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BENZBROMARONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This is a uricosuric drug used in Europe for some time (Masbernard & Giudicelli, 1981). At the time of this review, benzbromarone has not been approved by the USFDA.

Specific Substances

    1) benzbromaron
    2) benzbromaronum
    3) L-2214
    4) MJ-10061
    5) 3,5-dibromo-4-hydroxyphenyl-2-ethyl-3-benzofuranyl
    6) ketone
    7) (3,5-dibromo-4-hydroxyphenyl)-(2-ethyl-3-
    8) benzofuranyl) methanone
    9) CAS 3562-84-3

Available Forms Sources

    A) SOURCES
    1) TRADE NAMES IN OTHER COUNTRIES
    a) Trade names for benzbromarone in other countries include Azubromaron(R), Benzbromaron Ratiopharm(R), Benzbromaron 100 Stada(R), Benzbromaron RAN(R), Besuric(R), Desuric(R), Exurate(R), Harolan(R), Hipuric(R), Max-Uric(R), Minuric(R), Narcaricin(R), Narcaricina(R), Narcaricin-mite(R), Narcarizin(R), Normurat(R), Obaron(R), Uricovac(R), Urinome(R), and Urinorm(R).
    2) The USFDA has not provided approval for the use of benzbromarone for either adults or children.
    B) USES
    1) Benzbromarone is a uricosuric agent which is used to reduce plasma concentration of uric acid by blocking renal tubular reabsorption, and used in the treatment of hyperuricemia including conditions associated with chronic gout (JEF Reynolds , 2000). It is not used in the treatment of acute attacks of gout.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Therapeutic side effects include some diarrhea, two cases of hepatitis, and some allergic skin and eye reactions.
    B) WITH POISONING/EXPOSURE
    1) There have been little or no effects seen in overdose.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Allergic conjunctivitis has been seen with therapy.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Diarrhea has occasionally occurred with therapeutic use.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Benzbromarone-induced hepatic injury has occurred rarely following therapeutic use.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Rare reports of allergic dermatitis have occurred.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Elevations in SERUM CREATININE have been seen in patients receiving benzbromarone who develop acute uric acid nephropathy; serum creatinine normalizes upon treatment of the nephropathy.
    B) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.

Range Of Toxicity

    A) Minimum lethal human exposure is unknown.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Therapeutic side effects include some diarrhea, two cases of hepatitis, and some allergic skin and eye reactions.
    B) WITH POISONING/EXPOSURE
    1) There have been little or no effects seen in overdose.

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Allergic conjunctivitis has been seen with therapy.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Allergic conjunctivitis has been reported with benzbromarone (Reynolds et al, 1994).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Diarrhea has occasionally occurred with therapeutic use.
    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Mild, transient diarrhea has been observed in approximately 3 to 4% of patients during therapeutic use (Masbernard & Giudicelli, 1981; JEF Reynolds , 2000).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Benzbromarone-induced hepatic injury has occurred rarely following therapeutic use.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Rare reports of benzbromarone-induced hepatic injury has developed with therapeutic use (Sepulchre et al, 1990; (JEF Reynolds , 2000).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Rare reports of allergic dermatitis have occurred.
    3.14.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic skin reactions (pustules and petechiae) have been seen with therapeutic use (Masbernard & Giudicelli, 1981).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Elevations in SERUM CREATININE have been seen in patients receiving benzbromarone who develop acute uric acid nephropathy; serum creatinine normalizes upon treatment of the nephropathy.
    B) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Elevations in SERUM CREATININE have been reported in patients receiving benzbromarone who develop acute uric acid nephropathy; serum creatinine normalizes upon treatment of the nephropathy (Hess & Binswanger, 1990).
    2) Monitor hepatic function following significant exposure.
    4.1.3) URINE
    A) URINALYSIS
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.

Methods

    A) CHROMATOGRAPHY
    1) Benzbromarone and its metabolites can be identified by gas chromatographic/mass spectrometry methods (Maurer & Wollenberg, 1990), or high performance liquid chromatography (de Vries et al, 1987).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Elevations in SERUM CREATININE have been seen in patients receiving benzbromarone who develop acute uric acid nephropathy; serum creatinine normalizes upon treatment of the nephropathy.
    B) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no specific antidote for benzbromarone.
    B) MONITORING OF PATIENT
    1) Monitor hepatic function following significant exposure.

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Range Of Toxicity

Summary

    A) Minimum lethal human exposure is unknown.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) ORAL - The usual daily dose is 50 to 300 milligrams daily (JEF Reynolds , 2000).
    a) Benzbromarone should be combined with an NSAID or colchicine to reduce the risk of precipitating acute gout, along with an adequate fluid intake (JEF Reynolds , 2000).
    b) REDUCED DOSE - A lower dose (20 or 25 milligrams) are indicated when given as a combination product with allopurinol (JEF Reynolds , 2000).
    c) Similar to other uricosurics, treatment is NOT indicated during periods of an acute attack of gout. Administration during this period could result in exacerbation or prolongation of the symptoms (JEF Reynolds , 2000).
    B) DISEASE STATE
    1) DOSAGE IN RENAL FAILURE -
    a) Heel et al (1977) reported that the efficacy of benzbromarone is decreased in the presence of renal dysfunction. Its suggested that benzbromarone be avoided in patients with moderate to severe renal insufficiency, in individuals with uric acid renal calculi, and in patients with urinary uric acid excretion rates of greater than 700 mg per 24 hours (JEF Reynolds , 2000).
    b) Masbernard & Giudicelli (1981) reported a marked decrease in efficacy of benzbromarone in patients with renal insufficiency, and the drug was ineffective in patients undergoing hemodialysis.
    2) DOSAGE ADJUSTMENT DURING DIALYSIS -
    a) HEMODIALYSIS - Benzbromarone is reportedly ineffective in patients undergoing hemodialysis (Masbernard & Giudicelli, 1981).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) The maximum tolerated human exposure to this agent has not been delineated.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) THERAPEUTIC LEVELS -
    1) The uricosuric activity of benzbromarone is not correlated with serum level.
    2) The drug increases urinary uric acid excretion shortly after an oral dose, and reduces serum urate levels by 33 percent to 59 percent in a dose-dependent manner after single or repeated dosing (Heel et al, 1977; Masbernard & Giudicelli, 1981).
    3) One study reported an onset of uricosuric action of 3 hours with a single 100 milligram oral dose of benzbromarone, with peak activity occurring 8 to 12 hours after administration (Ferber et al, 1981).
    4) In one study, the mean peak serum benzbromarone concentration was 1.84 micrograms/milliliter after administration of a single 100 milligram oral dose (Ferber et al, 1981).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 248 mg/kg ((RTECS, 2000))
    B) LD50- (SUBCUTANEOUS)RAT:
    1) 1230 mg/kg ((RTECS, 2000))
    C) LD50- (ORAL)MOUSE:
    1) 618 mg/kg ((RTECS, 2000))
    D) LD50- (SUBCUTANEOUS)MOUSE:
    1) 4120 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) This drug is an inhibitor of renal urate reabsorption at 25 mg/day or more (Masbernard & Giudicelli, 1981). It increases urinary uric acid excretion shortly after an oral dose, and reduces serum urate levels by 33% to 59% in a dose-dependent manner after single or repeated dosing.
    B) The biologic effect of 100 mg of benzbromarone is approximately equivalent to 1.5 grams of probenecid and greater than 300 mg of allopurinol (Masbernard & Giudicelli, 1981).
    C) Although benzbromarone has been shown to inhibit xanthine oxidase and nucleotide dehydrogenases at high concentrations in vitro, this activity appears to be of little significance in humans, as in vivo inhibition has not been demonstrated (Heel et al, 1977).

Physicochemical

Molecular Weight

    A) 424.11 (RTECS , 2000)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Broekhuysen J, Pacco M, & Sion R: Metabolism of benzbromarone in man. Eur J Clin Pharmacol 1972; 4:125-130.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    6) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    7) Ferber H, Vergin H, & Hitzenberger G: Pharmacokinetics and biotransformation of benzbromarone in man. Eur J Clin Pharmacol 1981; 19:431-435.
    8) Gilman AG, Rall TW, & Nies AS: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, Pergamon Press, New York, NY, 1990.
    9) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    10) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    11) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    12) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    13) Heel RC, Brogden RN, & Speight TM: Benzbromarone: a review of its pharmacological properties and therapeutic use in gout and hyperuricaemia. Drugs 1977; 14:349-366.
    14) Hess B & Binswanger U: Acute uric acid nephropathy in two gouty patients with moderate hyperuricemia and high urine acidity. Klin Wochenschr 1990; 68:874-879.
    15) JEF Reynolds : Martindale: The Extra Pharmacopoeia (internet version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    16) Masbernard A & Giudicelli CP: Ten year's experience with benzbromarone in the management of gout and hyperuricaemia. S Afr Med J 1981; 59:701.
    17) Maurer H & Wollenberg P: Urinary metabolites of benzbromarone in man. Arzneim-Forsch/Drug Res 1990; 40:460-462.
    18) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    19) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    20) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    21) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    22) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    23) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    24) Takahashi H, Sato T, & Shimoyama Y: Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone. Clin Pharmacol Ther 1999; 66:569-581.
    25) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    26) Walter-Sack I, de Vries JX, & Ittensohn A: Benzbromarone disposition and uricosuric action; evidence for hydroxilation instead of debromination to benzarone. Klin Wochenschr 1988; 66:160-166.
    27) de Vries J, Walter-Sack I, & Ittensohn A: Analysis of benzbromarone in human plasma and urine by high-performance liquid chromatography and gas chromatography-mass spectrometry. J Chromatogr 1987; 417:420-427.