Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1) 4-Butyl-1,2-diphenylpyrazolidine-3,5-dione
2) Butadione
3) Fenilbutazona
4) Phenylbutazonum
5) Molecular Formula: C19-H2-0-N2-O2
6) CAS 50-33-9

1) 4-Dimethylamino-1,5-dimethyl-2-phenyl-4-pyrazolin
2) -3-one
3) Amidazofen
4) Aminophenazone
5) Dimethylaminoantipyrine
6) Dimethylaminophenazone
7) Molecular Formula: C13-H-17-N3-O
8) CAS 58-15-1

1) 5-Dimethylamino-9-methyl-2-propylpyrazolo(1,2-a)
2) (1,2,4)benzotriazine-1,3(2H)-dione dihydrate
3) AHR-3018
4) Apazone
5) Mi85
6) NSC 102824
7) Molecular Formula: C16-H2-0-N4-O2.2H2O
8) CAS 13539-59-8 (anhydrous)

1) Aminopyrine-sulphonate sodium
2) Analginum
3) Metamizole
4) Metampyrone
5) Natrium novaminsulfonicum
6) Noramidazophenum
7) Noraminophenazonum
8) Novamidazofen
9) Sodium noramidopyrine methanesulphonate
10) Sulpyrine
11) Sodium N-(2,3-dimethyl-5-oxo-1-phenyl-3-
12) pyrazolin-4yl)-N-methylaminomethanesulphonate
13) Molecular Formula: C13-H16-N3-Na-O4-S.H2O
14) CAS 68-89-3 (anhydrous)
15) CAS 5907-38-0 (monohydrate)

1) 4-Butyl-1-(4-hydroxyphenyl)-2-phenylpyrazolidine-3,
2) 5-dione monohydrate
3) G-27202
4) Hydroxyphenylbutazone
5) Molecular Formula: C19-H2-0-N2-O3.H2O
6) CAS 129-20-4 (anhydrous)
7) CAS 7081-38-1 (monohydrate)

1) 1,5-Dimethyl-2-phenyl-4-pyrazolin-3-one
2) Analgesine
3) Antipyrin
4) Antipyrine
5) Azophenum
6) Fenazona
7) Phenazon
8) Phenazonum
9) Molecular Formula: C11-H12-N2-O
10) CAS 60-80-0

1) 1,2-Diphenyl-4-(2-phenylsulphinyl-ethyl)
2) pyrazolidine-3,5-dione
3) G-28315
4) Sulfinpyrazonum
5) Sulphinpyrazone
6) Sulphoxyphenylpyrazolidine
7) Molecular Formula: C23-H2-0-N2-O3-S
8) CAS 57-96-5

Available Forms Sources

A)

1) Butazolidin: 100 mg tablet
2) Azolid: 100 mg tablet
3) Available in combination with steroids and antacids.
4) Tandaeril and oxalid are similar to phenylbutazone.
5) Aminopyrine, antipyrine, amidopyrine noramidoprine, sulfinpyrazone have similar toxic courses, particularily as related to the blood dyscrasias.
6) Some Chinese herbal preparations sold as relievers of musculoskeletal pain may actually contain from 0.6 to 198 mg phenylbutazone per tablet (Segasothy & Samad, 1991).

B)

1) WITHDRAWAL FROM US MARKET - Dipyrone was removed from the US market in the late 70's because of a risk of agranulocytosis with dipyrone use. It has also been banned in Canada, Japan, and some European countries. It is still available in some Latin American countries including Mexico. Although this drug has been banned for more than two decades, it can be bought in Mexico and brought into the US. There have been reports of dipyrone exposures in Texas, with cases more likely to occur near the Mexican border. Of note, dipyrone-containing products have also been found for sale in Latin markets within the US (Forrester, 2006).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) Pyrazole compounds cause similar signs and symptoms, but affect various target organs with differing frequency and severity.
B) PHENYLBUTAZONE/OXYPHENBUTAZONE - The most common effect is mild to moderate GI distress (nausea, vomiting, epigastric pain). Less commonly, severe toxicity with multiorgan failure (renal, hepatic, cardiac, pulmonary), metabolic acidosis, cardiogenic shock, coma, ARDS, and seizures occurs. Other reported effects include hyperglycemia, hypocalcemia, cyanosis, paresthesias, erythematous rash, profuse sweating, and dyspnea. Liver effects are more common than with other pyrazoles.
C) DIPYRONE - Common effects include vomiting, abdominal pain, and vertigo. In severe cases, coma, shock, seizures, tachycardia, and sudden apnea may occur. Blood dyscrasias (agranulocytosis, thrombocytopenia, aplastic anemia) have been reported, mostly with chronic use.

1) WITHDRAWAL FROM US MARKET - Dipyrone was removed from the US market in the late 70's because of a risk of agranulocytosis with use. It has also been banned in Canada, Japan, and some European countries. It is still available in some Latin American countries including Mexico. Although this drug has been banned for more than two decades, it can be bought in Mexico and brought into the US. There have been reports of dipyrone exposures in Texas.

D) AMINOPYRINE/PROPYPHENAZONE - Common effects include drowsiness, coma, and excitation. Less common effects include seizures, hyperthermia, shock, acidosis, and tachycardia. Liver damage is extremely rare.
E) ANTIPYRINE - Like other pyrazoles; although reported to be the only pyrazole that causes methemoglobinemia, no recent documentation could be found.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Vital sign changes in severe overdose may include hypertension or hypotension, tachycardia or bradycardia, apnea, and hyperthermia or hypothermia.

0.2.4)

A) Tinnitus and hearing loss may occur.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Severe phenylbutazone overdose is characterized by multiorgan failure, including cardiogenic shock and asystole. Shock was reported in 8% of dipyrone and 4% of aminopyrine overdoses. Both hypertension and hypotension have been reported. Sinus tachycardia has been reported after phenylbutazone overdose, and occurred in 8% of dipyrone and 3% of propyphenazone overdoses.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Dyspnea and ARDS have been reported with severe overdose. Sudden apnea has been reported with aminopyrine overdose. Patients with aspirin-induced asthma may develop bronchospasm after therapeutic use of pyrazoles.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Ataxia, lethargy, stupor, vertigo, seizures, agitation, coma, and hallucinations, and paresthesias may occur with severe overdose. CNS depression was less frequent with dipyrone than with aminopyrine and propyphenazone overdose.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Toxic gastroenteritis, with nausea, vomiting, and epigastric pain, is common, reported in 45% of dipyrone cases. Gastric ulceration may occur.

0.2.9)

A) Elevated hepatic enzymes, hepatic necrosis, and jaundice may occur, especially with phenylbutazone or oxyphenbutazone.

0.2.10)

A) Renal dysfunction is common, including proteinuria, hematuria, anuria, oliguria and in one fatal case, acute nephritis. Urine may be red due to a pyrazolone metabolite. Renal papillary necrosis and hypersensitivity-related renal dysfunction may occur during therapeutic use.

0.2.11)

A) Like the salicylates, phenylbutazone appears to stimulate the respiratory center resulting in respiratory alkalosis. Metabolic acidosis may then occur.

0.2.12)

A) Edema from sodium retention and hypocalcemia may occur.

0.2.13)

A) WITH POISONING/EXPOSURE

1) Blood dyscrasias (agranulocytosis, thrombocytopenic purpura, aplastic anemia) may occur, most likely following chronic ingestion of therapeutic doses of aminopyrine or dipyrone. Pancytopenia has been reported after overdose with phenylbutazone and oxyphenbutazone. Antipyrine may cause methemoglobinemia.
2) Coagulopathy has been reported following phenylbutazone overdose.

0.2.14)

A) WITH POISONING/EXPOSURE

1) Skin rash and excessive perspiration may occur following overdose.

0.2.15)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis has been reported following phenylbutazone overdose.

0.2.16)

A) WITH POISONING/EXPOSURE

1) Transient hyperglycemia has been reported after phenylbutazone overdose.

0.2.20)

A) Dipyrone has been found in infant's serum and urine after breast-feeding. Abortion has been reported following metamizol overdose.

Laboratory Monitoring

A)

B)

Treatment Overview

0.4.2)

A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.
B) 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.
C) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.

1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.

D) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).

1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
F) MONITOR FLUID, ELECTROLYTE, and acid-base balances carefully in symptomatic patients.
G) ALKALINE DIURESIS is of questionable value since pyrazoles are extensively metabolized and only 1 to 5% of drug is eliminated unchanged by the kidneys. Furthermore, there is danger of salt and water retention especially with phenylbutazone and oxyphenbutazone which may lead to hypervolemia and cardiac failure.
H) HEMOPERFUSION may be useful in those patients who continue to deteriorate clinically despite conventional therapy.
I) MULTIPLE DOSE ACTIVATED CHARCOAL: May enhance elimination, but not shown to affect outcome; consider in severely poisoned patients. DOSE: Optimal dose not established. ADULT: Initial dose of 50 to 100 g activated charcoal, administer subsequent doses at 1, 2 or 4 hour intervals at a dose equivalent to 12.5 grams/hour. CHILD (1 to 12 years): Initial dose of 25 to 50 g activated charcoal, administer subsequent doses at 1, 2 or 4 hour intervals at a rate equivalent to 6.25 g/hr. Continue until clinical and laboratory parameters are improving. Use of cathartics are NOT routinely recommended.

1) Evaluate frequently for ability to protect airway and evidence of decreased peristalsis or obstruction.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

1) WITHDRAWAL FROM US MARKET - Dipyrone was removed from the US market in the late 70's because of a risk of agranulocytosis with use. It has also been banned in Canada, Japan, and some European countries. It is still available in some Latin American countries including Mexico. Although this drug has been banned for more than two decades, it can be bought in Mexico and brought into the US. There have been reports of dipyrone exposures in Texas.

D)

E)

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Vital sign changes in severe overdose may include hypertension or hypotension, tachycardia or bradycardia, apnea, and hyperthermia or hypothermia.

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPERTHERMIA - was reported in 8% of patients with aminopyrine overdose summarized from German literature (Okonek & Reinecke, 1983), and has also been reported after phenylbutazone overdose.
2) HYPOTHERMIA may also occur.

a) CASE REPORT - A 10-month-old infant developed hypothermia (34 degrees C) and stupor approximately one hour after receiving 500 mg of dipyrone for a fever secondary to a suspected viral infection. Laboratory and diagnostic studies were normal (including sepsis work up). The patient was discharged to home after 24 hours of observation (Margolin & Engelhard, 2002).

3.3.4)

A) Both hypertension and hypotension have been reported (Prod Info Butazolidin(R), 1968; Prod Info Oxalid(R), 1977; Strong et al, 1979).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Sinus tachycardia has been reported after phenylbutazone overdose, and occurred in 8% of dipyrone and 3% of propyphenazone overdoses summarized from German case reports (Okonek & Reinecke, 1983). Severe bradycardia and asystole occurred in one phenylbutazone overdose (Newton & Rose, 1991).

Heent

3.4.1)

A) Tinnitus and hearing loss may occur.

3.4.4)

A) Tinnitus and hearing loss have been reported (Prod Info Butazolidin(R), 1968; Prod Info Tandearil(R), 1968a).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Severe phenylbutazone overdose is characterized by multiorgan failure, including cardiogenic shock and asystole. Shock was reported in 8% of dipyrone and 4% of aminopyrine overdoses. Both hypertension and hypotension have been reported. Sinus tachycardia has been reported after phenylbutazone overdose, and occurred in 8% of dipyrone and 3% of propyphenazone overdoses.

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Cardiogenic shock may occur with severe overdoses, presumably through direct toxicity on the conduction system and myocardium. Shock was reported in 8% of patients with dipyrone and 4% of patients with aminopyrine ingestions reported in the German literature (Okonek & Reinecke, 1983).
b) CASE REPORT - Severe hypotension requiring vasopressors was reported in an 18-year-old woman who ingested 16 grams of phenylbutazone and a 24- year-old man who ingested 17 grams; onset was about 60 hours postingestion in one case (Strong et al, 1979) and about 4.5 hours postingestion in the other case (Newton & Rose, 1991).
c) CASE REPORT - Tachycardia and hypotension were significant in a 9-year-old female with a phenylbutazone overdose. She expired due to cardiac arrest despite aggressive treatment measures. Autopsy revealed a terminal coagulopathy which contributed to this patient's demise (Gualtieri & Filandrinos, 1994).
d) CASE REPORT - Hypotension (90/60 mmHg) and abdominal pain were reported in a 16-year-old patient who ingested 10 g of dipyrone in a suicide attempt. The patient recovered with supportive care (Bentur & Cohen, 2004).

B) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypertension has been reported in association with an acute overdose of phenylbutazone and oxyphenbutazone (Prod Info Butazolidin(R), 1968; Prod Info Oxalid(R), 1977).

C) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia occurs in patients with shock following significant overdose. It was reported in 8% of dipyrone and 3% of propyphenazone cases reported in the German literature (Okonek & Reinecke, 1983).
b) CASE REPORT - Sinus tachycardia was reported in a 24-year-old man who ingested 17 grams of equine phenylbutazone over a 24-hour period to treat the pain of a toothache (Newton & Rose, 1991).

D) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT - Several episodes of severe bradycardia, with 2 episodes of asystole responding to atropine occurring during pulmonary suctioning at one week postingestion in a 24-year-old who ingested 17 grams equine phenylbutazone over a 24-hour period (Newton & Rose, 1991).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Dyspnea and ARDS have been reported with severe overdose. Sudden apnea has been reported with aminopyrine overdose. Patients with aspirin-induced asthma may develop bronchospasm after therapeutic use of pyrazoles.

3.6.2)

A) APNEA

1) WITH POISONING/EXPOSURE

a) Sudden apnea has been reported with aminopyrine intoxication (Okonek & Reinecke, 1983).

B) BRONCHOSPASM

1) WITH THERAPEUTIC USE

a) Patients with aspirin-induced asthma may develop bronchospasm after therapeutic use of pyrazoles.
b) CASE REPORT - A 33-year-old female with a history of asthma and marked hypersensitivity to aspirin and NSAIDS developed acute bronchospasm following an intravenous 2 mL dose of Avafortan (avapyrazone 24 mg/mL plus dipyrone 240 mg/mL) (Goblin et al, 1986).

C) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) CASE REPORT - Adult respiratory distress syndrome developed in conjunction with multiorgan failure following ingestion of phenylbutazone 17 grams by a 24-year-old man (Newton & Rose, 1991).

D) CYANOSIS

1) WITH POISONING/EXPOSURE

a) Patients with severe overdoses may become cyanotic due to respiratory distress or cardiogenic shock (Prod Info Butazolidin(R), 1968; Prod Info Tandearil(R), 1968a; Newton & Rose, 1991).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) Ataxia, lethargy, stupor, vertigo, seizures, agitation, coma, and hallucinations, and paresthesias may occur with severe overdose. CNS depression was less frequent with dipyrone than with aminopyrine and propyphenazone overdose.

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Lethargy, stupor, ataxia, and coma have been reported (Bury, 1983; (Prod Info Butazolidin(R), 1968; Prod Info Tandearil(R), 1968a). CNS depression was less frequent with dipyrone than with aminopyrine and propyphenazone overdose in a compilation of cases summarized from the German literature. The incidence of somnolence was 47% for aminopyrine, 44% for propyphenazone, and 8% for dipyrone. Coma occurred in 18% of propyphenazone, 13% of aminopyrine, and 8% of dipyrone cases (Okonek & Reinecke, 1983).
b) In a retrospective review of 40 dipyrone exposures reported to Texas Poison Control Centers from 1998 to 2004, 38 cases reported minor or no symptoms following exposure. Of 39 cases with known adverse effects and treatment, 6 patients developed neurologic symptoms. Mild reports of agitation, ataxia, dizziness, and drowsiness developed, with 1 case of seizures reported (Forrester, 2006).

B) CENTRAL STIMULANT ADVERSE REACTION

1) WITH POISONING/EXPOSURE

a) CNS excitation and agitation may precede development of CNS depression. Excitation was reported in 10% of propyphenazone and 4% of aminopyrine ingestions (Okonek & Reinecke, 1983).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT - Recurring generalized seizures were described after phenylbutazone overdose in a 2.5-year-old child (Bury et al, 1983), and a 24-year-old adult (Newton & Rose, 1991). Onset was 3 hours postingestion in the adult and unknown in the child. Generalized seizures developed in a 9-year-old girl, a 15-year-old girl, and a 34-year-old man following phenylbutazone overdose (Gualtieri & Filandrinos, 1994; Virji et al, 2003).
b) CASE SERIES - Seizures were reported in 8% of dipyrone, 8% of aminopyrine, and 3% of propyphenazone ingestions in a compilation of cases summarized from the German literature (Okonek & Reinecke, 1983).

D) ATAXIA

1) WITH POISONING/EXPOSURE

a) CASE SERIES - Ataxia and vertigo have been reported. Vertigo occurred in 15% of 23 dipyrone ingestions in a compilation of cases summarized from the German literature (Okonek & Reinecke, 1983).

E) PARESTHESIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT - Tingling and numbness of the feet were reported in an adult male following an ingestion of 4 grams of oxyphenbutazone (Prod Info Tandearil(R), 1968a).

F) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headaches and weakness were reported in 7 and 11 patients (n=39), respectively, following dipyrone overdose ingestions (Bentur & Cohen, 2004).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

1) Toxic gastroenteritis, with nausea, vomiting, and epigastric pain, is common, reported in 45% of dipyrone cases. Gastric ulceration may occur.

3.8.2)

A) GASTROENTERITIS

1) WITH POISONING/EXPOSURE

a) Gastrointestinal effects are common after acute overdose, including nausea, vomiting, and epigastric pain (Prod Info Butazolidin(R), 1968; Prod Info Tandearil(R), 1968a). Vomiting and abdominal pain were reported in 45% of 23 dipyrone overdoses summarized from German literature (Okonek & Reinecke, 1983).
b) Mild gastrointestinal distress was the most commonly occurring adverse effect (57%), in a series of 39 patients who were symptomatic following dipyrone overdose ingestions, and included vomiting (n=16), nausea (n=3), and abdominal pain (n=9). The median amount of dipyrone ingested was 7.5 g (range 1 to 25 g) (Bentur & Cohen, 2004).

B) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) In a retrospective review of 40 dipyrone exposures reported to Texas Poison Control Centers from 1998 to 2004, 38 cases reported minor or no symptoms following exposure. Of 39 cases with known adverse effects and treatment, 4 patients developed gastrointestinal symptoms. There was one case of nausea, and three cases of vomiting (Forrester, 2006).

C) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT - A 33-year-old male developed an upper gastrointestinal hemorrhage associated with self-administration of a phenylbutazone-containing horse pill (500 to 1000 mg every 1 to 3 days) for a severe toothache (Cohen et al, 1988).
b) CASE REPORT - A 34 year old man developed colonic hemorrhage after phenylbutazone overdose (Gualtieri & Filandrinos, 1994).

D) GASTRIC ULCER

1) WITH POISONING/EXPOSURE

a) CASE REPORT - Gastric ulceration was reported in a 73-year-old woman who had been ingesting an herbal preparation containing 240 mg phenylbutazone every day for 6 months (Segasothy & Samad, 1991).

Hepatic

3.9.1)

A) Elevated hepatic enzymes, hepatic necrosis, and jaundice may occur, especially with phenylbutazone or oxyphenbutazone.

3.9.2)

A) LIVER DAMAGE

1) WITH THERAPEUTIC USE

a) CHRONIC USE - Moderate to marked hepatocellular injury has been reported with chronic ingestion (less than 6 weeks) of therapeutic doses (Benjamin et al, 1981).
b) Evidence of liver damage was observed in a 15-year-old female with a serum AST of 140 U/L and an ALT of 126 U/L. Markers for liver necrosis were increased initially followed by a rapid decrease; markers for regeneration declined initially followed by a rapid increase. The patient was treated with plasmapheresis (Virji et al, 2003).

2) WITH POISONING/EXPOSURE

a) Elevated hepatic enzymes and jaundice have been reported (Bury et al, 1983), often in conjunction with multiorgan toxicity in severe overdose (Strong et al, 1979; Newton & Rose, 1991). Hepatotoxicity is most common with phenylbutazone or oxyphenbutazone, and is least common with antipyrine (Altmann, 1986; Okonek & Reinecke, 1983).

1) ONSET is delayed, usually after 24 hours (Okonek & Reinecke, 1983).

Genitourinary

3.10.1)

A) Renal dysfunction is common, including proteinuria, hematuria, anuria, oliguria and in one fatal case, acute nephritis. Urine may be red due to a pyrazolone metabolite. Renal papillary necrosis and hypersensitivity-related renal dysfunction may occur during therapeutic use.

3.10.2)

A) ABNORMAL RENAL FUNCTION

1) WITH POISONING/EXPOSURE

a) Renal dysfunction is common, including proteinuria, hematuria, anuria, oliguria and in one fatal case, acute nephritis (McDonald et al, 1967; Prod Info Butazolidin(R), 1968; Prod Info Tandearil(R), 1968a; De Flines et al, 1990).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORTS - Acute renal failure has been reported following phenylbutazone overdose. A 34-year-old male developed acute renal failure requiring hemodialysis. A 9-year-old female had laboratory values obtained during cardiac arrest: BUN 60 mg/dL; SCr 2.0 mg/dL; K+ 10.6 mmol/L; and PO4 15.2 mg/dL (Gualtieri & Filandrinos, 1994).
b) Acute renal failure was observed in a 15-year-old female patient following phenylbutazone poisoning. At the time of admission the serum creatinine was 3.6 mg/dL and BUN was 58 mg/dL (Virji et al, 2003).
c) CASE REPORT - In a suicide attempt, non-oliguric acute renal failure developed in a 14-year-old girl approximately 24 to 36 hours after ingesting twenty 575 mg metamizol capsules (11.5 g) . She also presented with proteinuria and microhematuria; renal function was rapidly reversed with steroid therapy. Since it was not reversible with volume repletion, the authors speculated that the renal damage occurred as a result of toxic tubular necrosis (Peces & Pedrajas, 2004).

C) ABNORMAL URINE

1) After a latent period of 24 hours a red discoloration of the urine, due to rubazonic acid, a pyrazolone metabolite, may be observed (Okonek & Reinecke, 1983).

D) PAPILLARY NECROSIS

1) WITH POISONING/EXPOSURE

a) CHRONIC - Renal papillary necrosis may have been attributable to ingestion of 240 mg phenylbutazone per day by a 73-year-old woman (Segasothy & Samad, 1991).

E) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) CHRONIC USE - Reversible non-oliguric hypersensitivity-mediated impairment of renal function has been reported in patients receiving azapropazone for treatment of various rheumatic disorders (Sipila et al, 1986).

Acid-Base

3.11.1)

A) Like the salicylates, phenylbutazone appears to stimulate the respiratory center resulting in respiratory alkalosis. Metabolic acidosis may then occur.

3.11.2)

A) ACIDOSIS

1) Salicylate-like symptoms including stimulation of the respiratory center, respiratory alkalosis, and metabolic acidosis have been reported (Prod Info Oxalid(R), 1977).

Hematologic

3.13.1)

A) WITH POISONING/EXPOSURE

1) Blood dyscrasias (agranulocytosis, thrombocytopenic purpura, aplastic anemia) may occur, most likely following chronic ingestion of therapeutic doses of aminopyrine or dipyrone. Pancytopenia has been reported after overdose with phenylbutazone and oxyphenbutazone. Antipyrine may cause methemoglobinemia.
2) Coagulopathy has been reported following phenylbutazone overdose.

3.13.2)

A) HEMATOLOGY FINDING

1) WITH THERAPEUTIC USE

a) Blood dyscrasias (agranulocytosis, thrombocytopenic purpura, aplastic anemia) may occur, most likely following chronic ingestion of therapeutic doses of aminopyrine or dipyrone.
b) CASE REPORT - A 12-year-old developed aplastic anemia after he was given an herbal medication, over several days, that contained phenylbutazone, chlorpheniramine, and diclofenac (Nelson et al, 1995).

2) WITH POISONING/EXPOSURE

a) Pancytopenia may occur following an acute overdose of phenylbutazone and oxyphenbutazone (Prod Info Butazolidin(R), 1968; Prod Info Tandearil(R), 1968a).

B) METHEMOGLOBINEMIA

1) WITH THERAPEUTIC USE

a) Antipyrine has been stated to be the only pyrazole to cause methemoglobinemia (Gosselin et al, 1984), but no recent documentation or case reports could be found.

C) BLOOD COAGULATION PATHWAY FINDING

1) Phenylbutazone has been reported to cause terminal coagulopathy in a human ingestion.

a) CASE REPORT - Phenylbutazone serum concentration was 1175 mcg/mL prior to cardiac arrest in a 9-year-old female. Postmortem exam was significant for blood in the CSF and subdural spaces. Subarachnoid, epidural, and pulmonary hemorrhages were noted, as well as numerous scattered petechiae over the pleural, epicardial, thymus, and renal hylar surfaces (Gualtieri & Filandrinos, 1994).

Dermatologic

3.14.1)

A) WITH POISONING/EXPOSURE

1) Skin rash and excessive perspiration may occur following overdose.

3.14.2)

A) SKIN FINDING

1) WITH POISONING/EXPOSURE

a) In a retrospective review of 40 dipyrone exposures reported to Texas Poison Control Centers from 1998 to 2004, 38 cases reported minor or no symptoms following exposure. Of 39 cases with known adverse effects and treatment, 3 patients developed dermal symptoms. There was one case each of erythema, hives, and pruritus (Forrester, 2006).

B) ERUPTION

1) WITH POISONING/EXPOSURE

a) Skin rash has been reported following acute overdose (Strong et al, 1979; Prod Info Butazolidin(R), 1968; Prod Info Tandearil(R), 1968a).

C) EXCESSIVE SWEATING

1) WITH POISONING/EXPOSURE

a) Perspiration has been reported following acute overdose of phenylbutazone and oxyphenbutazone (Prod Info Butazolidin(R), 1968; Prod Info Tandearil(R), 1968a).

Musculoskeletal

3.15.1)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis has been reported following phenylbutazone overdose.

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT - Rhabdomyolysis was reported in a 34-year-old male following an overdose ingestion of phenylbutazone. His serum creatine kinase level was reported to be 28,720 International Units/L. Acute renal failure requiring hemodialysis ensued. Thirty hours post-ingestion his PBZ serum level was reported to be 241 mcg/mL. Full renal function occurred prior to discharge (Gualtieri & Filandrinos, 1994).
b) CASE REPORT - A 9-year-old female who expired of a phenylbutazone overdose had a CK serum concentration of 12,200 International Units/mL and a phenylbutazone serum level of 1175 mcg/mL prior to cardiac arrest (Gualtieri & Filandrinos, 1994).

Endocrine

3.16.1)

A) WITH POISONING/EXPOSURE

1) Transient hyperglycemia has been reported after phenylbutazone overdose.

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Transient hyperglycemia for the first few hours of an intoxication has been reported after phenylbutazone overdose (Bury et al, 1983; Newton & Rose, 1991).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) CASE REPORT - A 35-year-old female with a history of penicillin allergy was administered 2 mL of a combination preparation containing avapyrazone 24 mg/mL and dipyrone 240 mg/mL. She developed dizziness, shortness of breath, and foamed at the mouth about 5 minutes after the injection. Despite immediate treatment with adrenaline, promethazine, and betamethasone she was not resuscitated (Fosseus & Straughan, 1983).

Reproductive

3.20.1)

A) Dipyrone has been found in infant's serum and urine after breast-feeding. Abortion has been reported following metamizol overdose.

3.20.3)

A) PREGNANCY CATEGORY

OXYPHENBUTAZONE	C
PHENYLBUTAZONE	C*
[*Risk Factor D if used in 3rd trimester or near delivery.]
Reference: Briggs et al, 1998

B) ABORTION

1) Abortion has been reported in a 14-year-old girl who ingested twenty 575 mg metamizol capsules (11.5 g). The authors speculated that part of the drug entered the fetal tissues and may have induced the abortion by a direct toxic effect (Peces & Pedrajas, 2004).

3.20.4)

A) BREAST MILK

1) DIPYRONE - Concentrations of dipyrone in mother's serum and milk and in infant's serum and urine were 3.3, 4.3, and 3.2, 3.74 mcg/mL, respectively, 2 hours after the last dose of 3 doses of 500 mg of dipyrone taken by the mother (Rizzoni & Furlanut, 1984).
2) CASE REPORT - Two episodes of cyanosis lasting 2 to 3 minutes each during a 30 minute period occurred in a 42-day-old breast-fed male which was associated with three 500 mg doses of dipyrone that the mother had taken for a sore throat (Rizzoni & Furlanut, 1984).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Phenylbutazone plasma levels are not clinically useful.
B) Obtain a baseline CBC, renal and liver function tests, and urinalysis in symptomatic patients.

4.1.2)

A) TOXICITY

1) Therapeutic blood levels of phenylbutazone fall between 20 to 70 mcg/dL (Anderson et al, 1976). Serum proteins are saturated at 10 to 11 mg/dL and thus increased toxicity would be expected above these levels.

a) A child consumed 120 mg/kg and had blood levels of 700 mcg/dL without intoxication or sequelae.

4.1.3)

A) URINALYSIS

1) URINE COLOR - After 24 hours, a red discoloration of the urine may be seen, due to rubazonic acid, a pyrazolone metabolite.

Methods

A)

1) The presence of phenylbutazone was confirmed by gas chromatography mass-spectrometry (GC-MS) analysis of an initial urine sample in a report of an intentional overdose of phenylbutazone. Sequential serum samples examined by GC-MS revealed elimination of phenylbutazone by day 5 of admission. The patient was treated with plasmapheresis (Virji et al, 2003).

Treatment

Life Support

A)

Monitoring

A)

B)

Oral Exposure

6.5.1)

A) EMESIS/NOT RECOMMENDED -

1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures.

B) 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)

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).

B) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

C) MULTIPLE DOSE ACTIVATED CHARCOAL

1) In studies in human volunteers, multiple doses of activated charcoal enhanced elimination of phenylbutazone (Neuvonen & Elonen, 1980). There are no studies confirming its value in overdose and it has never been shown to affect outcome after overdose. It may be considered in patients ingesting a life-threatening amount of phenylbutazone.
2) MULTIPLE DOSE ACTIVATED CHARCOAL

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

6.5.3)

A) 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).

B) MONITORING OF PATIENT

1) Monitor acid-base, fluid, and electrolyte balance closely.
2) A baseline CBC and renal and hepatic function tests should be obtained.

Enhanced Elimination

A)

1) Hemoperfusion is probably not warranted following phenylbutazone overdose but may be useful in those patients who continue to deteriorate clinically despite conventional therapy (Strong et al, 1979).
2) Phenylbutazone dialysance of 3.9 milliliters/minute and 9.5 milliliters/minute following charcoal and resin hemoperfusion, respectively was reported in one patient (Berlinger et al, 1982).

B)

1) Because of the low water solubility and high protein binding, hemodialysis is not likely to be effective for propyphenazone, phenylbutazone, and oxyphenbutazone (Prescott et al, 1980).
2) Aminopyrine and dipyrone are more freely soluble and may be better hemodialysis candidates in severe cases.

C)

1) It is postulated that the excretion of phenylbutazone, like salicylate, may be enhanced in an alkaline urine. This may be considered in very severely intoxicated patients. Clinical trials have not tested this hypothesis.
2) alkaline diuresis is be of questionable value since pyrazoles are extensively metabolized and only 1 to 5 percent of drug is eliminated unchanged by the kidneys.
3) Furthermore, there is danger of salt and water retention especially with phenylbutazone and oxyphenbutazone which may lead to hypervolemia and cardiac failure (Okonek & Reinecke, 1983).

D)

1) A 15-year-old female with an intentional phenylbutazone overdose underwent plasmapheresis to remove the drug. By day 5 of admission serum samples examined by gas chromatography mass-spectrometry revealed elimination of phenylbutazone and therapy was discontinued (Virji et al, 2003).

E)

1) In studies in human volunteers, multiple doses of activated charcoal enhanced elimination of phenylbutazone (Neuvonen & Elonen, 1980). There are no studies confirming its value in overdose and it has never been shown to affect outcome after overdose. It may be considered in patients ingesting a life-threatening amount of phenylbutazone.
2) MULTIPLE DOSE ACTIVATED CHARCOAL

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

Abstracts

Case Reports

A)

1) FATALITY - Rerrick (1968) reports a case of a 41-year-old male treated with a total dose of 40 grams of phenylbutazone over a 7 to 8 month period who developed polyuria, stiffness in the joints, anorexia, nausea, weakness, skin rashes, and an enlarged spleen with elevated renal function tests .

a) Subsequently the patient's renal function test deteriorated and despite discontinuation of the drug and supportive therapy, the patient became comatose, hypertensive, and subsequently died.
b) Autopsy revealed histological changes in the kidneys, heart, and in the vessels of the kidneys, brain, and bladder. Diffuse glomerulitis and an unusual periglomerular accumulation of inflammatory cells were noted.

B)

1) Juul (1965) reports a case of a 15-month-old female who ingested 10 to 15 tablets of phenylbutazone (2 to 3 grams) accidentally and developed hyperthermia, oliguria, acid base imbalance, and jaundice. Subsequently the patient's general condition improved within 16 days(Juul, 1965) .

C)

1) Selwyn (1967) reports 2 patients aged 53 and 71 years who had received a range of 300 to 600 mg/day of phenylbutazone for 3 weeks who developed a glandular-fever syndrome.

a) Both patients had rheumatoid arthritis and developed a generalized maculopapular rash with a sore throat but no lymphadenopathy or splenomegaly. Hemoglobin level and platelet counts were both noted to be normal in these 2 patients.
b) However, 1 patient developed a temperature of 100 to 101 degrees Fahrenheit with a large soft lymph gland in the left axilla. Eosinophilia and agranulocytosis was also noted in 1 of the patients. Discontinuation of phenylbutazone resulted in the blood picture returning to normal(Selwyn, 1967) .

D)

1) Acute accidental phenylbutazone overdose in a 2.5-year-old child resulted in coma, incontinence, and seizures. During the next 72 hours, the patient had recurrent grand mal seizures, persistent diarrhea and vomiting, and fluctuating level of consciousness.

a) Hyperglycemia which had occurred during the first few hours following ingestion resolved spontaneously within 6 hours; however acidemia persisted for 72 hours.
b) The patient developed a picture of cholestatic jaundice over the succeeding 10 days following overdose which remitted spontaneously over a period of one week (Bury et al, 1983).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) AMIDOPYRINE - Use of this product is discouraged due to the risk of agranulocytosis. It has been used in drug metabolism studies (JEF Reynolds , 2000).
2) AZAPROPAZONE -

a) ANTI-INFLAMMATORY - 300 milligrams orally four times daily or 600 milligrams orally twice daily (JEF Reynolds , 2000).

3) URICOSURIC -

a) ACUTE GOUT - 2.4 grams orally in divided doses for 24 hours, followed by 1.8 grams orally daily until symptoms are resolving, then 1.2 grams orally daily until symptoms have resolved (JEF Reynolds , 2000).
b) CHRONIC GOUT - 600 milligrams orally twice daily (JEF Reynolds , 1989).
c) Dosage reduction may be necessary in the elderly and in patients with renal and hepatic impairment (JEF Reynolds , 2000).

4) DIPYRONE - Use of this product is in serious or life-threatening situations where no other antipyretic is available (JEF Reynolds , 2000).

a) Oral - 0.5 to 4 grams daily in divided doses (JEF Reynolds , 2000)
b) Parenteral - 0.5 to 1 gram by subcutaneous, intramuscular, or intravenous injection (JEF Reynolds , 2000).

5) OXPHENBUTAZONE -

a) RHEUMATOID DISORDERS -

1) Initial dose - 300 to 600 milligrams orally with food daily in 3 to 4 divided doses, decrease dosage to the minimum effective level when improvement is obtained (Kastrup, 1988).
2) Maintenance dose - 100 to 200 milligrams orally with food daily, not to exceed 400 milligrams daily (Kastrup, 1988).

b) ACUTE GOUTY ARTHRITIS - 400 milligrams initially, followed by 100 milligrams orally with food every 4 hours until articular inflammation subsides (usually within 4 days), not to exceed 1 week (Kastrup, 1988).

6) PHENAZONE -

a) Analgesic/Antipyretic - 300 to 600 milligrams orally daily (JEF Reynolds , 1989).
b) Topical - 5 percent phenazone salicylate solutions are used locally as ear drops (JEF Reynolds , 2000).

7) PHENYLBUTAZONE -

a) RHEUMATOID DISORDERS -

1) Initial dose - 300 to 600 milligrams orally with food daily in 3 to 4 divided doses, decrease dosage to the minimum effective level when improvement is obtained (Kastrup, 1988).
2) Maintenance dose - 100 to 200 milligrams orally with food daily, not to exceed 400 milligrams daily (Kastrup, 1988).

b) ACUTE GOUTY ARTHRITIS - 400 milligrams initially, followed by 100 milligrams orally with food every 4 hours until articular inflammation subsides (usually within 4 days), not to exceed 1 week (Kastrup, 1988).

8) SULFINPYRAZONE -

a) URICOSURIC -

1) Initial dose - 100 to 200 milligrams orally with food once or twice daily, not to be initiated during or for 2 to 3 weeks following an acute attack. Dosage may be gradually increased over 1 to 3 weeks to 600 milligrams (JEF Reynolds , 2000).
2) Maximum daily dose - 800 milligrams (JEF Reynolds , 2000)

7.2.2)

A) SPECIFIC SUBSTANCE

1) PHENYLBUTAZONE - Safety and effectiveness have not been established in children 14 years of age or younger (Prod Info, 1988).

Minimum Lethal Exposure

A)

1) INFANT

a) A death from acute overdose was seen in a one-year-old child who took 2 grams (Court & Volans, 1984).

2) ADULT

a) A 45-year-old alcoholic who took 2.5 grams died.

Maximum Tolerated Exposure

A)

1) DIPYRONE - Mild gastrointestinal effects, including nausea, vomiting, and abdominal pain, occurred in 28 patients following a median overdose ingestion of 7.5 grams (range 1 to 25 grams) (Bentur & Cohen, 2004).

B)

1) INFANT

a) Recovery has followed the acute ingestion of 2 grams in a 15-month-old (Juul, 1965), 2.6 to 3 grams in a 26-month-old, 1.7 grams in a 2-year-old, and 2.6 grams in a 4-year-old (Strong et al, 1979).

2) ADULT

a) Patients have survived 16 grams in an 18-year-old (Strong et al, 1979), 17 grams in a 24-year-old (Newton & Rose, 1991), and 10 grams in both a 28- and 29-year-old.

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) THERAPEUTIC BLOOD LEVELS OF PHENYLBUTAZONE fall between 20 to 70 micrograms/deciliter (Anderson et al, 1976). Serum proteins are saturated at 10 to 11 micrograms/deciliter and thus increased toxicity would be expected above these levels.
b) NON-TOXIC LEVEL - A child consumed 120 milligrams/kilogram and had blood levels of 700 micrograms/deciliter without intoxication or sequelae.
c) TOXIC LEVELS -

1) Serum phenylbutazone concentrations of 120 to 670 micrograms/milliliter have been associated with reports of severe toxicity (Juul, 1976; (Prescott et al, 1980).
2) Serum phenylbutazone and oxyphenbutazone concentrations at 12 hours postingestion were 900 and 60 micrograms/milliliter, respectively, in a 24-year-old who ingested 17 grams of phenylbutazone over a 24-hour period (Newton & Rose, 1991).

Toxicity Information

7.7.1)

A) OXYPHENBUTAZONE

1) LD50- (ORAL)RAT:

a) 1,000 mg/kg (Tech Info, 1977)

Pharmacology Toxicology

Pharmacologic Mechanism

A)

1) It has analgesic, anti-inflammatory, and antipyretic actions. Phenylbutazone is normally not prescribed for minor pains.

B)

C)

D)

Toxicologic Mechanism

A)

B)

Physicochemical

Physical Characteristics

A)

B)

C)

D)

E)

F)

G)

Ph

A)

Molecular Weight

A)

Animal Toxicology

Clinical Effects

11.1.3)

A) Problems in dogs caused by phenylbutazone include widespread hemorrhages, degenerative changes in kidneys, biliary stasis, and severe blood dyscrasias (Humphreys, 1988).

1) Vomiting and diarrhea may be signs of gastrointestinal irritation or ulceration, the most common presenting problem. Lethargy, drowsiness, ataxia, and rarely seizures and metabolic acidosis are other signs (Beasley et al, 1990).

11.1.5)

A) The clinical signs associated with phenylbutazone toxicity include: anorexia; depression; oral and stomach ulcers; edema or ulceration of the colon; diarrhea; and abnormal laboratory values described below (Humphreys, 1988).

1) Phenylbutazone has been implicated in the development of acute renal failure and renal medullary crest necrosis (Beasley et al, 1990).
2) Phenylbutazone reduced sodium and chloride excretion in the first hour when given with the diuretic, furosemide (Dyke et al, 1999).
3) Phenylbutazone inhibited contractility of large-colon taenia in an in-vitro horse model. This may predispose horses to development of intestinal stasis and subsequent impaction (Van Hoogmoed et al, 1999).
4) Four cases of right dorsal colon ulceration and stricture were reported following recent phenylbutazone use. Three horses had been given doses well in excess of the recommended dose and in one horse marginally above the recommended dose but combined with other NSAIDS. All four horses presented with intermittent low-grade colic, weight loss, and ventral edema. Diarrhea was seen in three of the four horses. Diagnosis was by celiotomy in two and at necropsy in two. Three horses died. One was successfully managed with medical treatment of low-roughage pelleted food, corn oil, psyllium mucilloid, and discontinuation of the NSAID administration. This horse remained normal one year later (Hough et al, 1999).

11.1.6)

A) PHENYLBUTAZONE - Signs include loss of appetite, weight loss, dehydration, severe depression, renal disease, and death (Humphreys, 1988).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) Remove the patient and other animals from the source of contamination.
5) Treatment should always be done on the advice and with the consultation of a veterinarian.
6) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
7) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram).
d) ENHANCED ELIMINATION - Phenylbutazone clearance can be enhanced by alkaline diuresis, and this should be tried even if the animal is not acidotic (Beasley et al, 1990).

2) RUMINANTS/HORSES/SWINE

a) EMESIS - Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
b) ACTIVATED CHARCOAL -

1) Adult horses: Administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube. Neonates: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
2) Adult cattle: Administer 2 to 9 grams/kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube.
3) Sheep may be given 0.5 kilogram charcoal in slurry.

c) CATHARTIC - Administer an oral cathartic:

1) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon)
2) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram)
3) Or Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os).
4) Give these solutions via stomach tube and monitor for aspiration.

d) ENHANCED ELIMINATION - Phenylbutazone clearance can be enhanced by alkaline diuresis, and this should be tried even if the animal is not acidotic (Beasley et al, 1990).

11.2.5)

A) DOGS/CATS

1) MAINTAIN VITAL FUNCTIONS - as necessary.
2) SEIZURES -

a) DIAZEPAM - Dose of diazepam for DOGS & CATS: 0.5 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes.
b) PHENOBARBITAL - Phenobarbital may be used as adjunct treatment at 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously.
c) REFRACTORY SEIZURES - Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.

3) FLUIDS -

a) Begin fluid therapy at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema.

4) GASTROINTESTINAL TRACT IRRITATION -

a) Observe patients with ingestion carefully for esophageal or laryngeal burns prior to inducing emesis. If burns are present, consider esophagoscopy to determine their extent.

1) SUCRALFATE - For relief of gastric irritation or ulceration, administer sucralfate as follows:
2) DOGS - (body weight less than 20 kilograms) 500 milligrams three to four times daily; (weight greater than 20 kilograms) one gram three to four times daily. Give sucralfate one hour before feeding and wait two hours prior to cimetidine dosing.
3) CIMETIDINE - To decrease gastric acid, administer cimetidine: DOGS: 5 to 10 milligrams/kilogram per os, intravenously, or intramuscularly every 6 to 8 hours; CATS: 2.5 to 5 milligrams/kilogram per os, intravenously, or intramuscularly every 8 to 12 hours.

5) ACIDOSIS -

a) Add sodium bicarbonate to the intravenous fluids if metabolic acidosis is suspected, or to enhance elimination of phenylbutazone.

1) If using lactated ringers solution and precipitate forms upon addition of bicarbonate, discard and substitute a different solution.
2) Formula for bicarbonate addition when blood gases are available: milliequivalents bicarb added = base deficit x 0.5 x body weight in kilograms. Give one-half of the determined dose slowly over 3 to 4 hours intravenously.
3) Continue to dose based on blood gas determinations. When blood gases are not available, administer 1 to 4 milliequivalents/kilogram intravenously slowly over 4 to 8 hours (Beasley et al, 1990).

B) RUMINANTS/HORSES/SWINE

1) MAINTAIN VITAL FUNCTIONS -

a) Secure airway, supply oxygen and begin supportive fluid therapy if necessary.

2) SEIZURES -

a) Seizures may be controlled with diazepam. Doses of diazepam, given slowly intravenously:

1) HORSES - 1 milligram/kilogram
2) CATTLE, SHEEP AND SWINE - 0.5 to 1.5 milligrams/kilogram

3) FLUIDS -

a) Administer electrolyte and fluid therapy as needed. Maintenance dose of intravenous isotonic fluids: 10 to 20 milliliters/kilogram per day. High dose for shock: 20 to 45 milliliters/kilogram/hour.

1) Monitor for packed cell volume, adequate urine output and pulmonary edema. Goal is to maintain a urinary flow of 0.1 milliliter/kilogram/minute (2.4 liters/ hour for an 880 pound horse).
2) Administer electrolyte and fluid therapy, orally or parenterally as needed. Maintenance dose of intravenous isotonic fluids for calves and debilitated adult cattle: 140 milliliters/kilogram/day.
3) Dose for rehydration: 50 to 100 milliliters/kilogram given over 4 to 6 hours.

Range Of Toxicity

11.3.1)

A) HORSE

1) Phenylbutazone therapeutic dose: 1 to 2 grams per 1000 pounds per day intravenously. Oral dose: 2 to 4 grams per 1000 pounds per day (Prod Info Phen-Buta-Vet, 1990). This dosage must be decreased proportionally for ponies and foals.

B) DOG

1) Oral therapeutic dose phenylbutazone: 20 milligrams/pound body weight in three divided doses daily. Maximum dose is 800 milligrams/day regardless of weight. Intravenous dose: 10 milligrams/kilogram slowly to a maximum of 800 milligrams per day.

a) Intravenous injections should be limited to two consecutive days (Prod Info Butazolidin, 1990).

C) RUMINANTS/SWINE

1) CATTLE, SWINE, SHEEP - 4 to 8 milligrams/kilogram orally or 2 to 5 milligrams/kilogram intravenously. Phenylbutazone is not approved for use in animals to be consumed for food (Plumb, 1989).

11.3.2)

A) SPECIFIC TOXIN

1) HORSE

a) Oral administration of phenylbutazone in doses greater than 8.8 milligrams/kilogram/day for more than 4 days in horses and ponies is associated with abdominal pain, diarrhea, edema, renal disease, and gastric ulceration (Collins & Tyler, 1984).
b) Phenylbutazone may cause renal papillary necrosis at therapeutic doses especially if animals are dehydrated or have received multiple doses (Beasley et al, 1990).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) Remove the patient and other animals from the source of contamination.
5) Treatment should always be done on the advice and with the consultation of a veterinarian.
6) Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
7) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram).
d) ENHANCED ELIMINATION - Phenylbutazone clearance can be enhanced by alkaline diuresis, and this should be tried even if the animal is not acidotic (Beasley et al, 1990).

2) RUMINANTS/HORSES/SWINE

a) EMESIS - Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
b) ACTIVATED CHARCOAL -

1) Adult horses: Administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube. Neonates: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
2) Adult cattle: Administer 2 to 9 grams/kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube.
3) Sheep may be given 0.5 kilogram charcoal in slurry.

c) CATHARTIC - Administer an oral cathartic:

1) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon)
2) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram)
3) Or Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os).
4) Give these solutions via stomach tube and monitor for aspiration.

d) ENHANCED ELIMINATION - Phenylbutazone clearance can be enhanced by alkaline diuresis, and this should be tried even if the animal is not acidotic (Beasley et al, 1990).

11.4.3)

11.4.3.5) SUPPORTIVE CARE

A) GENERAL

1) Ongoing treatment is symptomatic and supportive.

11.4.3.6) OTHER

A) OTHER

1) SPECIFIC TOXIN

a) LABORATORY--PREMORTEM -

1) HORSES - Phenylbutazone toxicity may cause an increase in BUN, creatinine, and inorganic phosphate; and a decrease in total protein and absolute total neutrophil count (Humphreys, 1988).

b) LABORATORY--POSTMORTEM -

1) HORSES - Lesions include degeneration of the walls of the small veins and renal papillary necrosis (Humphreys, 1988).

Kinetics

11.5.1)

A) SPECIFIC SUBSTANCE

1) SUXIBUZONE -

a) HORSE - Maximum serum concentrations of the metabolites phenylbutazone and oxyphenbutazone were 5 to 7 hours and 9 to 12 hours after administration, respectively, of granulate and paste formulations of suxibuzone, with the paste formulation providing greater bioavailability (Jaraiz et al, 1999a).
b) HORSE - Suxibuzone was administered intravenously to six horses. Plasma concentrations rapidly decreased and the parent drug was not detectable in the synovial fluid. Maximum plasma concentrations of phenylbutazone and oxyphenbutazone were seen at 0.76 and 7.17 hours. Synovial fluid concentrations tend to approximate plasma concentrations within the first 9 hours (Jaraiz et al, 1999b).

Pharmacology Toxicology

A)

1) Phenylbutazone interferes with prostaglandin synthesis via inhibition of the cyclooxygenase pathway. It is irritating to the mucosa of the gastrointestinal tract.
2) Dogs appear to be very sensitive to the proprionic acid group of NSAIDs (phenylbutazone) and easily develop gastric ulcers and renal failure.

Sources

A)

1) Phenylbutazone is supplied in 30, 50, and 100 milliliter bottles with 200 milligrams phenylbutazone per milliliter. Tablets (1000 milligrams each) come in bottles of 100; tablets of 100 milligrams come in bottles of 100 and 500; and 400 milligram tablets come in bottles of 200.
2) A paste product containing 6 or 12 grams phenylbutazone is available in dosing syringes (Prod Info Butazolidin Paste, 1990).

Other

A)

1) CASE REPORTS

a) A 16-year-old, 184 kg pony was depressed and appeared to be in pain at referral after completing a course of phenylbutazone 1 gram every 12 hours for 3 days. Gastric ulceration was noted by gastroscopy (Hondalus & Lofstedt, 1988).

1) The gastric ulcer may have been present prior to phenylbutazone therapy. Toxicosis was considered because the dose given was in excess of the currently recommended dosage maximum of 8.8 mg/kg/day orally (Hondalus & Lofstedt, 1988).

References

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