Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

PROBENECID

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Probenecid is a uricosuric and renal tubular blocking agent.

Specific Substances

    1) 4-((Dipropylamino)sulfonyl)benzoic acid
    2) 4-(dipropylsulphamoyl)benzoic acid
    3) Probenecidum
    4) p-(dipropylsulfamoyl)benzoic acid
    5) p-(dipropylsulfamyl)benzoic acid
    6) Molecular Formula: C13-H19-N-O4-S
    7) CAS 57-66-9

Available Forms Sources

    A) FORMS
    1) Probenecid is available as 500 mg oral tablets (Prod Info probenecid oral tablets, 2006).
    B) USES
    1) Probenecid is used to treat hyperuricemia associated with gout and gouty arthritis. Probenecid also increases and prolongs the plasma concentrations of penicillin and some of the penicillin derived antibiotics (Prod Info probenecid oral tablets, 2006).
    2) Intramuscular cefoxitin plus oral probenecid is recommended by the CDC as an alternative to the preferred regimens of IM ceftriaxone or oral cefixime for the treatment of uncomplicated urogenital and anorectal gonococcal infections (Centers for Disease Control and Prevention, 2010).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Probenecid is used to treat hyperuricemia associated with gout and gouty arthritis. Probenecid also increases and prolongs the plasma concentrations of penicillin and some of the penicillin derived antibiotics. Intramuscular cefoxitin plus oral probenecid is recommended by the CDC as an alternative to the preferred regimens of IM ceftriaxone or oral cefixime for the treatment of uncomplicated urogenital and anorectal gonococcal infections.
    B) PHARMACOLOGY: Probenecid is a uricosuric agent which promotes urinary excretion of uric acid, thereby reducing serum urate levels by inhibiting active reabsorption of uric acid at the proximal convoluted tubules in the kidney. Probenecid is a competitive inhibitor of the secretion of weak organic acids, including penicillins and some of the cephalosporin antibiotics, at the proximal and distal renal tubules. It thereby increases blood concentrations of these antibiotics (penicillin concentrations may increase 2- to 4-fold).
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following therapeutic use of probenecid: Headache, dizziness, hepatic necrosis, nausea, vomiting, anorexia, sore gums, nephrotic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequency, anaphylaxis, fever, urticaria, pruritus, nephrotic syndrome, aplastic anemia, leukopenia, neutropenia, thrombocytopenia, hemolytic anemia (may be related to genetic deficiency of glucose-6-phosphate dehydrogenase in RBC), anemia, dermatitis, alopecia, and flushing.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Nausea, vomiting, anorexia, diarrhea, tremors, seizures, visual hallucinations, acute gouty attack, coma, respiratory failure, hypotension, and cardiac arrest may occur following an overdose.
    0.2.20) REPRODUCTIVE
    A) Probenecid is in pregnancy category B. The colchicine and probenecid combination is contraindicated during pregnancy due to the colchicine component.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential and platelets and renal function and hepatic enzymes.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression, respiratory failure, or severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) MYELOSUPPRESSION
    1) Severe neutropenia: filgrastim 5 mcg/kg/day IV or SubQ or sargramostim 250 mcg/m(2)/day IV infused over 4 hours. Monitor serial CBC with differential. Transfusions as needed for severe thrombocytopenia, bleeding.
    G) HYPERSENSITIVITY
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    H) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted. Patients with severe neutropenia, significant CNS depression, or persistent seizures should be admitted to the hospital.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected probenecid overdose, the possibility of multidrug involvement should be considered.
    K) PHARMACOKINETICS
    1) Onset of action: about 1 hour after an oral dose. Maximum effect: about 3 hours. Oral absorption is rapid with peak concentrations after an oral dose being between 1 and 5 hours in adults and 3 to 9 hours in children. Protein binding: 80% to 99%. Vd: 11 L after IV administration. Excretion: Renal: 5% to 11% is excreted unchanged in the urine. Elimination half-life: 6 to 12 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression, hepatotoxicity, or seizures.

Range Of Toxicity

    A) TOXICITY: An adult developed seizures and coma after ingesting 47.5 g of probenecid. A man ingested about 75 g of probenecid with ethanol and developed vomiting, diarrhea, seizures, coma, hypotension, and a cardiac arrest. He died 4 hours post-admission.
    B) THERAPEUTIC DOSES: ADULT: Hyperuricemia: Initial, 250 mg orally twice daily for 1 week. Maintenance, 500 mg orally twice daily; if symptoms persist or 24 hour urate excretion below 700 mg, may incrementally increase by 500 mg every 4 weeks as tolerated; MAX: 2 g/day. Adjunct to antibiotic therapy: 2 grams/day orally in divided doses. Gonorrhea: 1 g orally with IM aqueous procaine penicillin G, or oral amoxicillin, or oral ampicillin. PEDIATRIC: Adjunct to antibiotic therapy: WEIGHT 50 KG OR LESS: Initial dose: 25 mg/kg/day orally; maintenance dose: 40 mg/kg/day orally in 4 divided doses. WEIGHT GREATER THAN 50 KG: 2 g/day orally in divided doses.

Clinical Effects

Summary Of Exposure

    A) USES: Probenecid is used to treat hyperuricemia associated with gout and gouty arthritis. Probenecid also increases and prolongs the plasma concentrations of penicillin and some of the penicillin derived antibiotics. Intramuscular cefoxitin plus oral probenecid is recommended by the CDC as an alternative to the preferred regimens of IM ceftriaxone or oral cefixime for the treatment of uncomplicated urogenital and anorectal gonococcal infections.
    B) PHARMACOLOGY: Probenecid is a uricosuric agent which promotes urinary excretion of uric acid, thereby reducing serum urate levels by inhibiting active reabsorption of uric acid at the proximal convoluted tubules in the kidney. Probenecid is a competitive inhibitor of the secretion of weak organic acids, including penicillins and some of the cephalosporin antibiotics, at the proximal and distal renal tubules. It thereby increases blood concentrations of these antibiotics (penicillin concentrations may increase 2- to 4-fold).
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following therapeutic use of probenecid: Headache, dizziness, hepatic necrosis, nausea, vomiting, anorexia, sore gums, nephrotic syndrome, uric acid stones with or without hematuria, renal colic, costovertebral pain, urinary frequency, anaphylaxis, fever, urticaria, pruritus, nephrotic syndrome, aplastic anemia, leukopenia, neutropenia, thrombocytopenia, hemolytic anemia (may be related to genetic deficiency of glucose-6-phosphate dehydrogenase in RBC), anemia, dermatitis, alopecia, and flushing.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Nausea, vomiting, anorexia, diarrhea, tremors, seizures, visual hallucinations, acute gouty attack, coma, respiratory failure, hypotension, and cardiac arrest may occur following an overdose.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever has been reported with probenecid use (Prod Info probenecid oral tablets, 2006).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 36-year-old man ingested about 75 g of probenecid with ethanol after attempting to stab himself in the chest in a suicide attempt. He was found at home semi-conscious after developing vomiting and severe diarrhea. He was transported to an ED where he developed coma, seizures, hypotension, and a cardiac arrest. He died 4 hours post-admission (McIntyre et al, 1992).
    B) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 36-year-old man ingested about 75 g of probenecid with ethanol after attempting to stab himself in the chest in a suicide attempt. He was found at home semi-conscious after developing vomiting and severe diarrhea. He was transported to an ED where he developed coma, seizures, hypotension, and a cardiac arrest. He died 4 hours post-admission (McIntyre et al, 1992).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) Respiratory failure may occur in overdose (S Sweetman , 2001).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPERVENTILATION
    a) Fatally poisoned animals developed tachypnea (McKinney et al, 1951).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Stimulation of the CNS, with seizures and death from respiratory failure has been reported with massive overdosages of probenecid (S Sweetman , 2001).
    b) Seizures and tremors were reported in one overdose case where 47.5 grams of probenecid was ingested. Several instances of grand mal seizures were seen in the first 16 hours; each lasted about 30 seconds (Rizzuto et al, 1965).
    c) CASE REPORT: A 36-year-old man ingested about 75 g of probenecid with ethanol after attempting to stab himself in the chest in a suicide attempt. He was found at home semi-conscious after developing vomiting and severe diarrhea. He was transported to an ED where he developed coma, seizures, hypotension, and a cardiac arrest. He died 4 hours post-admission (McIntyre et al, 1992).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma may be seen in overdose. A patient who had ingested 95 tablets of 0.5 g each became progressively stuporous and lapsed into a coma (Rizzuto et al, 1965).
    b) CASE REPORT: A 36-year-old man ingested about 75 g of probenecid with ethanol after attempting to stab himself in the chest in a suicide attempt. He was found at home semi-conscious after developing vomiting and severe diarrhea. He was transported to an ED where he developed coma, seizures, hypotension, and a cardiac arrest. He died 4 hours post-admission (McIntyre et al, 1992).
    C) TREMOR
    1) WITH POISONING/EXPOSURE
    a) In one case, generalized mild tremors were seen 3 days after the ingestion of probenecid (Rizzuto et al, 1965).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006; Rizzuto et al, 1965).
    E) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported in patients receiving probenecid (Prod Info probenecid oral tablets, 2006; Rizzuto et al, 1965).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Vomiting was reported in one overdose case where 47.5 g of probenecid was ingested (Rizzuto et al, 1965).
    b) CASE REPORT: A 36-year-old man ingested about 75 g of probenecid with ethanol after attempting to stab himself in the chest in a suicide attempt. He was found at home semi-conscious after developing vomiting and severe diarrhea. He was transported to an ED where he developed coma, seizures, hypotension, and a cardiac arrest. He died 4 hours post-admission (McIntyre et al, 1992).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006).
    D) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 36-year-old man ingested about 75 g of probenecid with ethanol after attempting to stab himself in the chest in a suicide attempt. He was found at home semi-conscious after developing vomiting and severe diarrhea. He was transported to an ED where he developed coma, seizures, hypotension, and a cardiac arrest. He died 4 hours post-admission (McIntyre et al, 1992).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) Hepatic necrosis has been observed with use of probenecid (Prod Info probenecid oral tablets, 2006; Sweetman, 2001; Reynolds et al, 1957).
    b) CASE REPORT: A fatal case of hepatic necrosis has been reported. The necrosis may have been allergic in nature (Reynolds et al, 1957).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) KIDNEY DISEASE
    1) WITH THERAPEUTIC USE
    a) Nephrotic syndrome has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006; Hertz et al, 1972). Characteristically, the nephrotic syndrome presents with proteinuria and edema of the face and extremities (Hertz et al, 1972).
    b) Discontinuation of the drug has resulted in remission of symptoms in 2 to 4 weeks, although one case has been reported in which the patient's condition deteriorated and eventually led to death (Sokol, 1967).
    B) URINARY SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Urinary frequency has been reported with therapeutic doses (S Sweetman , 2001).
    C) KIDNEY STONE
    1) WITH THERAPEUTIC USE
    a) Uric acid stones with or without hematuria has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) A number of blood dyscrasias have been seen with probenecid therapy. Isolated cases of aplastic anemia, leukopenia, neutropenia, and thrombocytopenia have been reported (Prod Info probenecid oral tablets, 2006; Swanson & Cook, 1977).
    2) WITH POISONING/EXPOSURE
    a) Various blood dyscrasias, including hemolytic anemia, have been reported with probenecid administered therapeutically (Prod Info Benemid(R), probenecid tablets, 2000; Swanson & Cook, 1977a). It is unknown if these would be seen in overdose.
    B) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Pancytopenia developed in a 67-year-old woman. It was attributed to methotrexate toxicity potentiated by probenecid and other risk factors such as renal insufficiency and hypoalbuminemia (Basin et al, 1991).
    C) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Hemolytic anemia has been reported with probenecid use. Genetic deficiency of glucose-6-phosphate dehydrogenase in red blood cells may be a predisposing factor (Prod Info probenecid oral tablets, 2006).
    b) Probenecid has been associated with the occurrence of immune hemolytic anemia, confirmed by a positive direct antiglobulin test. Antibody was detected in the patient's serum, reacting only with red blood cells when probenecid was added (Sosler et al, 1985). Hemolytic anemia may be associated with glucose-6-phosphate dehydrogenase deficiency (S Sweetman , 2001).
    c) Hemolytic anemia occurred in a 56-year-old man following a week of treatment with probenecid 0.5 g twice daily in combination with colchicine 0.5 mg twice daily (Kickler et al, 1986).
    D) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006).
    E) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been reported in patients receiving probenecid (Prod Info probenecid oral tablets, 2006).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Flushing has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006).
    B) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Dermatitis has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006).
    D) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria has been reported in patients receiving probenecid therapy (Prod Info probenecid oral tablets, 2006).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) GOUT
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Gout attacks were seen in one case of overdose (Rizzuto et al, 1965).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis has been reported in people taking therapeutic amounts of probenecid (Prod Info probenecid oral tablets, 2006; Hilleck, 1965).
    B) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions, with fever, dermatitis, pruritus, urticaria, and Stevens Johnson syndrome have been reported following probenecid use (S Sweetman , 2001).

Reproductive

    3.20.1) SUMMARY
    A) Probenecid is in pregnancy category B. The colchicine and probenecid combination is contraindicated during pregnancy due to the colchicine component.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Probenecid is classified as pregnancy category B (Prod Info Benemid(R), 1998).
    2) The colchicine and probenecid combination is contraindicated during pregnancy due to the colchicine component. Colchicine may interrupt cell division in animals. Teratogenicity was reported with colchicine use in certain animal species under certain conditions. Such effects may also occur in humans. Probenecid crosses the placenta and appears in cord blood. Prior to using the colchicine and probenecid combination in women of childbearing potential, weigh the anticipated benefits against the potential hazards (Prod Info probenecid colchicine oral tablets, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential and platelets and renal function and hepatic enzymes.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor CBC with differential and platelets and renal function and hepatic enzymes.
    2) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4.1.3) URINE
    A) URINALYSIS
    1) GLUCOSE TESTS: Probenecid may cause a false positive test when testing for urinary glucose using the Clinitest or Benedict's solution (Hansten, 1979).
    2) PROTEIN: Proteinuria secondary to probenecid-induced nephrotoxicity may develop (Hansten, 1979).
    B) OTHER
    1) URINARY FUNCTION TESTS should be considered in those individuals who have ingested large amounts of probenecid.

Treatment

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status.
    C) Monitor CBC with differential and platelets and renal function and hepatic enzymes.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.
    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) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status.
    3) Monitor CBC with differential and platelets and renal function and hepatic enzymes.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    5) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) MYELOSUPPRESSION
    1) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.
    a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
    b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
    c) Monitor CBC with differential.
    2) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.
    E) HYPERSENSITIVITY REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted. Patients with severe neutropenia, significant CNS depression, or persistent seizures should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Abstracts

Case Reports

    A) ADULT
    1) A 49-year-old man ingested 47.5 g of probenecid in a suicide attempt. His serum urate fell to low levels, he became comatose, and developed status epilepticus. Laboratory analysis showed no changes in either the calcium or phosphorus levels or metabolism. The patient recovered with supportive care (Rizzuto et al, 1965).

Range Of Toxicity

Summary

    A) TOXICITY: An adult developed seizures and coma after ingesting 47.5 g of probenecid. A man ingested about 75 g of probenecid with ethanol and developed vomiting, diarrhea, seizures, coma, hypotension, and a cardiac arrest. He died 4 hours post-admission.
    B) THERAPEUTIC DOSES: ADULT: Hyperuricemia: Initial, 250 mg orally twice daily for 1 week. Maintenance, 500 mg orally twice daily; if symptoms persist or 24 hour urate excretion below 700 mg, may incrementally increase by 500 mg every 4 weeks as tolerated; MAX: 2 g/day. Adjunct to antibiotic therapy: 2 grams/day orally in divided doses. Gonorrhea: 1 g orally with IM aqueous procaine penicillin G, or oral amoxicillin, or oral ampicillin. PEDIATRIC: Adjunct to antibiotic therapy: WEIGHT 50 KG OR LESS: Initial dose: 25 mg/kg/day orally; maintenance dose: 40 mg/kg/day orally in 4 divided doses. WEIGHT GREATER THAN 50 KG: 2 g/day orally in divided doses.

Therapeutic Dose

    7.2.1) ADULT
    A) HYPERURICEMIA ASSOCIATED WITH GOUT AND GOUTY ARTHRITIS
    1) The recommended initial dose is 250 mg (one-half tablet) orally twice daily for 1 week, followed by a maintenance dose of 500 mg (1 tablet) orally twice daily thereafter. Doses should usually not exceed 2000 mg/day (Prod Info probenecid oral tablets, 2012).
    B) CHRONIC GOUTY ARTHRITIS
    1) COLCHICINE AND PROBENECID: The recommended dose is colchicine 0.5 mg/probenecid 500 mg once daily for one week, followed by 0.5 mg/500 mg twice daily thereafter (Prod Info probenecid colchicine oral tablets, 2009).
    C) ADJUNCT TO ANTIBIOTIC THERAPY
    1) The recommended dose is 2 g (4 tablets)/day orally in divided doses (Prod Info probenecid oral tablets, 2012)
    D) GONORRHEA
    1) The recommended dose is 1 g orally with 4.8 million units of aqueous procaine penicillin G administered IM, 3 g amoxicillin oral, or 3.5 g ampicillin oral (Prod Info probenecid oral tablets, 2012).
    7.2.2) PEDIATRIC
    A) ADJUNCT TO ANTIBIOTIC THERAPY
    1) Probenecid is contraindicated in children under age 2 years (Prod Info probenecid oral tablets, 2012).
    2) CHILDREN AGED 2 TO 14 YEARS
    a) WEIGHT 50 KG OR LESS: The recommended initial dose is 25 mg/kg orally; the recommended maintenance dose is 40 mg/kg/day orally in 4 divided doses (Prod Info probenecid oral tablets, 2012).
    b) WEIGHT GREATER THAN 50 KG: The recommended dose is 2 g (4 tablets)/day orally in divided doses (Prod Info probenecid oral tablets, 2012).

Minimum Lethal Exposure

    A) CASE REPORT: A 36-year-old man ingested about 75 g of probenecid with ethanol after attempting to stab himself in the chest in a suicide attempt. He was found at home semi-conscious after developing vomiting and severe diarrhea. He was transported to an ED where he developed seizures, coma, hypotension, and a cardiac arrest. He died 4 hours post-admission. Postmortem concentrations of probenecid were as follow: Serum: 710 mg/L; liver: 550 mg/kg; blood: 460 mg/L; bile: 340 mg/L; urine: 240 mg/L; vitreous humor: 180 mg/L; gastric contents: 11 mg. Postmortem ethanol concentrations in blood and urine were 0.13 g/100 mL and 0.16 g/100 mL, respectively (McIntyre et al, 1992).

Maximum Tolerated Exposure

    A) CASE REPORT: A 49-year-old man ingested 47.5 g of probenecid in a suicide attempt. His serum urate fell to low levels, he became comatose, and developed status epilepticus. Laboratory analysis showed no changes in either the calcium or phosphorus levels or metabolism. The patient recovered with supportive care (Rizzuto et al, 1965).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: A 36-year-old man ingested about 75 g of probenecid with ethanol after attempting to stab himself in the chest in a suicide attempt. He was found at home semi-conscious after developing vomiting and severe diarrhea. He was transported to an ED where he developed coma, seizures, hypotension, and a cardiac arrest. He died 4 hours post-admission. Postmortem concentrations of probenecid were as follow: Serum: 710 mg/L; liver: 550 mg/kg; blood: 460 mg/L; bile: 340 mg/L; urine: 240 mg/L; vitreous humor: 180 mg/L; gastric contents: 11 mg. Postmortem ethanol concentrations in blood and urine were 0.13 g/100 mL and 0.16 g/100 mL, respectively (McIntyre et al, 1992).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 1666 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)RAT:
    a) 1600 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Probenecid is a uricosuric agent which promotes urinary excretion of uric acid, thereby reducing serum urate levels by inhibiting active reabsorption of uric acid at the proximal convoluted tubules in the kidney. It may also inhibit renal secretion of uric acid in subtherapeutic doses. Plasma protein binding of urate is thought to be reduced by probenecid as well (Prod Info probenecid oral tablets, 2006).

Physicochemical

Physical Characteristics

    A) Probenecid has a slightly bitter taste and an unpleasant aftertaste. It is odorless or almost odorless (Budavari, 1996; S Sweetman , 2001).

Ph

    A) pKa: 5.8 (Budavari, 1996)

Molecular Weight

    A) 285.36 (S Sweetman , 2001)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Anderson RJ, Gambertoglio JG, & Schrier RW: Clinical Use of Drugs in Renal Failure, Charles C. Thomas, Springfield, IL, 1976.
    3) Basin KS, Escalante A, & Beardmore TD: Severe pancytopenia in a patient taking low dose methotrexate and probenecid. J Rheumatol 1991; 18:609-610.
    4) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    5) Bennett WM, Aronoff GR, & Morrison G: Drug prescribing in renal failure: dosing guidelines for adults. Am J Kidney Dis 1983; 3:155-193.
    6) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    7) Budavari S: The Merck Index, 12th ed, Merck & Co, Inc, Whitehouse Station, NJ, 1996.
    8) Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines, 2010. Centers for Disease Control and Prevention. Atlanta, GA. 2010. Available from URL: http://www.cdc.gov/mmwr/pdf/rr/rr5912.pdf. As accessed 2010-12-16.
    9) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    10) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    11) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    12) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    13) Cunningham RF, Israili ZH, & Dayton PG: Clinical pharmacokinetics of probenecid. Clin Pharmacol 1981; 6:135-151.
    14) Dayton PG: The physiological disposition of probenecid, including renal clearance in man studied by an improved method for its estimation in biological material. J Pharmacol Exp Ther 1963; 140:278.
    15) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    16) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    17) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    18) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    19) Hansten PD: Drug Interactions, 4th ed, Lea & Febiger, Philadelphia, PA, 1979.
    20) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    21) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    22) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    23) Hertz P, Yager H, & Richardson JA: Probenecid-induced nephrotic syndrome. Arch Pathol 1972; 94:241-243.
    24) Hilleck NA: Acute anaphylactoid reaction to probenecid. JAMA 1965; 193:740.
    25) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    26) Israili ZH, Perel JM, & Cunningham RF: Metabolites of probenecid. Chemical, physical, and pharmacological studies. J Med Chem 1972; 15:709-713.
    27) Jusko WJ & Gretch M: Plasma and tissue protein binding of drugs in pharmacokinetics. Drug Metab Rev 1976; 5:43.
    28) Kickler TS, Buck S, & Ness P: Probenecid induced immune hemolytic anemia. J Rheumatol 1986; 13:208-209.
    29) Koch-Weser J & Sellers EM: Binding of drugs to serum albumin (two parts). N Eng J Med 1976; 294:311.
    30) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    31) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    32) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    33) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    34) McIntyre IM, Crump K, Roberts AN, et al: A death involving probenecid. J Forensic Sci 1992; 37(4):1190-1193.
    35) McKinney SE, Peck HM, & Bochey JM: "Benemid", p-(di-n-propylsulfamyl)-benzoic acid: toxicologic properties. J Pharmacol Exper Ther 1951; 102:208.
    36) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    37) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    38) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    39) Perel JM, Cunningham RF, & Fales HM: Identification and renal excretion of probenecid metabolites in man. Life Sci 1970; 9(Part 1):1337-1343.
    40) Perel JM: Plasma and cerebrospinal fluid probenecid concentrations as related to accumulation of acidic biogenic amine metabolites in man. Psychopharmacologia 1974; 35:83.
    41) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    42) Product Information: Benemid(R), probenecid tablets. Merck & Co, Inc, West Point, PA, 2000.
    43) Product Information: Benemid(R), probenecid tablets. Merck & Company, West Point, PA, 1998.
    44) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    45) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    46) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    47) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    48) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    49) Product Information: probenecid colchicine oral tablets, probenecid colchicine oral tablets. Watson Pharma, Inc. (per DailyMed), Corona, CA, 2009.
    50) Product Information: probenecid oral tablets, probenecid oral tablets. Lannett Company,Inc, Philadelphia, PA, 2006.
    51) Product Information: probenecid oral tablets, probenecid oral tablets. Marlex Pharmaceuticals, Inc. (per DailyMed), New Castle, DE, 2012.
    52) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires July/31/2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    53) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    54) Reynolds ES, Schlant RC, Gonick, et al: Fatal massive necrosis of the liver as a manifestation of hypersensitivity to probenecid. N Engl J Med 1957; 256:592-596.
    55) Rizzuto VJ, Inglesby TV, & Grace WJ: Probenecid (Benemid)(R) intoxication with status epilepticus. Am J Med 1965; 38:646.
    56) S Sweetman : Martindale: The Complete Drug Reference. London: Pharmaceutical Press (Internet version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    57) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    58) Sokol A: Nephrotic syndrome caused by probenecid. JAMA 1967; 199:43.
    59) Sosler SD, Behzad O, & Garratty G: Immune hemolytic anemia associated with probenecid. Am J Clin Pathol 1985; 84:391-394.
    60) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    61) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
    62) Swanson M & Cook R: Drugs, Chemicals and Blood Dyscrasias, Drug Intell Publications, Hamilton, Il, 1977.
    63) Swanson M & Cook R: Drugs, Chemicals and Blood Dyscrasias, Drug Intelligence Publications, Hamilton, IL, 1977a.
    64) Sweetman S (Ed): Martindale: The Complete Drug Reference. London: Pharmaceutical Press (Internet Version), Micromedex, Inc, Englewood, CO, 2001.
    65) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.