Diflunisal

Carefully consider the potential benefits and risks of diflunisal tablets and other treatment options before deciding to use diflunisal tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals . Diflunisal tablets are indicated for acute or long-term use for symptomatic treatment of the following: 1. Mild to moderate pain 2.

Osteoarthritis 3. Rheumatoid arthritis

Carefully consider the potential benefits and risks of diflunisal tablets and other treatment options before deciding to use diflunisal tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals . After observing the response to initial therapy with diflunisal tablets, the dose and frequency should be adjusted to suit an individual patient's needs. 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. For mild to moderate pain, an initial dose of 1000 mg followed by 500 mg every 12 hours is recommended for most patients. Following the initial dose, some patients may require 500 mg every 8 hours. A lower dosage may be appropriate depending on such factors as pain severity, patient response, weight, or advanced age; for example, 500 mg 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.

Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.

However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize 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 . 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 . 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)] . 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 . Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs. Serious Skin Reactions NSAIDs, including diflunisal, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diflunisal tablets at the first appearance of skin rash or any other sign of hypersensitivity. diflunisal tablets are contraindicated in patients with previous serious skin reactions to NSAIDs . Hypersensitivity Syndrome A potentially life-threatening, apparent hypersensitivity syndrome has been reported.

This multisystem syndrome includes constitutional symptoms (fever, chills), and cutaneous findings . 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. Pregnancy In late pregnancy, as with other NSAIDs, diflunisal tablets should be avoided because they may cause premature closure of the ductus arteriosus.

Diflunisal tablets are contraindicated in patients with known hypersensitivity to diflunisal or the excipients . Diflunisal tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/analphylactoid reactions to NSAIDs have been reported in such patients . Diflunisal tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery .

Pregnancy In late pregnancy, as with other NSAIDs, diflunisal tablets should be avoided because they may cause premature closure of the ductus arteriosus. Pregnancy Teratogenic Effects Pregnancy category C A dose of 60 mg/kg/day of diflunisal (equivalent to two times the maximum human dose) was maternotoxic, embryotoxic, and teratogenic in rabbits. In three of six studies in rabbits, evidence of teratogenicity was observed at doses ranging from 40 to 50 mg/kg/day.

Teratology studies in mice, at doses up to 45 mg/kg/day, and in rats at doses up to 100 mg/kg/day, revealed no harm to the fetus due to diflunisal. Aspirin and other salicylates have been shown to be teratogenic in a wide variety of species, including the rat and rabbit, at doses ranging from 50 to 400 mg/kg/day (approximately one to eight times the human dose). Animal reproduction studies are not always predictive of human response.

There are no adequate and well controlled studies with diflunisal in pregnant women. Diflunisal tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis. In rats at a dose of one and one-half times the maximum human dose, there was an increase in the average length of gestation. Similar increases in the length of gestation have been observed with aspirin, indomethacin, and phenylbutazone, and may be related to inhibition of prostaglandin synthetase.

Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of diflunisal tablets on labor and delivery in pregnant women are unknown. Nursing Mothers Diflunisal is excreted in human milk in concentrations of 2 to 7% of those in plasma.

Because of the potential for serious adverse reactions in nursing infants from diflunisal, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of diflunisal in pediatric patients below the age of 12 have not been established. Use of diflunisal tablets in pediatric patients below the age of 12 is not recommended.

The adverse effects observed following diflunisal administration to neonatal animals appear to be species, age, and dose-dependent. At dose levels approximately 3 times the usual human therapeutic dose, both aspirin (200 to 400 mg/kg/day) and diflunisal (80 mg/kg/day) resulted in death, leukocytosis, weight loss, and bilateral cataracts in neonatal (4 to 5 day-old) beagle puppies after 2 to 10 doses. Administration of an 80 mg/kg/day dose of diflunisal to 25 day-old puppies resulted in lower mortality, and did not produce cataracts.

In newborn rats, a 400 mg/kg/day dose of aspirin resulted in increased mortality and some cataracts, whereas the effects of diflunisal administration at doses up to 140 mg/kg/day were limited to a decrease in average body weight gain. Geriatric Use As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population . This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function .

The adverse reactions observed in controlled clinical trials encompass observations in 2,427 patients. Listed below are the adverse reactions reported in the 1,314 of these patients who received treatment in studies of two weeks or longer. Five hundred thirteen patients were treated for at least 24 weeks, 255 patients were treated for at least 48 weeks, and 46 patients were treated for 96 weeks.

In general, the adverse reactions listed below were 2 to 14 times less frequent in the 1,113 patients who received short-term treatment for mild to moderate pain. Incidence Greater Than 1% Gastrointestinal The most frequent types of adverse reactions occurring with diflunisal are gastrointestinal: these include nausea*, vomiting, dyspepsia*, gastrointestinal pain*, diarrhea*, constipation, and flatulence. Psychiatric Somnolence, insomnia.

Central Nervous System Dizziness. Special Senses Tinnitus. Dermatologic Rash*. Miscellaneous Headache*, fatigue/tiredness. * Incidence between 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 (SJS), toxic epidermal necrolysis (TEN), fixed drug reaction (FDE), urticaria, pruritus, sweating, dry mucous membranes, stomatitis, and 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 . 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 . 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.