Brands, Medical Use, Clinical Data
Drug Category
- Anti-Inflammatory Agents, Non-Steroidal
- Cyclooxygenase Inhibitors
Dosage Forms
- Tablets for oral administration (250 mg or 500 mg)
Brands / Synonyms
Adomal; Difludol; Dolisal; Dolobid; Dolobil; Dolobis; Flovacil; Fluniget; Fluodonil; Flustar
Indications
For acute or long-term use for symptomatic treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis.
Pharmacology
Diflunisal is a nonsteroidal 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 0-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.
Mechanism of Action
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.
Absorption
Rapidly and completely absorbed following oral administration, with a bioavailability of 80-90%.
Toxicity
Oral LD50 in rat, mouse, and rabbit is 392 mg/kg, 439 mg/kg, and 603 mg/kg, respectively. Symptoms of overdose include coma, tachycardia, stupor, and vomiting. The lowest dose without the presence of other medicines which caused death was 15 grams.
Biotrnasformation / Drug Metabolism
Hepatic, primarily via glucuronide conjugation (90% of administered dose).
Contraindications
Patients who are hypersensitive to this product. Patients in whom acute asthmatic attacks, urticaria, or rhinitis
are precipitated by aspirin or other nonsteroidal anti-inflammatory drugs.
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 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.
Tolbutamide: In diabetic patients receiving diflunisal and tolbutamide, no significant effects were seen on
tolbutamide plasma levels or fasting blood glucose.
Hydrochlorothiazide: In normal volunteers, concomitant administration of diflunisal and hydrochlorothiazide
resulted in significantly increased plasma levels of hydrochlorothiazide. Diflunisal decreased the hyperuricemic
effect of hydrochlorothiazide.
Furosemide: In normal volunteers, the concomitant administration of diflunisal and furosemide had no effect
on the diuretic activity of furosemide. Diflunisal decreased the hyperuricemic effect of furosemide.
Antacids: Concomitant administration of antacids may reduce plasma levels of diflunisal. This effect is
small with occasional doses of antacids, but may be clinically significant when antacids are used on a continuous
schedule.
Acetaminophen: In normal volunteers, concomitant administration of diflunisal and acetaminophen resulted in
an approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma levels of
diflunisal. Since acetaminophen in high doses has been associated with hepatotoxicity, concomitant administration of
diflunisal and acetaminophen should be used cautiously, with careful monitoring of patients.
Concomitant administration of diflunisal and acetaminophen in dogs, but not in rats, at approximately 2 times the
recommended maximum human therapeutic dose of each (40 to 52 mg/kg/day of diflunisal/acetaminophen) resulted in
greater gastrointestinal toxicity than when either drug was administered alone. The clinical significance of these
findings has not been established.
Methotrexate: Caution should be used if diflunisal is administered concomitantly with methotrexate.
Nonsteroidal anti-inflammatory drugs have been reported to decrease the tubular secretion of methotrexate and to
potentiate its toxicity.
Cyclosporine: Administration of nonsteroial 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.
Nonsteroidal Anti-Inflammatory Drugs
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
diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, indomethacin and diflunisal should
not be used concomitantly.
The concomitant use of diflunisal tablets 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.
Aspirin: In normal volunteers, a small decrease in diflunisal levels was observed when multiple doses of
diflunisal and aspirin were administered concomitantly.
Sulindac: The concomitant administration of 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 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 diflunisal.
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.
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