nimize the potential risk for an adverse cv event in nsaid-treated patients, use the lowest effective dose for the shortest duration possible. physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous cv symptoms. patients should be informed about the symptoms of serious cv events and the steps to take if they occur. there is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cv thrombotic events associated with nsaid use. the concurrent use of aspirin and an nsaid, such as diflunisal, increases the risk of serious gastrointestinal (gi) events (see warnings ) . status post coronary artery bypass graft (cabg) surgery two large, controlled clinical trials of a cox-2 selective nsaid for the treatment of pain in the first 10–14 days following cabg surgery found an increased incidence of myocardial infarction and stroke. nsaids are contraindicated in the setting of cabg (see contraindications ) . post-mi patients observational studies conducted in the danish national registry have demonstrated that patients treated with nsaids in the post-mi period were at increased risk of reinfarction, cv-related death, and all-cause mortality beginning in the first week of treatment. in this same cohort, the incidence of death in the first year post mi was 20 per 100 person years in nsaid-treated patients compared to 12 per 100 person years in non-nsaid exposed patients. although the absolute rate of death declined somewhat after the first year post-mi, the increased relative risk of death in nsaid users persisted over at least the next four years of follow-up. avoid the use of diflunisal tablets in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if diflunisal tablets is used in patients with a recent mi, monitor patients for signs of cardiac ischemia. hypertension nsaids, including diflunisal tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cv events. patients taking thiazides or loop diuretics may have impaired response to these therapies when taking nsaids. nsaids, including diflunisal tablets, should be used with caution in patients with hypertension. blood pressure (bp) should be monitored closely during the initiation of nsaid treatment and throughout the course of therapy. heart failure and edema the coxib and traditional nsaid trialists' collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in cox-2 selective-treated patients and nonselective nsaid-treated patients compared to placebo-treated patients. in a danish national registry study of patients with heart failure, nsaid use increased the risk of mi, hospitalization for heart failure, and death. additionally, fluid retention and edema have been observed in some patients treated with nsaids. use of diflunisal may blunt the cv effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ace inhibitors, or angiotensin receptor blockers (arbs)] (see drug interactions ). avoid the use of diflunisal tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if diflunisal tablets is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. gastrointestinal effects – risk of ulceration, bleeding and perforation nsaids, including diflunisal tablets, can cause serious gastrointestinal (gi) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. these serious adverse events can occur at any time, with or without warning symptoms, in patients treated with nsaids. only one in five patients, who develop a serious upper gi adverse event on nsaid therapy, is symptomatic. upper gi ulcers, gross bleeding, or perforation caused by nsaids occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. these trends continue with longer duration of use, increasing the likelihood of developing a serious gi event at some time during the course of therapy. however, even short-term therapy is not without risk. nsaids should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use nsaids have a greater than 10 fold increased risk for developing a gi bleed compared to patients with neither of these risk factors. other factors that increase the risk for gi bleeding in patients treated with nsaids include concomitant use of oral corticosteroids or anticoagulants, longer duration of nsaid therapy, smoking, use of alcohol, older age, and poor general health status. most spontaneous reports of fatal gi events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. to minimize the potential risk for an adverse gi event in patients treated with an nsaid, the lowest effective dose should be used for the shortest possible duration. patients and physicians should remain alert for signs and symptoms of gi ulceration and bleeding during nsaid therapy and promptly initiate additional evaluation and treatment if a serious gi adverse event is suspected. this should include discontinuation of the nsaid until a serious gi adverse event is ruled out. for high risk patients, alternate therapies that do not involve nsaids should be considered. renal effects long-term administration of nsaids has resulted in renal papillary necrosis and other renal injury. renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. in these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ace inhibitors, patients who are volume depleted, and the elderly. discontinuation of nsaid therapy is usually followed by recovery to the pretreatment state. advanced renal disease no information is available from controlled clinical studies regarding the use of diflunisal tablets in patients with advanced renal disease. therefore, treatment with diflunisal tablets is not recommended in these patients with advanced renal disease. if diflunisal tablet therapy must be initiated, close monitoring of the patient's renal function is advisable. anaphylactic/anaphylactoid reactions as with other nsaids, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to diflunisal tablets. diflunisal tablets should not be given to patients with the aspirin triad. this symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other nsaids (see contraindications and precautions, preexisting asthma ). emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs. skin reactions nsaids, including diflunisal tablets, can cause serious skin adverse events such as exfoliative dermatitis, stevens-johnson syndrome (sjs), and toxic epidermal necrolysis (ten), which can be fatal. these serious events may occur without warning. patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. drug reaction with eosinophilia and systemic symptoms (dress) drug reaction with eosinophilia and systemic symptoms (dress) has been reported in patients taking nsaids such as diflunisal tablets. some of these events have been fatal or life-threatening. dress typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. sometimes symptoms of dress may resemble an acute viral infection. eosinophilia is often present. because this disorder is variable in its presentation, other organ systems not noted here may be involved. it is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. if such signs or symptoms are present, discontinue diflunisal tablets and evaluate the patient immediately. hypersensitivity syndrome a potentially life-threatening, apparent hypersensitivity syndrome has been reported. this multisystem syndrome includes constitutional symptoms (fever, chills), and cutaneous findings (see adverse reactions, dermatologic ). it may also include involvement of major organs (changes in liver function, jaundice, leukopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal impairment, including renal failure), and less specific findings (adenitis, arthralgia, myalgia, arthritis, malaise, anorexia, disorientation). if evidence of hypersensitivity occurs, therapy with diflunisal tablets should be discontinued. fetal toxicity premature closure of fetal ductus arteriosus: avoid use of nsaids, including diflunisal tablets, in pregnant women at about 30 weeks gestation and later. nsaids including diflunisal tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. oligohydramnios/neonatal renal impairment: use of nsaids, including diflunisal tablets, at about 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, for example, 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 necessary between about 20 weeks and 30 weeks gestation, limit diflunisal tablets use to the lowest effective dose and shortest duration possible. consider ultrasound monitoring of amniotic fluid if diflunisal tablets treatment extends beyond 48 hours. discontinue diflunisal tablets if oligohydramnios occurs and follow up according to clinical practice [ see precautions; pregnancy ] .

g initially, followed by 250 mg every 8 to 12 hours. for osteoarthritis and rheumatoid arthritis, the suggested dosage range is 500 mg to 1000 mg daily in two divided doses. the dosage of diflunisal may be increased or decreased according to patient response. maintenance doses higher than 1500 mg a day are not recommended. tablets should be swallowed whole, not crushed or chewed.

en 3% and 9%. those reactions occurring in 1% to 3% are not marked with an asterisk. incidence less than 1 in 100 the following adverse reactions, occurring less frequently than 1 in 100, were reported in clinical trials or since the drug was marketed. the probability exists of a causal relationship between diflunisal and these adverse reactions. dermatologic erythema multiforme, exfoliative dermatitis, stevens-johnson syndrome, toxic epidermal necrolysis, urticaria, pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity. gastrointestinal peptic ulcer, gastrointestinal bleeding, anorexia, eructation, gastrointestinal perforation, gastritis. liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis. hematologic thrombocytopenia; agranulocytosis; hemolytic anemia. genitourinary dysuria; renal impairment, including renal failure; interstitial nephritis; hematuria; proteinuria. psychiatric nervousness, depression, hallucinations, confusion, disorientation. central nervous system vertigo; light-headedness; paresthesias. special senses transient visual disturbances including blurred vision. hypersensitivity reactions acute anaphylactic reaction with bronchospasm; angioedema; flushing. hypersensitivity vasculitis. hypersensitivity syndrome (see precautions ). miscellaneous asthenia, edema. causal relationship unknown other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. however, in these rarely reported events, that possibility cannot be excluded. therefore, these observations are listed to serve as alerting information to physicians. respiratory dyspnea. cardiovascular palpitation, syncope. musculoskeletal muscle cramps. genitourinary nephrotic syndrome. special senses hearing loss. miscellaneous chest pain. a rare occurrence of fulminant necrotizing fasciitis, particularly in association with group a β -hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including diflunisal, sometimes with fatal outcome (see also precautions, general ). potential adverse effects in addition, a variety of adverse effects not observed with diflunisal in clinical trials or in marketing experience, but reported with other non-steroidal analgesic/anti-inflammatory agents should be considered potential adverse effects of diflunisal.

tion, invasive procedures such as exchange transfusion or dialysis were required. if nsaid treatment is necessary between about 20 weeks and 30 weeks gestation, limit diflunisal tablets use to the lowest effective dose and shortest duration possible. consider ultrasound monitoring of amniotic fluid if diflunisal tablets treatment extends beyond 48 hours. discontinue diflunisal tablets if oligohydramnios occurs and follow up according to clinical practice [ see precautions; pregnancy ] .

ediators of pain and inflammation, the mode of action of diflunisal may be due to a decrease of prostaglandins in peripheral tissues. pharmacokinetics and metabolism diflunisal is rapidly and completely absorbed following oral administration with peak plasma concentrations occurring between 2 to 3 hours. the drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. little or no diflunisal is excreted in the feces. diflunisal appears in human milk in concentrations of 2 to 7% of those in plasma. more than 99% of diflunisal in plasma is bound to proteins. as is the case with salicylic acid, concentration-dependent pharmacokinetics prevail when diflunisal is administered; a doubling of dosage produces a greater than doubling of drug accumulation. the effect becomes more apparent with repetitive doses. following single doses, peak plasma concentrations of 41 ± 11 mcg/ml (mean ± s.d.) were observed following 250 mg doses, 87 ± 17 mcg/ml were observed following 500 mg and 124 ± 11 mcg/ml following single 1000 mg doses. however, following administration of 250 mg b.i.d., a mean peak level of 56 ± 14 mcg/ml was observed on day 8, while the mean peak level after 500 mg b.i.d. for 11 days was 190 ± 33 mcg/ml. in contrast to salicylic acid which has a plasma half-life of 2 1/2 hours, the plasma half-life of diflunisal is 3 to 4 times longer (8 to 12 hours), because of a difluorophenyl substituent at carbon 1. because of its long half-life and nonlinear pharmacokinetics, several days are required for diflunisal plasma levels to reach steady state following multiple doses. for this reason, an initial loading dose is necessary to shorten the time to reach steady-state levels, and 2 to 3 days of observation are necessary for evaluating changes in treatment regimens if a loading dose is not used. studies in baboons to determine passage across the blood-brain barrier have shown that only small quantities of diflunisal, under normal or acidotic conditions are transported into the cerebrospinal fluid (csf). the ratio of blood/csf concentrations after intravenous doses of 50 mg/kg or oral doses of 100 mg/kg of diflunisal was 100:1. in contrast, oral doses of 500 mg/kg of aspirin resulted in a blood/csf ratio of 5:1. mild to moderate pain diflunisal is a peripherally-acting analgesic agent with a long duration of action. diflunisal produces significant analgesia within 1 hour and maximum analgesia within 2 to 3 hours. consistent with its long half-life, clinical effects of diflunisal mirror its pharmacokinetic behavior, which is the basis for recommending a loading dose when instituting therapy. patients treated with diflunisal, on the first dose, tend to have a slower onset of pain relief when compared with drugs achieving comparable peak effects. however, diflunisal produces longer lasting responses than the comparative agents. comparative single dose clinical studies have established the analgesic efficacy of diflunisal at various dose levels relative to other analgesics. analgesic effect measurements were derived from hourly evaluations by patients during eight and twelve hour postdosing observation periods. the following information may serve as a guide for prescribing diflunisal. diflunisal 500 mg was comparable in analgesic efficacy to aspirin 650 mg, acetaminophen 600 mg or 650 mg, and acetaminophen 650 mg with propoxyphene napsylate 100 mg. patients treated with diflunisal had longer lasting responses than the patients treated with the comparative analgesics. diflunisal 1000 mg was comparable in analgesic efficacy to acetaminophen 600 mg with codeine 60 mg. patients treated with diflunisal had longer lasting responses than the patients who received acetaminophen with codeine. a loading dose of 1000 mg provides faster onset of pain relief, shorter time to peak analgesic effect, and greater peak analgesic effect than an initial 500 mg dose. in contrast to the comparative analgesics, a significantly greater proportion of patients treated with diflunisal did not remedicate and continued to have a good analgesic effect eight to twelve hours after dosing. seventy-five percent (75%) of patients treated with diflunisal continued to have a good analgesic response at four hours. when patients having a good analgesic response at four hours were followed, 78% of these patients continued to have a good analgesic response at eight hours and 64% at twelve hours. chronic anti-inflammatory therapy in osteoarthritis and rheumatoid arthritis in the controlled, doubleblind clinical trials in which diflunisal (500 mg to 1000 mg a day) was compared with anti-inflammatory doses of aspirin (2 to 4 grams a day), patients treated with diflunisal had a significantly lower incidence of tinnitus and of adverse effects involving the gastrointestinal system than patients treated with aspirin (see also effect on fecal blood loss ). osteoarthritis the effectiveness of diflunisal for the treatment of osteoarthritis was studied in patients with osteoarthritis of the hip and/or knee. the activity of diflunisal was demonstrated by clinical improvement in the signs and symptoms of disease activity. in a doubleblind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, diflunisal 500 or 750 mg daily was shown to be comparable in effectiveness to aspirin 2000 or 3000 mg daily. in open-label extensions of this study to 24 or 48 weeks, diflunisal continued to show similar effectiveness and generally was well tolerated. rheumatoid arthritis in controlled clinical trials, the effectiveness of diflunisal was established for both acute exacerbations and long-term management of rheumatoid arthritis. the activity of diflunisal was demonstrated by clinical improvement in the signs and symptoms of disease activity. in a doubleblind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, diflunisal 500 or 750 mg daily was comparable in effectiveness to aspirin 2600 or 3900 mg daily. in open-label extensions of this study to 52 weeks, diflunisal continued to be effective and was generally well tolerated. diflunisal 500, 750, or 1000 mg daily was compared with aspirin 2000, 3000, or 4000 mg daily in a multicenter study of 8 weeks’ duration in which dosages were adjusted according to patient response. in this study, diflunisal was comparable in efficacy to aspirin. in a doubleblind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient needs, diflunisal 500 or 750 mg daily and ibuprofen 1600 or 2400 mg daily were comparable in effectiveness and tolerability. in a doubleblind multicenter study of 12 weeks' duration, diflunisal 750 mg daily was comparable in efficacy to naproxen 750 mg daily. the incidence of gastrointestinal adverse effects and tinnitus was comparable for both drugs. this study was extended to 48 weeks on an open-label basis. diflunisal continued to be effective and generally well tolerated. in patients with rheumatoid arthritis, diflunisal and gold salts may be used in combination at their usual dosage levels. in clinical studies, diflunisal added to the regimen of gold salts usually resulted in additional symptomatic relief but did not alter the course of the underlying disease. antipyretic activity diflunisal tablets are not recommended for use as an antipyretic agent. in single 250 mg, 500 mg, or 750 mg doses, diflunisal produced measurable but not clinically useful decreases in temperature in patients with fever; however, the possibility that it may mask fever in some patients, particularly with chronic or high doses, should be considered. uricosuric effect in normal volunteers, an increase in the renal clearance of uric acid and a decrease in serum uric acid was observed when diflunisal was administered at 500 mg or 750 mg daily in divided doses. patients on long-term therapy taking diflunisal at 500 mg to 1000 mg daily in divided doses showed a prompt and consistent reduction across studies in mean serum uric acid levels, which were lowered as much as 1.4 mg%. it is not known whether diflunisal interferes with the activity of other uricosuric agents. effect on platelet function as an inhibitor of prostaglandin synthetase, diflunisal has a dose-related effect on platelet function and bleeding time. in normal volunteers, 250 mg b.i.d. for 8 days had no effect on platelet function, and 500 mg b.i.d., the usual recommended dose, had a slight effect. at 1000 mg b.i.d., which exceeds the maximum recommended dosage, however, diflunisal inhibited platelet function. in contrast to aspirin, these effects of diflunisal were reversible, because of the absence of the chemically labile and biologically reactive o -acetyl group at the carbon 4 position. bleeding time was not altered by a dose of 250 mg b.i.d., and was only slightly increased at 500 mg b.i.d. at 1000 mg b.i.d., a greater increase occurred, but was not statistically significantly different from the change in the placebo group. effect on fecal blood loss when diflunisal was given to normal volunteers at the usual recommended dose of 500 mg twice daily, fecal blood loss was not significantly different from placebo. aspirin at 1000 mg four times daily produced the expected increase in fecal blood loss. diflunisal at 1000 mg twice daily (note: exceeds the recommended dosage) caused a statistically significant increase in fecal blood loss, but this increase was only one-half as large as that associated with aspirin 1300 mg twice daily. effect on blood glucose diflunisal did not affect fasting blood sugar in diabetic patients who were receiving tolbutamide or placebo.