DIFLUNISAL MODE OF ACTION:
The precise mechanism of the analgesic and anti-inflammatory actions of diflunisal is not known. Diflunisal is a prostaglandin synthetase inhibitor.
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.
Diflunisal is indicated for acute or long-term use for symptomatic treatment of the following:
- Mild to moderate pain
- Rheumatoid arthritis
DOSAGE AND ADMINISTRATION:
For mild to moderate pain, an initial dose of 1000 mg followed by 500 mg every 12 hours is recommended for most patients. Following the initial dose, some patients may require 500 mg every 8 hours.
A lower dosage may be appropriate depending on such factors as pain severity, patient response, weight, or advanced age; for example, 500 mg initially, followed by 250 mg every 8 to 12 hours.
For osteoarthritis and rheumatoid arthritis, the suggested dosage range is 500 mg to 1000 mg daily in two divided doses. The dosage of diflunisal may be increased or decreased according to patient response.
Maintenance doses higher than 1500 mg a day are not recommended.
Diflunisal is contraindicated in patients with known hypersensitivity to diflunisal or the excipients .
Diflunisal should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/analphylactoid reactions to NSAIDs have been reported in such patients .
Diflunisal is contraindicated in the setting of coronary artery bypass graft (CABG) surgery
DIFLUNISAL DRUG INTERACTIONS:
ACE-inhibitors and Angiotensin II Anagonists
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 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 tablets and acetaminophen should be used cautiously, with careful monitoring of patients.
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.
When diflunisal is administered with aspirin, its protein binding is reduced, although the clearance of free diflunisal is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diflunisal tablets and aspirin is not generally recommended because of the potential of increased adverse effects.
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.
During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure , as well as to assure diuretic efficacy.
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance.
Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
Caution should be used when NSAIDs are administered concomitantly with methotrexate as they may enhance the toxicity of methotrexate.
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.
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.
Concomitant administration of diflunisal and warfarin, acenocoumarol, or phenprocoumon results in prolongation of prothrombin time. This may occur because diflunisal competitively displaces coumarins from protein binding sites. Accordingly, when diflunisal 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.
In diabetic patients receiving 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.
DIFLUNISAL DRUG ADVERSE REACTIONS / EFFECTS:
The inhibition of prostaglandins has the effect of decreasing the protection given to the stomach from its own acid. Like all NSAIDS, this leads to an increased risk of stomach ulcers, and their complications, with long-term use. Elderly users of diflunisal are at greater risk for serious GI events.
- Increased risk of GI events including bleeding, ulceration, and stomach or intestine perforation.
- Abdominal pain or cramps
- Nausea and vomiting
- Irregular heart beat
- Possible increased risk of serious and potentially fatal cardiovascular thrombotic events, MI, and stroke
- Risks may increase with duration of use and for cardiovascular disease history
Ear, nose, throat, and eye
- Ringing in the ears
- Yellowing of eyes
Central nervous system
- Swelling of the feet, ankles, lower legs, and hands
- Yellowing of skin
Clinical | Pharmacokinetic data
Routes of Administration: Oral
Protein Binding: >99%
Onset of Action:
Elimination Half life: 8 to 12 hours
Legal Status | Dosage forms & Strengths
Prescription only Medicine (POM) , ℞-only
Narcotic Drugs and Psychotropic Substances (Control ) Act Schedule:
This Drug is not Subject to DDA drugs Act
Dosage Forms | Strengths:
|CompTox Dashboard (EPA)|
- PPB Drug Retention Register
- Stone, C. A., et al. “Pharmacology and toxicology of diflunisal.” British journal of clinical pharmacology 4.Suppl 1 (1977): 19S.
- Sekijima, Yoshiki, Maria A. Dendle, and Jeffery W. Kelly. “Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis.” Amyloid 13.4 (2006): 236-249.
- FORBES, JAMES A., et al. “A 12‐hour evaluation of the analgesic efficacy of diflunisal, aspirin, and placebo in postoperative dental pain.” The Journal of Clinical Pharmacology 22.2‐3 (1982): 89-96.
- Brogden RN, Heel RC, Pakes GE, Speight TM, Avery GS (February 1980). “Diflunisal: a review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis”. Drugs. 19 (2): 84–106.