Action

Dolobid is a non-steroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a peripherally-acting non-narcotic analgesic drug. Habituation, tolerance, and addiction have not been reported.

Diflunisal is a difluorophenyl derivative of salicylic acid. Chemically, diflunisal differs from aspirin (acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent at carbon 1. The second difference is the removal of the O-acetyl group from the carbon 4 position. Diflunisal is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the difluorophenyl ring structure.

The precise mechanism of the analgesic and anti-inflammatory actions of diflunisal is not known. Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the mediators of pain and inflammation, the mode of action of diflunisal may be due to a decrease of prostaglandins in peripheral tissues.

Pharmacokinetics and Metabolism

Dolobid 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 Dolobid 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 1,000 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

Dolobid is a peripherally-acting analgesic agent with a long duration of action. Dolobid produces significant analgesia within 1 hour and maximum analgesia within 2 to 3 hours.

Consistent with its long half-life, clinical effects of Dolobid mirror its pharmacokinetic behavior, which is the basis for recommending a loading dose when instituting therapy. Patients treated with Dolobid, on the first dose, tend to have a slower onset of pain relief when compared with drugs achieving comparable peak effects. However, Dolobid produces longer lasting responses than the comparative agents.

Comparative single dose clinical studies have established the analgesic efficacy of  Dolobid 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 Dolobid.

Dolobid 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 Dolobid had longer lasting responses than the patients treated with the comparative analgesics.

Dolobid 1,000 mg was comparable in analgesic efficacy to acetaminophen 600 mg with codeine 60 mg. Patients treated with Dolobid had longer lasting responses than the patients who received acetaminophen with codeine.

A loading dose of 1,000 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 Dolobid 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, double-blind clinical trials in which Dolobid (500 mg to 1,000 mg a day) was compared with anti-inflammatory doses of aspirin (2 to 4 grams a day), patients treated with Dolobid 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 Dolobid for the treatment of osteoarthritis was studied in patients with osteoarthritis of the hip and/or knee. The activity of Dolobid was demonstrated by clinical improvement in the signs and symptoms of disease activity.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, Dolobid 500 or 750 mg daily was shown to be comparable in effectiveness to aspirin 2,000 or 3,000 mg daily. In open-label extensions of this study to 24 or 48 weeks, Dolobid continued to show similar effectiveness and generally was well tolerated.

Rheumatoid Arthritis

In controlled clinical trials, the effectiveness of Dolobid was established for both acute exacerbations and long-term management of rheumatoid arthritis. The activity of Dolobid was demonstrated by clinical improvement in the signs and symptoms of disease activity.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, Dolobid 500 or 750 mg daily was comparable in effectiveness to aspirin 2,600 or 3,900 mg daily. In open-label extensions of this study to 52 weeks, Dolobid continued to be effective and was generally well tolerated.

Dolobid 500, 750, or 1,000 mg daily was compared with aspirin 2,000, 3,000, or 4,000 mg daily in a multicenter study of 8 weeks' duration in which dosages were adjusted according to patient response. In this study, Dolobid was comparable in efficacy to aspirin.

In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient needs, Dolobid 500 or 750 mg daily and ibuprofen 1,600 or 2,400 mg daily were comparable in effectiveness and tolerability.

In a double-blind multicenter study of 12 weeks' duration, Dolobid 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. Dolobid continued to be effective and generally well tolerated.

In patients with rheumatoid arthritis, Dolobid and gold salts may be used in combination at their usual dosage levels. In clinical studies, Dolobid 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

Dolobid is not recommended for use as an antipyretic agent. In single 250 mg, 500 mg, or 750 mg doses, Dolobid 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 Dolobid was administered at 500 mg or 750 mg daily in divided doses. Patients on long-term therapy taking diflunisal at 500 mg to 1,000 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 Dolobid 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 1,000 mg b.i.d., which exceeds the maximum recommended dosage, however, Dolobid 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 1,000 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 Dolobid 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 1,000 mg four times daily produced the expected increase in fecal blood loss. Dolobid at 1,000 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 1,300 mg twice daily.

Effect on Blood Glucose

Dolobid did not affect fasting blood sugar in diabetic patients who were receiving tolbutamide or placebo.

Cardiovascular Effects

Gastrointestinal Effects – Risk of Ulceration, Bleeding and Perforation

NSAIDs, including Dolobid, 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 bleedingwho 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 Dolobid in patients with advanced renal disease. Therefore, treatment with Dolobid is not recommended in these patients with advanced renal disease. If Dolobid 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 Dolobid. Dolobid 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 CONTRAINDICATIONSand PRECAUTIONS, Preexisting Asthma). 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 Dolobid at the first appearance of skin rash or any other sign of hypersensitivity. Dolobid is contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS)

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 Dolobid. 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, hematological 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 Dolobid 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 Dolobid should be discontinued.

Fetal Toxicity

General

Dolobid cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of Dolobid in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Dolobid. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

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 Dolobid . If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Dolobid should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Dolobid. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Dolobid, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving diflunisal tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, diflunisal tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Ocular Effects

Because of reports of adverse eye findings with agents of this class, it is recommended that patients who develop eye complaints during treatment with Dolobid have ophthalmologic studies.

Reye’s Syndrome

Acetylsalicylic acid has been associated with Reye’s syndrome. Because Dolobid is a derivative of salicylic acid, the possibility of its association with Reye’s syndrome cannot be excluded.

Information for Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Dolobid should be discontinued.

Drug Interactions

Oral Anticoagulants

In some normal volunteers, the concomitant administration of diflunisal and warfarin, acenocoumarol, or phenprocoumon resulted in prolongation of prothrombin time. This may occur because diflunisal competitively displaces coumarins from protein binding sites. Accordingly, when Dolobid tablets are administered with oral anticoagulants, the prothrombin time should be closely monitored during and for several days after concomitant drug administration. Adjustment of dosage of oral anticoagulants may be required. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

Tolbutamide

In diabetic patients receiving Dolobid and tolbutamide, no significant effects were seen on tolbutamide plasma levels or fasting blood glucose.

Drug/Laboratory Test Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Diflunisal did not affect the type or incidence of neoplasia in a 105 week study in the rat given doses up to 40 mg/kg/day (equivalent to approximately 1.3 times the maximum recommended human dose), or in long-term carcinogenic studies in mice given diflunisal at doses up to 80 mg/kg/day (equivalent to approximately 2.7 times the maximum recommended human dose). It was concluded that there was no carcinogenic potential for diflunisal.

Diflunisal passes the placental barrier to a minor degree in the rat. Diflunisal had no mutagenic activity after oral administration in the dominant lethal assay, in the Ames microbial mutagen test or in the V-79 Chinese hamster lung cell assay.

No evidence of impaired fertility was found in reproduction studies in rats at doses up to 50 mg/kg/day.

Pregnancy

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 Dolobid on labor and delivery in pregnant women are unknown.

Nursing Mothers

Dolobid 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 Dolobid, 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 Dolobid in pediatric patients below the age of 12 have not been established. Use of Dolobid 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 (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation).

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 (see WARNINGS, Renal Effects).

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.

Skin and Appendages:

Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and can fixed drug reaction (FDE)

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), and fixed drug eruption (FDE), 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 Dolobid.

To report SUSPECTED ADVERSE REACTIONS, contact INA Pharmaceutics, Inc. at 866-835-0469. or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch.