Diflunisal

Pronunciation

(dye FLOO ni sal)

U.S. Brand Names

Dolobid®

Generic Available

Yes

Canadian Brand Names

Apo-Diflunisal®; Novo-Diflunisal; Nu-Diflunisal

Use

Management of inflammatory disorders usually including rheumatoid arthritis and osteoarthritis; can be used as an analgesic for treatment of mild to moderate pain

Use - Dental

Treatment of postoperative pain

Pregnancy Risk Factor

C (1st and 2nd trimesters); D (3rd trimester)

Lactation

Enters breast milk/use caution

Contraindications

Hypersensitivity to diflunisal or any component of the formulation; may be a cross-sensitivity with other NSAIDs including aspirin; should not be used in patients with active GI bleeding; pregnancy (3rd trimester)

Warnings/Precautions

Peptic ulceration and GI bleeding have been reported; platelet function and bleeding time are inhibited; ophthalmologic effects; impaired renal function, use lower dosage; dehydration; peripheral edema; possibility of Reye's syndrome; elevation in liver tests. Withhold for at least 4-6 half-lives prior to surgical or dental procedures.

Adverse Reactions

>10%:

Central nervous system: Headache

Endocrine & metabolic: Fluid retention

1% to 10%:

Cardiovascular: Angina pectoris, arrhythmia

Central nervous system: Dizziness

Dermatologic: Rash

Gastrointestinal: GI ulceration

Genitourinary: Vaginal bleeding

Otic: Tinnitus

<1%: Chest pain, vasculitis, tachycardia, convulsions, hallucinations, mental depression, drowsiness, nervousness, insomnia, toxic epidermal necrolysis, urticaria, exfoliative dermatitis, itching, erythema multiforme, Stevens-Johnson syndrome, angioedema, stomatitis, esophagitis or gastritis, cystitis, hemolytic anemia, agranulocytosis, thrombocytopenia, hepatitis, peripheral neuropathy, trembling, weakness, blurred vision, change in vision, decreased hearing, interstitial nephritis, nephrotic syndrome, renal impairment, wheezing, dyspnea, anaphylaxis, diaphoresis (increased)

Overdosage/Toxicology

Symptoms of overdose include drowsiness, nausea, vomiting, hyperventilation, tachycardia, tinnitus, stupor, coma, renal failure, and leukocytosis. Management of NSAID intoxication is supportive and symptomatic.

Drug Interactions

ACE inhibitors: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure

Angiotensin II antagonists: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure

Antacids: Decreased effect (may decrease absorption)

Increased effect/toxicity: Digoxin, anticoagulants, phenytoin, sulfonylureas, sulfonamides, lithium, hydrochlorothiazide, acetaminophen (levels)

Methotrexate: Severe bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant NSAID therapy. Avoid use during moderate or high-dose methotrexate (increased and prolonged methotrexate levels). NSAID use during low-dose treatment of rheumatoid arthritis has not been fully evaluated; extreme caution is warranted.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may enhance gastric mucosal irritation).

Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng (all have additional antiplatelet activity).

Mechanism of Action

Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase, which results in decreased formation of prostaglandin precursors

Pharmacodynamics/Kinetics

Onset of action: Analgesic: ~1 hour

Duration: 8-12 hours

Absorption: Well absorbed

Distribution: Enters breast milk

Metabolism: Extensively hepatic

Half-life elimination: 8-12 hours; prolonged with renal impairment

Time to peak, serum: 2-3 hours

Excretion: Urine (~3% as unchanged drug, 90% as glucuronide conjugates) within 72-96 hours

Dosage

Adults: Oral:

Osteoarthritis: 500-750 mg/day in divided doses

Pain: Initial: 500-1000 mg followed by 250-500 mg every 8-12 hours; maximum daily dose: 1.5 g

Inflammatory condition: 500-1000 mg/day in 2 divided doses; maximum daily dose: 1.5 g

Dosing adjustment in renal impairment: Clcr<50 mL/minute: Administer 50% of normal dose

Administration

Tablet should be swallowed whole; do not crush or chew.

Test Interactions

Decrease in uric acid (S), increase in salicylate levels (S), increase in bleeding time

Dietary Considerations

Should be taken with food to decrease GI distress.

Patient Education

If self-administered, use exactly as directed; do not increase dose or frequency. Adverse reactions can occur with overuse. Consult your prescriber before use if you have hypertension or heart failure. Do not take longer than 3 days for fever, or 10 days for pain without consulting medical advisor. Take with food or milk. While using this medication, do not use alcohol, excessive amounts of vitamin C, or salicylate-containing foods (curry powder, prunes, raisins, tea, or licorice), other prescription or OTC medications containing aspirin or salicylate, or other NSAIDs without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience nausea, vomiting, gastric discomfort (frequent mouth care, small, frequent meals, chewing gum, or sucking lozenges may help). GI bleeding, ulceration, or perforation can occur with or without pain. Stop taking medication and report ringing in ears; persistent stomach pain; unresolved nausea or vomiting; respiratory difficulty or shortness of breath; unusual bruising or bleeding (mouth, urine, stool); skin rash; unusual swelling of extremities; chest pain; or palpitations. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 3rd trimester of pregnancy. Consult prescriber if breast-feeding.

Additional Information

Diflunisal is a salicylic acid derivative which is chemically different than aspirin and is not metabolized to salicylic acid. It is not considered a salicylate. Diflunisal 500 mg is equal in analgesic efficacy to aspirin 650 mg, acetaminophen 650 mg, and acetaminophen 650 mg/propoxyphene napsylate 100 mg, but has a longer duration of effect (8-12 hours). Not recommended as an antipyretic. Not found to be clinically useful to treat fever; at doses

2 g/day, platelets are reversibly inhibited in function. Diflunisal is uricosuric at 500-750 mg/day; causes less GI and renal toxicity than aspirin and other NSAIDs; fecal blood loss is ¹ /2 that of aspirin at 2.6 g/day.

Anesthesia and Critical Care Concerns/Other Considerations

The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) suggest that NSAIDs may be used in combination with opioids in select patients for pain management. Concern about adverse events (increased risk of renal dysfunction, altered platelet function and gastrointestinal irritation) limits its use in patients who have other underlying risks for these events.

In short-term use, NSAIDs vary considerably in their effect on blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema; may precipitate renal failure in dehydrated patients.

Diflunisal is a salicylic acid derivative which is chemically different than aspirin and is not metabolized to salicylic acid. Diflunisal 500 mg is equal in analgesic efficacy to aspirin 650 mg, acetaminophen 650 mg, and acetaminophen 650 mg/propoxyphene napsylate 100 mg, but has a longer duration of effect (8-12 hours). It is not recommended as an antipyretic. At doses 2 g/day, platelets are reversibly inhibited in function. Diflunisal is uricosuric at 500-750 mg/day. It causes less GI and renal toxicity than aspirin and other NSAIDs. Fecal blood loss is ¹ /2 that of aspirin at 2.6 g/day.

Cardiovascular Considerations

In short-term use, NSAIDs vary considerably in their effect on blood pressure. A recent meta-analysis (see References) showed that indomethacin and naproxen had the largest effect on blood pressure. Other NSAIDs, including piroxicam, ibuprofen, and sulindac had less of an effect. Ibuprofen combined with captopril or losartan may attenuate the antihypertensive effects of ACE inhibition or receptor blockade on sitting or 24-hour ambulatory diastolic blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema. One study showed that NSAID use in elderly patients had an increased risk of hospitalization for heart failure. This study gives compelling reasons to avoid or limit the use of NSAIDs in patients with congestive heart failure, particularly in the elderly population.

Dental Health: Effects on Dental Treatment

NSAID formulations are known to reversibly decrease platelet aggregation via mechanisms different than observed with aspirin. The dentist should be aware of the potential of abnormal coagulation. Caution should also be exercised in the use of NSAIDs in patients already on anticoagulant therapy with drugs such as warfarin (Coumadin®).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness; rarely may cause insomnia, nervousness, depression, and hallucinations

Mental Health: Effects on Psychiatric Treatment

May rarely cause may agranulocytosis; use caution with clozapine and carbamazepine; may decrease the clearance of lithium resulting in elevated serum levels and potential toxicity; monitor serum lithium levels

Dosage Forms

Tablet: 250 mg, 500 mg

References

Arias J, Fernandez-Rivas M, Moral A, et al, "Selective Adverse Reactions to Diflunisal," Ann Allergy Asthma Immunol , 1995, 74(2):160-2.

Balali-Mood M and Prescott LF, "Failure of Alkaline Diuresis to Enhance Diflunisal Elimination," Br J Clin Pharmacol , 1980, 10(2):163-5.

Brooks PM and Day RO, "Nonsteroidal Anti-inflammatory Drugs-Differences and Similarities," N Engl J Med , 1991, 324(24):1716-25.

Conlin P, Moore T, Swartz S, et al, "Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients," Hypertension , 2000, 36(3):461-5.

Dionne RA, "New Approaches to Preventing and Treating Postoperative Pain," J Am Dent Assoc , 1992, 123(6):26-34.

"Drugs for Pain," Med Lett Drugs Ther , 1998, 40(1033):79-84.

Forbes JA, Butterworth GA, Burchfield WH, et al, "A 12-Hour Evaluation of the Analgesic Efficacy of Diflunisal, Zomepirac Sodium, Aspirin, and Placebo in Postoperative Oral Surgery Pain," Pharmacotherapy , 1983, 3(2 Pt 2):38S-46S.

Forbes JA, Calderazzo JP, Bowser MW, et al, "A 12-Hour Evaluation of the Analgesic Efficacy of Diflunisal, Aspirin, and Placebo in Postoperative Dental Pain," J Clin Pharmacol , 1982, 22(2-3):89-96.

Gobetti JP, "Controlling Dental Pain," J Am Dent Assoc , 1992, 123(6):47-52.

Gurwitz JH, Avorn J, Ross-Degnan D, et al, "Nonsteroidal Anti-Inflammatory Drug-Associated Azotemia in the Very Old," JAMA , 1990, 264(4):471-5.

Hawkey CJ, Karrasch JA, Szczepañski L, et al, "Omeprazole Compared With Misoprostrol for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):727-34.

Heerdink ER, Leufkens HG, Herings RM, et al, "NSAIDs Associated With Increased Risk of Congestive Heart Failure in Elderly Patients Taking Diuretics," Arch Intern Med , 1998, 158(10):1108-12.

Jacobi J, Fraser GL, Coursin DB, et al, "Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult," Crit Care Med , 2002, 30(1):119-41. Available at: http://www.sccm.org/pdf/sedatives.pdf. Accessed August 2, 2003.

Morgan TO, Anderson A, and Bertram D, "Effect of Indomethacin on Blood Pressure in Elderly People With Essential Hypertension Well Controlled on Amlodipine or Enalapril," Am J Hypertens , 2000, 13(11):1161-7.

Page J and Henry D, "Consumption of NSAIDs and the Development of Congestive Heart Failure in Elderly Patients: An Underrecognized Public Health Problem," Arch Intern Med , 2000, 160(6):777-84.

Pope JE, Anderson JJ, and Felson DT, "A Meta-analysis of the Effects of Nonsteroidal Anti-inflammatory Drugs on Blood Pressure," Arch Intern Med , 1993, 153(4):477-84.

Upadhyay HP and Gupta SK, "Diflunisal (Dolobid®) Overdosage," Br Med J , 1978, 2(6137):640.

Yeomans ND, Tulassay Z, Juhasz L, et al, "A Comparison of Omeprazole With Ranitidine for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):719-26.

International Brand Names

Apo-Diflunisal® (CA); Artrodol® (IT); Biartac® (BE, LU); Diflusal® (BE, LU); Dolobid® (AU, EG, ES, GB, HK, IE, IT, MX, PT, TH, ZA); Dolobis® (FR); Dolocid® (NL); Dolphin® (TR); Donobid® (DK, FI, NO, SE); Dorbid® (BR); Fluniget® (AT); Novo-Diflunisal (CA); Nu-Diflunisal (CA); Unisal® (CZ)

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