Skip Navigation

 

 

DRUG RECORD

 

BENZBROMARONE

OVERVIEW
Benzbromarone

 

Benzbromarone is a nonpurine xanthine oxidase inhibitor used for the treatment of gout, but never approved for use in the United States because of concerns over reports of acute liver injury and deaths with its use.

 

Background

Benzbromarone (benz broe' ma rone) is a nonpurine inhibitor of xanthine oxidase that shares no structural homology to allopurinol or to hypoxanthine, but rather is a structural homologue of amiodarone and dronedarone.  Therapy leads to lowering of serum uric acid levels within a few weeks, and chronic therapy has been shown to decrease uric acid levels into target levels of <6 mg/dL and to decrease acute gouty attacks.  Benzbromarone was approved for use in Europe and Asia, but was not licensed in the United States because of concerns over hepatotoxicity.  Benzbromarone was withdrawn by its sponsor in 2003 because of continuing concerns over hepatotoxicity.

 

Hepatotoxicity

Liver test abnormalities have been reported to occur rarely during benzbromarone therapy, in only 0.1% of patients in clinical trials.  Furthermore, it was used widely for many years without reports of hepatotoxicity until the late 1980s, after which several cases of acute liver injury and acute liver failure during benzbromarone therapy were published.  Hepatic injury arises after 1 to 6 months of therapy presenting with jaundice and fatigue, usually with a hepatocellular pattern of enzyme elevations.  Immunoallergic symptoms (rash, fever) are uncommon.  Low levels of autoantibodies have been reported in some cases with liver histology demonstrating chronic active hepatitis, but in most instances resolution with stopping therapy is typical.  The hepatic injury from benzbromarone is similar to that reported with benzarone, a structurally related drug that was used for peripheral vascular disease, but also withdrawn also because of concerns over hepatotoxicity.

 

Mechanism of Injury

The mechanism of benzbromarone hepatotoxicity is believed to be due to its hepatic metabolism by CYP 2C9 and possible effects of the parent compound or its metabolites on mitochondrial function.  Benzbromarone is a benzofuran and shares structural similarities with benzarone and amiodarone, all three of which affect mitochondrial function.

 

Outcome and Management

Acute cases of benzbromarone and benzarone hepatotoxicity have varied in severity, but a high proportion of cases developed acute liver failure leading to death or emergency liver transplantation.  Chronic liver injury and vanishing bile duct syndrome related to these agents have not been reported.  Recurrence is common and can be severe with rechallenge which should be avoided.

 

Drug Class:  Antigout Agents

 

Other Drugs in the Class:  Allopurinol, Colchicine, Febuxostat, Probenecid

 

Top of page


CHEMICAL FORMULAS AND STRUCTURES
Benzbromarone and Related Compounds
DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Benzbromarone 3562-84-3 C17-H12-Br2-O3 Benzbromarone chemical structure
Amiodarone 1951-25-3 C25-H29-12-N-O3 Amiodarone chemical structure
Benzarone 1477-19-6 C17-H14-O3
Dronedarone 141626-36-0 C31-H45-CIN2-O5-S

Top of page


REFERENCES
Benzbromarone and Benzarone

 

References updated: 16 May 2014

 

  1. Grosser T, Smyth E, FitzGerald GA. Pharmacology 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. 994-1004.  (Textbook of pharmacology and therapeutics).

  2. Babany G, Larrey D, Pessayre D, Degott C, Rueff B, Benhamou JP. Chronic active hepatitis caused by benzarone. J Hepatol 1987; 5: 332-5. PubMed Citation  (61 year old woman developed jaundice after more than a year of benzarone therapy [bilirubin 4.4 mg/dL, ALT 38 times ULN, Alk P 1.5 times ULN], with recovery on stopping, but patient started medication again on her own twice, each time redeveloping jaundice; liver biopsy showed bridging fibrosis and chronic hepatitis; eventually recovered completely; SMA 1:500 but ANA negative).

  3. Nakad A, Azzouzi K, Gerbaux A, Delcourt A, Sempoux C, Tamo F, Rahier J, Geubel AP. [Hepatitis due to benzarone: a second case] Gastroenterol Clin Biol 1990; 14: 782-4. PubMed Citation  (70 year old woman developed jaundice 1 month after starting benzarone [a benzofurane used for peripheral vascular disease and available in France since 1964] with bilirubin 6 mg/dL, ALT 400 U/L, Alk P 415 U/L; positive rechallenge after another month of therapy with bilirubin rising to 7.1 mg/dL, ALT 1015 U/L, Alk P 392 U/L, slow recovery).

  4. Sepulchre D, De Plaen JL, Geubel AP. [Drug-induced hepatitis due to benzarone (Fragivix): apropos of a clinical case report] Acta Gastroenterol Belg 1990; 53: 499-503. PubMed Citation  (46 year old woman developed fatigue and jaundice one month after starting benzarone [bilirubin 11.3 mg/dL, ALT 1340 U/L, Alk P 400 U/L], resolution in several months; recurrence 14 days after restarting [bilirubin 16 mg/dL, ALT 1012 U/L, Alk P 157 U/L and hyperglobulinemia], resolving within 2 months of stopping).

  5. van der Klauw MM, Houtman PM, Stricker BH, Spoelstra P. Hepatic injury caused by benzbromarone. J Hepatol 1994; 20: 376-9. PubMed Citation  (68 year old woman developed malaise and jaundice 3 months after switching from allopurinol to benzbromarone [bilirubin 4.9 mg/dL, ALT 793 U/L, Alk P 217 U/L], full recovery and positive rechallenge 6 weeks after restarting therapy).

  6. Gehenot M, Horsmans Y, Rahier J, Geubel AP. Subfulminant hepatitis requiring liver transplantation after benzarone administration. J Hepatol 1994; 20: 842. PubMed Citation  (62 year old woman developed jaundice and fatigue 10 weeks after starting benzarone therapy for venous insufficiency [bilirubin 2.1 rising to 8.0 mg/dL, ALT 160 rising to 3792 U/L], with subsequent hepatic failure and death, autopsy showing confluent necrosis).

  7. Hautekeete ML, Henrion J, Naegels S, deNeve A, Alder M, Deprez C, Devis G, Kloppel G. Severe hepatotoxicity related to benzarone: a report of three cases with two fatalities. Liver 1995; 15: 25-9. PubMed Citation  (2 women and 1 man, ages 35, 67 and 68 years, developed jaundice 1.5-5 months after starting benzarone for peripheral vascular disease [bilirubin 4.6-29 mg/dL, ALT 819-1810 U/L, Alk P 164-282 U/L]; 1 died, 1 transplanted, 1 developed cirrhosis).

  8. Wagayama H, Shiraki K, Sugimoto K, et al. Fatal fulminant hepatic failure associated with benzbromarone. J Hepatol 2000; 32: 874. PubMed Citation  (62 year old man developed jaundice 5 months after starting benzbromarone with bilirubin rising to 31.2 mg/dL, AST 1369 U/L, progressing to hepatic failure and death; lymphocyte stimulation test negative).

  9. Suzuki T, Suzuki T, Kimura M, Shinoda M, Fujita T, Miyake N, Yamamoto S, Tashiro K. A case of fulminant hepatitis, possibly caused by benzbromarone. Nippon Shokakibyo Gakkai Zasshi 1001; 98: 421-5. PubMed Citation  (58 year old man developed jaundice after 7 months of benzbromarone therapy [bilirubin 7.9 mg/dL, ALT 1168, Alk P 792 U/L], progressing to hepatic failure, lymphocyte stimulation test negative).

  10. Arai M, Yokosuka O, Fujiwara K, Kojima H, Kanda T, Hirasawa H, Saisho H. Fulminant hepatic failure associated with benzbromarone treatment: a case report. J Gastroenterol Hepatol 2002; 17: 625-6. PubMed Citation  (53 year old woman developed jaundice 2 months after starting benzbromarone for hyperuricemia [bilirubin 23.3 mg/dL, ALT 1140 U/L and Alk P 123 U/L], with progressive downhill course despite stopping the medication; living donor liver transplantation done and explant showed massive necrosis).

  11. Kaufmann P, Trk M, Hnni A, Roberts P, Gasser R, Krhenbhl S. Mechanisms of benzarone and benzbromarone-induced hepatic toxicity. Hepatology 2005; 41: 925-35. PubMed Citation  (In vitro studies showing effects of benzarone and benzbromarone on hepatic mitochondrial function, inhibiting beta-oxidation and uncoupling oxidative phosphorylation, causing hepatocellular apoptosis).

  12. Lee MH, Graham GG, Williams KM, Day RO. A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients? Drug Saf 2008; 31: 643-65. PubMed Citation  (Benzbromarone was introduced in 1970s and available in ~20 countries, never in the US, withdrawn by sponsor in 2003 because of hepatotoxicity; among 11 published cases, 9 were fatal; estimated rate of hepatotoxicity 1:17,000; authors argue for its use in refractory gout).

  13. Haring B, Kudlich T, Rauthe S, Melcher R, Geier A. Benzbromarone: a double-edged sword that cuts the liver? Eur J Gastroenterol Hepatol 2013; 25: 119-21. PubMed Citation  (77 year old woman developed jaundice 4 months after starting benzbromarone [bilirubin 9.5 mg/dL, ALT 1771 U/L, Alk P 194 U/L, ANA positive] with progressive hepatic failure and death 53 days after presentation).

 

 

Top of page


OTHER REFERENCE LINKS
Benzbromarone

  1. PubMed logoRecent References on Benzbromarone

  2. Clinical Trials logoTrials on Benzbromarone

  3. TOXLINE logoTOXLINE Citations on Benzbromarone

Top of page