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DRUG RECORD

 

DIFLUNISAL

OVERVIEW
Diflunisal

 

Diflunisal is a salicylic acid derivative that is used in the therapy of chronic arthritis and mild to moderate acute pain.  Diflunisal has been linked mild, transient elevations in serum aminotransferase levels during therapy as well as to rare instances of idiosyncratic drug-induced liver disease.

 

Background

Diflunisal (dye floo' ni sal) is a difluorophenol derivative of salicylic acid that has anti-inflammatory, analgesic and antipyretic actions similar to aspirin. Diflunisal is metabolized by the liver but not to salicylate.  Diflunisal is considered a non-steroidal anti-inflammatory agent (NSAID) and is believed to act by inhibition of tissue cyclo-oxygenases (Cox-1 and Cox-2) which leads to a decrease in synthesis of proinflammatory prostaglandins, important mediators in inflammatory and pain pathways.  Diflunisal was approved for use in the United States in 1982 and current indications are for chronic arthritis due to osteoarthritis or rheumatoid arthritis and for mild-to-moderate pain. Diflunisal has been shown to stabilize transthyretin variants which are involved in the pathogenesis of amyloidosis which has led to the off-label use of diflunisal in familial amyloidosis.  Diflunisal is available as tablets of 500 mg in generic forms and formerly under the brand name of Dolobid. Diflunisal is available by prescription only.  The recommended regimen in adults is an initial dose of 1000 mg, followed by 500 to 1500 mg daily in two to three divided doses based upon response and tolerance.   Diflunisal, like most NSAIDs, is generally well tolerated but side effects can include intestinal upset, nausea, heartburn, headache, somnolence, dizziness, peripheral edema and hypersensitivity reactions.

 

Hepatotoxicity

Diflunisal therapy is reported to be associated with a low rate of asymptomatic and transient serum aminotransferase elevations, which may resolve even with drug continuation. Marked aminotransferase elevations (>3 fold elevated) occur rarely. Clinically apparent liver injury with jaundice from diflunisal is uncommon; only case reports have been published. The clinical and histologic features of diflunisal hepatotoxicity, however, are distinct and resemble an immunoallergic hepatitis which is quite different from the liver injury that occurs with aspirin or other salicylates.  The latency to onset ranges from 1 to 4 weeks and the pattern of enzyme elevations is typically cholestatic but can also be mixed. Most patients have immunoallergic manifestations such as rash, fever and arthralgias; eosinophilia or atypical lymphocytosis are also common. A history of aspirin allergy has not been reported among cases with allergic reactions to diflunisal. Diflunisal is not a commonly used drug and is not mentioned in large case series on drug-induced liver injury or acute liver failure.

 

Mechanism of Injury

The mechanism of diflunisal hepatotoxicity is likely hypersensitivity and is different from that of acetylsalicylic acid (aspirin).

 

Outcome and Management

Severity ranges from asymptomatic elevations in serum aminotransferase levels, to symptomatic cholestatic hepatitis with or without jaundice. It is not clear if there is cross-sensivitiy to liver injury between diflunisal an other salicylates.

 

Drug Class: Salicylates

Other drugs within this class: Salsalate, Aspirin, Trisalicylate

 

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CASE REPORT
Diflunisal

 

Case 1. Cholestatic jaundice arising after a few days of diflunisal therapy.
[Modified from: Geoffroy P, Carteret E, Salagnac V, Kalis B, Zeitoun P. [Hepatitis caused by diflunisal (Dolobis). Apropos of a case]. Therapie. 1987; 42: 253. French. PubMed Citation.

 

A 65 year-old woman with venous stasis ulcers was given diflunisal (750 mg daily) for leg pain while being treated with intravenous penicillin for suspected cellulitis. When therapy was started, serum enzymes and bilirubin levels were normal (Table). Diflunisal was stopped after 3 days because of gastrointestinal intolerance. Five days later blood tests showed marked elevations of alkaline phosphatase with mild hyperbilirubinemia. There was eosinophilia but no rash, lymphadenopathy or further fever. She had had a cholecystectomy in the past, but no history of liver disease or risk factors for viral hepatitis were mentioned. Ultrasound of the abdomen and endoscopic retrograde cholangiopancreatography were unrevealing. A liver biopsy showed portal inflammation with eosinophils and lobular histocytic granulomas. Over the next weeks laboratory test abnormalities fell toward normal despite continuation of penicillin and her medications for depression (clorazepam and viloxazine). Four months later all blood test results were normal.

 

Key Points

 

Medication:Diflunisal (750 mg daily for 3 days)
Pattern: Cholestatic (R=0.3)
Severity: 3+ (Jaundice and prolongation of hospitalization)
Latency: 3 Days to symptoms, 8 days to detection of jaundice
Recovery: 2-4 Months
Other medications:Penicillin (iv), clorazepam, viloxazine

 

Laboratory Values

 

Time After Starting Time After Stopping AST (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
1 day 0 13 80 0.3 eosinophils 2%
8 days 5 days 60 1216 2.6 eosinophils 12%
13 days 10 days 50 1474 1.0 Liver biopsy
30 days 27 days 16 672 0.6 eosinophils 34%
2 months 2 months 19 193 0.3 eosinophils 23%
5 months 5 months 18 70 0.2 eosinophils 3%
Normal Values Not given

Comment

Despite absence of some clinical information, this is a convincing case of cholestatic jaundice caused by diflunisal. As in other cases, the latency was quite short and there was at least some evidence for an immunoallergic reaction (eosinophilia). Granulomas found on liver biopsy do not indicate “granulomatous hepatitis” but are rather further evidence of a generalized immunoallergic reaction. The rapid clinical recovery (1 month) but delayed fall of alkaline phosphatase to the normal range  (between 2 and 5 months) is typical of cholestatic drug-induced liver injury.

 

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PRODUCT INFORMATION
Diflunisal

 

REPRESENTATIVE TRADE NAMES
Diflunisal, Generic

DRUG CLASS
Anti-Inflammatory Agents

COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH

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DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Diflunisal 22494-42-4 C13-H8-F2-O3 Diflunisal  chemical structure

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REFERENCES
Diflunisal

 

References Last Updated: 22 July 2013

  1. Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. Chapter 19: The NSAIDS. In Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott Williams & Williams, 1999, pp. 517-41.  (Review of hepatotoxicity of NSAIDs published in 1999).

  2. Lewis JH, Stine JG. Nonsteroidal anti-inflammatory drugs and leukotriene receptor antagonists. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 369-402.  (Expert review of liver injury caused by NSAIDs mentions that diflunisal is a difluorophenol derivative of salicylate and can cause cholestatic injury but that there have been few published reports).

  3. Grosser T, Smyth E, FitzGerald GA. Anti-inflammatory, antipyretic, and analgesic agents; pharmacotherapy of gout. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 959-1004.  (Textbook of pharmacology and therapeutics).

  4. Warren NS. Diflunisal-induced cholestatic jaundice. Br Med J 1978; 2: 736-7. PubMed Citation.  (64 year old man who was previously treated with multiple NSAIDs without relief was placed on diflunisal [while also receiving indomethacin] and developed itching 5 days later [bilirubin 3.4 mg/dL, AST 120 U/L, Alk P 780 U/L] without eosinophilia, rash or fever and resolving within 2 months of stopping).

  5. Brogden RN, Heel RC, Pakes GE, Speight TM, Avery GS. Diflunisal: a review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis. Drugs 1980; 19: 84-106. PubMed Citation(Review of pharmacology, pharmokinetics, clinical efficacy and safety of diflunisal; "no consistent alteration in tests of renal or liver function have been reported").

  6. Umbenhauer ER. Diflunisal in the treatment of the pain of osteoarthritis. Summary of clinical studies. Pharmacotherapy 1983; 3(2 Pt 2): 55S-60S. PubMed Citation(Review of results of 5 controlled studies of diflunisal vs aspirin or ibuprofen or placebo in 1218 patients; side effects were more frequent with aspirin and ibuprofen than diflunisal but discontinuations for AST elevations occurred in 0.9% of diflunisal- vs 1% of aspirin- and none of ibuprofen-treated patients).

  7. Geoffroy P, Carteret E, Salagnac V, Kalis B, Zeitoun P. [Hepatitis caused by diflunisal  (Dolobis). Apropos of a case]. Therapie. 1987; 42: 253. French. PubMed Citation.  (65 year old woman developed mild cholestatic jaundice 5 days after a 3-day course of diflunisal [bilirubin 2.6 mg/dL, AST 60 U/L and Alk P 1216 U/L, eosinophilia], resolving in several months: Case #1).

  8. Cook DJ, Achong MR, Murphy FR. Three cases of diflunisal hypersensitivity. Canad Med Assoc J 1988; 138: 1029-30. PubMed Citation.  (Three patients with onset of fever, rash and eosinophilia [23-31%] or atypical lymphocytosis after 2-4 weeks of diflunisal therapy responding to oral and topical steroids; with bilirubin levels of normal, 0.9 and 4.9 mg/dL, ALT normal, 500 and 810 U/L, Alk P 185, 545 and 349 U/L).

  9. Zimmerman HJ. Update of hepatotoxicity due to classes of drugs in common clinical use: non-steroid drugs, anti-inflammatory drugs, antibiotics, antihypertensives, and cardiac and psychotropic agents. Semin Liver Dis 1990; 10: 322-8. PubMed Citation.  (Extensive review article on liver injury due to NSAIDs; diflunisal said to cause cholestatic injury rarely).

  10. Muller AF, Toghill PJ, Smith P. "Relapse of chronic active hepatitis"not always what it seems. Postgrad Med J 1996; 72: 431-2. PubMed Citation.  (Patient with typical autoimmune hepatitis treated with excellent response with steroids and then switched to azathioprine alone for 6 years; developed jaundice 1 month after starting diflunisal [bilirubin 2.9 mg/dL, ALT 668 U/L, Alk P 262 U/L], resolving upon stopping).

  11. Bjorsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-1101. PubMed Citation.  (Survey of all cases of drug-induced liver injury with fatal outcome from Swedish Adverse Drug Reporting system from 1966-2002: among 103 cases, none attributed to diflunisal).

  12. Rostom A, Goldkind L, Laine L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol 2005; 3: 489-98. PubMed Citation.  (Review of randomized clinical trials of NSAIDS for frequency of adverse events; ALT >3 fold ULN in 0.43% of ibuprofen, 0.43% naproxen, 0.42% celecoxib, 1.8% rofecoxib, 3.55% diclofenac and 0.29% of placebo recipients, rare liver-related serious adverse events or deaths with any; deals largely with commonly used NSAIDs and does not mention diflunisal).

  13. Lapeyre-Mestre M, de Castro AM, Bareille MP, et al. Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems. Fundam Clin Pharmacol 2006; 20: 391-5. PubMed Citation.  (Analysis of reports of liver injury from NSAIDs from France and Spain from 1982-2001; diflunisal is not listed in tables of adverse event reports from NSAIDs).

  14. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation.  (Among 300 cases of drug-induced liver disease in the U.S. collected from 2004 to 2008, NSAIDs were implicated as a sole agent in 8 cases [4 diclofenac, 2 celecoxib, 1 meloxicam and 1 oxaprozin] and as one of several agents in 3 cases [1 diclofenac, 1 celecoxib, 1 ibuprofen]; diflunisal not mentioned).

  15. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation(Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug-induced liver injury of which 7 were due to NSAIDs, including 4 attributed to bromfenac, 2 to diclofenac and 1 to etodolac, but none to diflunisal). 

  16. Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, Jové J, Gatta A, et al. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study. Drug Saf 2013; 36: 135-44. PubMed Citation. (Analysis of cases of idopathic acute liver failure undergoing liver transplantation in 52 centers in Europe between 2005 and 2007, found 40 had been exposed to an NSAID but none to diflunisal).

  17. Lapeyre-Mestre M, Grolleau S, Montastruc JL; Adsociation Française des Centres Régionaux de Pharmacovigilance (CRPV). Adverse drug reactions associated with the use of NSAIDs: a case/noncase analysis of spontaneous reports from the French pharmacovigilance database 2002-2006. Fundam Clin Pharmacol 2013; 27: 223-30. PubMed Citation(Analysis of 42,389 spontaneous serious adverse event reports to the French Pharmacovigilance database on 8 NSAIDs between 2002 and 2006; liver adverse events were most frequent with nimesulide [0.15 per million daily doses] compared to diclofenac [0.09], ketoprofen [0.90] piroxicam [0.60], naproxen [0.04], meloxicam [0.03], and tenoxicam [0.03]; diflunisal is not discussed). 

 

 

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Diflunisal

 

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