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indicationFor symptomatic treatment of mild to moderate pain accompanied by inflammation (e.g. musculoskeletal trauma, post-dental extraction, post-episiotomy), osteoarthritis, and rheumatoid arthritis.
pharmacologyDiflunisal 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 actionThe 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.
toxicityOral LD50 in rat, mouse, and rabbit is 392 mg/kg, 439 mg/kg, and 603 mg/kg, respectively. Symptoms of overdose include drowsiness, nausea, vomiting, diarrhea, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, and coma. The lowest dose without the presence of other medicines which caused death was 15 grams.
Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e.g. myocardial infarction, stroke) in some patients. Current data is insufficient to assess the cardiovascular risk of diflunisal. Short-term use does not appear to be associated with increased cardiovascular risk (except when used immediately following coronary artery bypass graft (CABG) surgery). Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Severe hepatic reactions, including cholestasis and/or jaundice, have been reported. May cause rash or hypersensitivity syndrome.
biotransformationHepatic, primarily via glucuronide conjugation (90% of administered dose).
absorptionRapidly and completely absorbed following oral administration, with a bioavailability of 80-90%. Peak plasma concentrations are achieved 2 - 3 hours following oral administration.
half life8 to 12 hours
route of eliminationThe 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.
drug interactionsAcenocoumarol: The NSAID, diflunisal, may increase the anticoagulant effect of acenocoumarol.
Alendronate: Increased risk of gastric toxicity
Anisindione: The NSAID, diflunisal, may increase the anticoagulant effect of anisindione.
Colesevelam: Bile acid sequestrants may decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Monitor for decreased serum concentrations/therapeutic effects of nonsteroidal anti-inflammatory agents (NSAID) if coadministered with bile acid sequestrants. Separating the administration of doses by 2 or more hours may reduce (but not eliminate) the risk of interaction. The manufacturer of colesevelam recommends that drugs should be administered at least 1 hour before or 4 hours after colesevelam.
Dicumarol: The NSAID, diflunisal, may increase the anticoagulant effect of dicumarol.
Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
Indomethacin: Concomitant therapy with the two NSAIDs, indomethacin and diflunisal, increases the risk of NSAID-related adverse effects (e.g. GI ulcers, bleeds, increased blood pressure).
Lithium: The NSAID, diflunisal, may decrease the renal excretion of lithium. Increased risk of lithium toxicity.
Methotrexate: The NSAID, diflunisal, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Probenecid: Probenecid increases toxicity of diflunisal
Telmisartan: Concomitant use of Telmisartan and Diflunisal may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.
Timolol: The NSAID, Diflunisal, may antagonize the antihypertensive effect of Timolol.
Trandolapril: The NSAID, Diflunisal, may reduce the antihypertensive effect of Trandolapril. Consider alternate therapy or monitor for changes in Trandolapril efficacy if Diflunisal is initiated, discontinued or dose changed.
Treprostinil: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Diflunisal. Monitor for increased bleeding during concomitant thearpy.
Warfarin: The antiplatelet effects of diflunisal may increase the bleed risk associated with warfarin. Consider alternate therapy or monitor for signs and symptoms of bleeding during concomitant therapy.