Diflunisal

Diflunisal has slow onset and long duration of action. Diflunisal produces significant analgesia in 1 hour and maximum analgesia in 2 to 4 hours. Analgesic effect lasts 8 to 12 hours. These characteristics should be considered when prescribing this drug.

Tablets should be swallowed whole, not crushed or chewed. Diflunisal may be administered with water, milk or meals.

Dose in Adult Patients with Renal Impairment: In patients with creatinine clearance <50 mL/min, administer 50% of the normal dose.

nephrotic syndrome.

fever, fulminant necrotizing fasciitis, hearing loss, muscle cramps.

dyspnea.

palpitation, syncope, hypertension, hypotension, heart failure, chest pain, arrhythmias.

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. See Warnings and 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.

Long-term administration of nonsteroidal anti-inflammatory drugs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with pre-renal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function (GFR < 60 mL/min or 1 mL/s), patients on salt-restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction, those taking diuretics, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, cyclosporine, ASA and the elderly. Serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short-term therapy with NSAIDs. Even patients at risk who demonstrate the ability to tolerate an NSAID under stable conditions may decompensate during periods of added stress, for example during states of fluid restriction as can occur during gastroenteritis. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.

NSAIDs can increase the risk of hyperkalemia (see Fluid and Electrolyte Balance). In patients on dialysis, NSAIDs should be used with caution.

Serious GI toxicity, such as ulceration, perforation, obstruction and gastrointestinal bleeding, sometimes severe and occasionally fatal, can occur at any time, with or without symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) including diflunisal.

GI symptoms, such as dyspepsia, are common, usually developing early in therapy. Health providers should remain alert for ulceration and bleeding in patients treated with nonsteroidal anti-inflammatory drugs, even in the absence of previous GI tract symptoms.

In patients observed in clinical trials of NSAIDs, symptomatic upper GI ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months and in about 2 to 4% of patients treated for 1 year. The risk continues beyond 1 year. The incidence of these complications is related to dose, past history of known ulcer disease, and advanced age (see Special Populations).

Diflunisal should be given under close medical supervision to patients with a history of ulcer of the upper gastrointestinal tract or inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn's disease. In these cases the health provider must weigh the benefits of treatment against the possible hazards.

Health providers should inform patients about the signs and symptoms of serious GI toxicity and instruct them to contact a health provider immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.

Because serious GI tract ulceration and bleeding can occur without warning symptoms, health providers should follow chronically treated patients and watch for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.

If ulceration is suspected or confirmed, or if GI bleeding occurs, diflunisal should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.

No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. The major risk factors are a prior history of serious GI events and increasing age. Possible risks factors include H. pylori infection, excess alcohol intake, smoking, and concomitant oral steroids, anticoagulants, antiplatelet agents (including ASA), or selective serotonin reuptake inhibitors (SSRIs).

Habituation, tolerance and addiction have not been reported.

ASA-induced asthma is an uncommon but very important indication of ASA and NSAID sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

Blurred and/or diminished vision has been reported with the use of diflunisal and other nonsteroidal anti-inflammatory drugs. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

Until more is known about the safety of diflunisal, it should not be used during pregnancy. A positive association has been reported between NSAIDs and spontaneous abortions. It is suggested that diflunisal not be used in women attempting to conceive as it blocks blastocyte implantation in animals.

In the latter half of pregnancy, due to the diverse recorded and potential effects of NSAIDs such as premature closure of the ductus arteriosus and pulmonary hypertension or oligohydramnios, it is recommended that the use of these agents be avoided. If therapeutic use in pregnancy is required, the pregnancy should be managed by obstetricians or other health providers with particular expertise in high-risk pregnancies.

As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver enzyme tests (AST, ALT, ALP) may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with nonsteroidal anti-inflammatory drugs.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g., jaundice), or if systemic manifestations occur (e.g., eosinophilia, associated with rash, etc.), the drug should be discontinued.

If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

Patients older than 65 years (hereafter referred to as older or elderly) and frail or debilitated patients are most susceptible to a variety of adverse reactions from nonsteroidal anti-inflammatory drugs (NSAIDs); the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant of ulceration and bleeding. Most reports of fatal GI events are in this population, especially those with cardiovascular disease. Older patients are also at risk of lower esophageal ulceration and bleeding.

For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision.

Some NSAIDs are associated with persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Should urinary symptoms occur, in the absence of an alternate explanation, treatment with diflunisal should be stopped to ascertain if symptoms disappear. This should be done before urological investigations or treatments are considered.

Drugs inhibiting prostaglandin biosynthesis interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action, such as those on anticoagulants or suffering from hemophilia or platelet disorders should be carefully observed when diflunisal is administered.

Antiplatelet agents are used for the prevention of thrombosis or to reduce the risk of nonfatal myocardial infarction (MI), non-fatal cerebral thrombosis or embolism, and death in the following clinical situations: acute MI, secondary prevention following MI, patients with a history of transient ischemic attack(s), ischemic stroke, chronic stable angina, unstable angina or coronary artery disease. Whether antiplatelet agents confer significant benefit as primary prevention in low-risk patient populations remains unclear.

Antiplatelet agents are used to prevent thrombotic complications in patients undergoing procedures such as coronary angioplasty, coronary artery bypass or carotid endarterectomy. They are used to prevent thrombosis in patients with atrial fibrillation who cannot take warfarin. Diflunisal and other NSAIDs have no proven efficacy as antiplatelet agents and cannot be used as a substitute for acetylsalicylic acid (ASA) or other antiplatelet agents under these conditions.

Concomitant administration of diflunisal with low-dose ASA increases the risk of GI ulceration and associated complications. If the two drugs must be used together, extra caution is warranted.

Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of nonsteroidal anti-inflammatory drugs are rare, but could occur with severe consequences.

Cross-sensitivity: Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may be sensitive to any of the other NSAIDs also.

ASA-Intolerance: As with NSAIDs in general, some patients may experience urticaria and angioedema upon exposure to diflunisal. Diflunisal should not be given to patients with the complete or partial syndrome of ASA-intolerance (see Contraindications).

Serious Skin Reactions: In rare cases, serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of some NSAIDs. Because the incidence of these reactions is low, they have usually been noted during post-marketing surveillance in patients taking other medications also associated with the potential development of these serious skin reactions. Thus, causality is not clear. These reactions are potentially life threatening but may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a skin rash they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.

Aseptic Meningitis: In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be predisposed. Therefore, in such patients, the health provider must be vigilant to the development of this complication.

Infection: In common with other anti-inflammatory drugs, diflunisal may suppress fever.

Reye's Syndrome: ASA has been associated with Reye's syndrome. Because diflunisal is a derivative of salicylic acid, the possibility of its association with Reye's syndrome cannot be excluded.

Diflunisal may cause falsely elevated values of serum salicylate when measured by various laboratory assays; therefore, serum salicylate concentrations should be interpreted with caution in patients receiving diflunisal.

Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus or hearing loss with the use of diflunisal. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may be sensitive to any of the other NSAIDs also.

Fluid retention and edema have been observed in patients treated with diflunisal. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Diflunisal should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention. Ask patients who are at risk for fluid retention to weigh themselves at regular intervals to assist in monitoring for fluid accumulation. With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with angiotensin-II receptor antagonists, adrenergic blockers, angiotensin-converting enzyme inhibitors or potassium-sparing diuretics. Patients at risk should be monitored periodically during long-term therapy.

Diflunisal is excreted in human milk in concentrations of 2 to 7% of those in plasma. Experience with the use of diflunisal in lactating women is not available. Shorter-acting agents with more available published information (e.g., ibuprofen) may be preferable, especially while nursing a newborn or preterm infant.

Some patients with pre-existing hypertension may develop worsening of blood pressure control when placed on an NSAID and regular monitoring of blood pressure should be performed under such circumstances. NSAIDs may exacerbate congestive heart failure.

The risk of cardiovascular complications in patients receiving NSAIDs is not clearly defined. Short-term use of NSAIDs, especially at low doses, does not appear to be associated with an increased risk of serious cardiovascular events except immediately following coronary artery bypass graft (CABG) surgery.

At least 98 to 99% of diflunisal in plasma is bound to proteins. In healthy individuals, diflunisal has an apparent volume of distribution of 7.53 L.

Diflunisal is rapidly and completely absorbed following oral administration, with peak plasma concentrations occurring between 2 to 3 hours.

In healthy adults, the plasma half-life of diflunisal ranges from 8 to 12 hours. Diflunisal is excreted in the urine as 2 soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no diflunisal is excreted in the feces.

The volume of distribution reportedly has increased to 16.2 L in patients with impaired renal function.

Diflunisal is metabolized in the liver to glucuronide conjugates. The drug is not metabolized to salicylic acid.

Your Shopping Cart

You currently have no items in your cart.