids may result in decreased plasma diflunisal concentrations. Although this effect on plasma concentrations of diflunisal is slight when antacids are used intermittently, the clinical importance of this effect may increase when antacids are used routinely.

Acetaminophen

Following concomitant administration of diflunisal and acetaminophen in healthy individuals, plasma concentrations of acetaminophen have reportedly increased by about 50%; plasma concentrations of diflunisal have not been affected. Diflunisal and acetaminophen should be administered concomitantly with caution and patients receiving both drugs should be carefully monitored, since high dosages of acetaminophen have been associated with hepatotoxicity. Although the clinical importance to humans has not been established, concomitant administration of large dosages (approximately 2 times the maximum recommended human dosage) of diflunisal and acetaminophen in dogs, but not in rats, has been associated with increased GI toxicity compared with either drug alone.

Diuretics

Patients receiving diuretics may have an increased risk of developing renal failure secondary to decreased renal blood flow resulting from prostaglandin inhibition by NSAIAs, including diflunisal. NSAIAs may interfere with the natriuretic response to diuretics whose activity depends in part on prostaglandin-mediated alterations in renal blood flow (e.g., loop diuretics).

Concomitant administration of diflunisal and hydrochlorothiazide in healthy individuals has resulted in substantial increases in plasma hydrochlorothiazide concentrations. In addition, diflunisal appears to decrease the hyperuricemic effects of hydrochlorothiazide.

Nonsteroidal Anti-inflammatory Agents

Concomitant administration of diflunisal with another NSAIA is not recommended since such use may increase the possibility of adverse GI effects with little or no increase in efficacy.

Concomitant use of aspirin and an NSAIA increases the risk of serious GI events. Because of the potential for increased adverse effects, patients receiving diflunisal should be advised not to take aspirin. There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs. Concomitant administration of multiple doses of aspirin and diflunisal may slightly decrease plasma diflunisal concentrations; the clinical importance of this pharmacokinetic interaction is not known.

Concomitant administration of diflunisal and indomethacin in healthy individuals has resulted in decreased renal clearance and substantial increases in plasma concentrations of indomethacin. In addition, concomitant use of diflunisal and indomethacin has been associated with fatal GI hemorrhage in some patients. The manufacturers recommend that diflunisal and indomethacin not be used concomitantly.

Concurrent administration of diflunisal and sulindac to healthy individuals resulted in about a 33% reduction in plasma concentrations of sulindac's active sulfide metabolite.

Concomitant administration of diflunisal and naproxen in healthy individuals did not affect plasma concentrations of naproxen, but substantially decreased urinary excretion of naproxen and its glucuronide metabolite; naproxen did not affect plasma concentrations of diflunisal.

Methotrexate

The manufacturers state that diflunisal and methotrexate should be used concomitantly with caution. Severe, sometimes fatal, toxicity has occurred following administration of an NSAIA concomitantly with methotrexate (principally high-dose therapy) in patients with various malignant neoplasms or rheumatoid arthritis. The toxicity was associated with elevated and prolonged blood concentrations of methotrexate. The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination. Further studies are needed to evaluate the interaction between NSAIAs and methotrexate.

Cyclosporine

Concomitant administration of an NSAIA and cyclosporine may increase the nephrotoxic effects of cyclosporine; this interaction may be related to inhibition of renal prostaglandin (e.g., prostacyclin) synthesis. The manufacturers of diflunisal state that an NSAIA and cyclosporine should be used concomitantly with caution and renal function should be closely monitored.

Lithium

NSAIAs increase plasma lithium concentrations and reduce renal lithium clearance. The mechanism involved in the reduction of lithium clearance by NSAIAs (including diflunisal) is not known, but has been attributed to inhibition of prostaglandin synthesis, which may interfere with the renal elimination of lithium.If an NSAIA and lithium are administered concomitantly, the patient should be closely observed for signs of lithium toxicity.

Other Drugs

Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration and the drugs should be used concomitantly with caution.

Pharmacokinetics

Absorption

Diflunisal is rapidly and completely absorbed from the GI tract. Food slightly decreases the rate of absorption of diflunisal but has little or no effect on the extent of absorption. Absorption of diflunisal may be decreased by concomitant administration of antacids.(See Drug Interactions: Antacids.)

Peak plasma concentrations of diflunisal usually are reached within 2-3 hours following oral administration. Diflunisal produces analgesic effect within 1 hour following oral administration, with maximum analgesic effect occurring within 2-3 hours. Like salicylates, plasma diflunisal concentrations increase more than proportionally with increasing and/or multiple doses of the drug. Steady-state plasma concentrations of diflunisal are not reached for several days because of the drug's long half-life and nonlinear pharmacokinetics.

Distribution

At least 98-99% of diflunisal is bound to plasma proteins. In healthy individuals, diflunisal has an apparent volume of distribution (Vd) of 7.53 L; Vd reportedly has increased to 16.2 L in patients with impaired renal function.

Diflunisal is distributed into CSF in small amounts (about 1% of blood concentrations) in animals following IV or oral administration of 50 or 100 mg/kg, respectively. The drug also crosses the placenta in small amounts in animals. Diflunisal is distributed into human milk in concentrations about 2-7% of the simultaneous maternal plasma concentrations.

Elimination

In healthy adults, the plasma half-life of diflunisal ranges from 8-12 hours. The difluorophenyl substituent at C1 is responsible for the relatively long half-life of the drug. In one study, the terminal half-life of diflunisal was 68-138 hours in patients with severe renal impairment (i.e., creatinine clearance less than 2 mL/minute).

Diflunisal is metabolized in the liver to glucuronide conjugates. The drug is not metabolized to salicylic acid. Diflunisal and its metabolites are excreted principally in urine; about 90% of an administered dose is excreted in urine as glucuronide conjugates. Less than 5% of a single oral dose of diflunisal is present in feces. It is not known whether fecal concentrations of diflunisal represent unabsorbed drug or biliary excretion.

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