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 DOLOBID (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 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 DOLOBID (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 WARNINGS, 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 α-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 DOLOBID (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 (diflunisal) .

**Incidence between 3% and 9%. Those reactions occurring in 1% to 3% are not marked with an asterisk.

Read the Dolobid (diflunisal) Side Effects Center for a complete guide to possible side effects »

ACE-Inhibitors and Angiotensin II Antagonists

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the co-administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.

Acetaminophen

In normal volunteers, concomitant administration of DOLOBID (diflunisal) and acetaminophen resulted in an approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma levels of DOLOBID (diflunisal) . Since acetaminophen in high doses has been associated with hepatotoxicity, concomitant administration of DOLOBID (diflunisal) and acetaminophen should be used cautiously, with careful monitoring of patients. Concomitant administration of DOLOBID (diflunisal) and acetaminophen in dogs, but not in rats, at approximately 2 times the recommended maximum human therapeutic dose of each (40-52 mg/kg/day of DOLOBID (diflunisal) /acetaminophen), resulted in greater gastrointestinal toxicity than when either drug was administered alone. The clinical significance of these findings has not been established.

Antacids

Concomitant administration of antacids may reduce plasma levels of DOLOBID (diflunisal) . This effect is small with occasional doses of antacids, but may be clinically significant when antacids are used on a continuous schedule.

Aspirin

When DOLOBID (diflunisal) is administered with aspirin, its protein binding is reduced, although the clearance of free DOLOBID (diflunisal) is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diflunisal and aspirin is not generally recommended because of the potential of increased adverse effects.

In normal volunteers, a small decrease in diflunisal levels was observed when multiple doses of DOLOBID (diflunisal) and aspirin were administered concomitantly.

Cyclosporine

Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.

Diuretics

Clinical studies, as well as post marketing observations, have shown that DOLOBID (diflunisal) can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

In normal volunteers, concomitant administration of DOLOBID (diflunisal) and hydrochlorothiazide resulted in significantly increased plasma levels of hydrochlorothiazide. DOLOBID (diflunisal) decreased the hyperuricemic effect of hydrochlorothiazide. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

NSAIDs

The administration of diflunisal to normal volunteers receiving indomethacin decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients the combined use of indomethacin and DOLOBID (diflunisal) has been associated with fatal gastrointestinal hemorrhage. Therefore, indomethacin and DOLOBID (diflunisal) should not be used concomitantly.

The concomitant use of DOLOBID (diflunisal) and other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy. The following information was obtained from studies in normal volunteers.

Sulindac: The concomitant administration of DOLOBID (diflunisal) and sulindac in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.

Naproxen: The concomitant administration of DOLOBID (diflunisal) and naproxen in normal volunteers had no effect on the plasma levels of naproxen, but significantly decreased the urinary excretion of naproxen and its glucuronide metabolite. Naproxen had no effect on plasma levels of DOLOBID (diflunisal) .

Oral Anticoagulants

In some normal volunteers, the concomitant administration of DOLOBID (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 (diflunisal) is 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 (diflunisal) and tolbutamide, no significant effects were seen on tolbutamide plasma levels or fasting blood glucose.

Drug/Laboratory Test Interactions

Serum Salicylate Assays: Caution should be used in interpreting the results of serum salicylate assays when diflunisal is present. Salicylate levels have been found to be falsely elevated with some assay methods.

Last reviewed on RxList: 2/27/2008
This monograph has been modified to include the generic and brand name in many instances.