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OBIDOXIME

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Obidoxime is a cholinesterase reactivator used in the treatment of organophosphate poisoning, and as a nerve agent antidote.

Specific Substances

    1) 1,3-Bis(4-hydroxyiminomethyl-1 pyridinio)-2 oxapropane dichloride
    2) Obidoxime chloride
    3) LuH-6
    4) Toxogonin
    5) CAS 7683-36-5 (obidoxime)
    6) CAS 114-90-9 (obidoxime chloride)
    1.2.1) MOLECULAR FORMULA
    1) C(14)H(16)C1(2)N(4)O(3)

Available Forms Sources

    A) FORMS
    1) Obidoxime is marketed in Europe, Israel, Portugal, and Chile, but is NOT approved for use in the U.S.
    2) Obidoxime chloride is available as an auto-injector, in combination with atropine, for intramuscular administration. The auto-injector contains 220 mg obidoxime chloride and 2 mg atropine sulfate in 2 mL for immediate therapy following exposure to organophosphorus nerve agents (Prod Info ATOX(TM) ComboPen(R) IM injection, 2007; Kassa, 2002).
    3) Obidoxime chloride is also available as 250 mg in 1 mL of solution for injection (Prod Info TOXOGONIN(R) IV injection, 2007).
    B) USES
    1) Obidoxime chloride is used, typically in combination with atropine, as an antidote to treat poisoning due to those pesticides and chemicals of the organophosphate class which have anticholinesterase activity. The intramuscular auto-injector is used as an adjunct to atropine in the treatment of poisoning by nerve agents having anticholinesterase activity (Kassa, 2002; Bentur et al, 1993).
    2) As a nerve agent antidote, obidoxime appeared to be ineffective against soman poisoning during animal studies; however, it appeared to be very potent against tabun, sarin, and VX, although this may be species-specific (Antonijevic & Stojiljkovic, 2007; Kassa, 2002).
    3) In vitro studies have shown that obidoxime chloride may be more effective than pralidoxime in reactivation of cholinesterase inhibited by several organophosphorus insecticides (Antonijevic & Stojiljkovic, 2007).

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: Obidoxime chloride is used, typically in combination with atropine, as an antidote to treat poisoning due to those pesticides and chemicals of the organophosphate class which have anticholinesterase activity. The intramuscular auto-injector is used as an adjunct to atropine in the treatment of poisoning by nerve agents having anticholinesterase activity. As a nerve agent antidote, obidoxime appeared to be ineffective against soman poisoning during animal studies; however, it appeared to be very potent against tabun, sarin, and VX, although this may be species-specific. Obidoxime is not approved for use in the US but is available in other countries.
    B) PHARMACOLOGY: Obidoxime, a bispyridinium aldoxime, reactivates acetylcholinesterase that is inhibited by organophosphorous compound through phosphorylation. At low doses, obidoxime is believed to act upon nicotinic sites only and not able to cross the blood-brain barrier very easily. However, at high doses, when administered intravenously, obidoxime can reach higher peak plasma levels and is able to cross the blood-brain barrier and thereby can reactivate cholinesterase at the muscarinic sites of the CNS.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Hypertension, tachycardia, pain at the injection site, flushing, drowsiness, dry mouth, a menthol-like taste, nausea and vomiting, headache, generalized weakness, elevated liver enzyme levels, and facial paresthesias have been reported following therapeutic administration of obidoxime. Cardiac dysrhythmias occurred in 6 patients, with organophosphate intoxication, who were given high doses of atropine and obidoxime. A woman with organophosphate intoxication developed QT interval prolongation that progressed to torsade de pointes after receiving obidoxime in combination with atropine. Although torsade de pointes has occurred with organophosphate poisoning, it was suggested that obidoxime administration may have been a contributing factor.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Hepatotoxicity, with rare cases of fatal liver failure, has been reported following administration of large cumulative doses of obidoxime.

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 liver enzymes in symptomatic patients. Hepatitis has been reported following cumulative high-dose exposure to obidoxime.
    D) Obtain an ECG, and institute continuous cardiac monitoring. Dysrhythmias, including torsades de pointes, have been reported with obidoxime therapy.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Obidoxime is primarily administered parenterally; however, ingestion of obidoxime tablets has occurred. In case of acute overdose ingestions, treatment is symptomatic and supportive. Refer to PARENTERAL OVERVIEW sections for more treatment information.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. A woman with organophosphate intoxication developed QT interval prolongation that progressed to torsade de pointes after receiving obidoxime in combination with atropine. Although torsade de pointes has occurred with organophosphate poisoning, it was suggested that obidoxime administration may have been a contributing factor. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.
    C) DECONTAMINATION
    1) The primary route of administration is parenterally; however, ingestion of obidoxime tablets has occurred. Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias or hemodynamic instability.
    E) ANTIDOTE
    1) None.
    F) TORSADES DE POINTES
    1) Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Symptomatic patients should be observed with frequent monitoring of vital signs.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    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.
    H) PITFALLS
    1) It is difficult to differentiate side effects of obidoxime from effects of the poison or atropine. Patients may already be experiencing symptoms of toxicity from exposure to other chemicals. When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Absorption: Poorly absorbed following oral administration. Protein binding: Less than 1% bound to serum albumin. Vd: The mean steady-state Vd following intravenous administration of obidoxime to 5 healthy volunteers at doses ranging from 0.5 to 1 mg/kg, was 173.3 +/- 21.8 mL/kg. Excretion: Primarily renally excreted. Elimination half-life: 1 to 1.5 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hepatotoxicity, hypertension, or dysrhythmias.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Hepatitis was reported in 3 patients following an obidoxime loading dose of 8 mg/kg followed by a continuous IV infusion of 2 mg/kg/hour. Two of the 3 patients subsequently died due to liver failure.
    B) THERAPEUTIC DOSE: ADULT: As an antidote for organophosphorus pesticide poisoning, 250 mg IM or IV bolus, followed by a continuous IV infusion of 750 mg/24 hours. As an antidote for nerve agent poisoning, 250 mg IV or IM bolus as a single dose (mild toxicity) or 250 mg IV or IM bolus initially, with a second 250 mg dose administered 2 hours later, followed by 250-mg doses every 6 to 12 hours as needed (moderate to severe toxicity). PEDIATRIC: As an antidote for organophosphorus pesticide poisoning, 4 to 8 mg/kg IV bolus dose, followed by an IV infusion of 0.45 mg/kg/hour.

Clinical Effects

Summary Of Exposure

    A) USES: Obidoxime chloride is used, typically in combination with atropine, as an antidote to treat poisoning due to those pesticides and chemicals of the organophosphate class which have anticholinesterase activity. The intramuscular auto-injector is used as an adjunct to atropine in the treatment of poisoning by nerve agents having anticholinesterase activity. As a nerve agent antidote, obidoxime appeared to be ineffective against soman poisoning during animal studies; however, it appeared to be very potent against tabun, sarin, and VX, although this may be species-specific. Obidoxime is not approved for use in the US but is available in other countries.
    B) PHARMACOLOGY: Obidoxime, a bispyridinium aldoxime, reactivates acetylcholinesterase that is inhibited by organophosphorous compound through phosphorylation. At low doses, obidoxime is believed to act upon nicotinic sites only and not able to cross the blood-brain barrier very easily. However, at high doses, when administered intravenously, obidoxime can reach higher peak plasma levels and is able to cross the blood-brain barrier and thereby can reactivate cholinesterase at the muscarinic sites of the CNS.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Hypertension, tachycardia, pain at the injection site, flushing, drowsiness, dry mouth, a menthol-like taste, nausea and vomiting, headache, generalized weakness, elevated liver enzyme levels, and facial paresthesias have been reported following therapeutic administration of obidoxime. Cardiac dysrhythmias occurred in 6 patients, with organophosphate intoxication, who were given high doses of atropine and obidoxime. A woman with organophosphate intoxication developed QT interval prolongation that progressed to torsade de pointes after receiving obidoxime in combination with atropine. Although torsade de pointes has occurred with organophosphate poisoning, it was suggested that obidoxime administration may have been a contributing factor.
    E) WITH POISONING/EXPOSURE
    1) Overdose information is limited. Hepatotoxicity, with rare cases of fatal liver failure, has been reported following administration of large cumulative doses of obidoxime.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Mild to moderate transient increases in blood pressure occurred in all 10 volunteers who received obidoxime intramuscularly at doses that ranged from 2.5 to 10 mg/kg during a clinical trial (Sidell & Groff, 1970).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) Mild to moderate transient increases in heart rate occurred in all 10 volunteers who received obidoxime intramuscularly at doses that ranged from 2.5 to 10 mg/kg during a clinical trial. The change in heart rate appeared to be dose-related, with an average maximal heart rate change of 8 beats per minute (bpm) following the 2.5 mg/kg dose, 15 bpm following the 5 mg/kg dose, and 32 bpm following the 10 mg/kg dose (Sidell & Groff, 1970).

Heent

    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) MENTHOL-LIKE TASTE - A menthol-like taste was commonly reported following intramuscular and oral administration of obidoxime (Simon et al, 1976; Sidell & Groff, 1971; Sidell & Groff, 1970)
    2) SORE THROAT - During a clinical study, involving 24 healthy male volunteers, a sore throat was reported in one individual who ingested a total of 7.36 g of obidoxime in 4 divided doses (Simon et al, 1976).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Mild to moderate transient increases in blood pressure occurred in all 10 volunteers who received obidoxime intramuscularly at doses that ranged from 2.5 to 10 mg/kg during a clinical trial (Sidell & Groff, 1970).
    B) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Mild to moderate transient increases in heart rate occurred in all 10 volunteers who received obidoxime intramuscularly at doses that ranged from 2.5 to 10 mg/kg during a clinical trial. The change in heart rate appeared to be dose-related, with an average maximal heart rate change of 8 beats per minute (bpm) following the 2.5 mg/kg dose, 15 bpm following the 5 mg/kg dose, and 32 bpm following the 10 mg/kg dose (Sidell & Groff, 1970).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Cardiac dysrhythmias occurred in 6 patients, with organophosphate intoxication, who were given high doses of atropine (2 mg IV every 10 minutes) and obidoxime (6 mg/kg every 4 hours). With 47 patients, who were given low doses of obidoxime (less than a total dose of 5 grams), the incidence of cardiac dysrhythmias was only proportional to the dose of atropine (Finkelstein et al, 1989).
    D) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 20-year-old woman with organophosphate intoxication, was given obidoxime, at a dose of 8 mg/kg administered every 4 hours for 3 consecutive doses followed by 4 mg/kg every 6 hours, in combination with atropine. The next day the patient developed QT interval prolongation that progressed to torsade de pointes. The dysrhythmias resolved following insertion of a temporary pacemaker. Although torsade de pointes has occurred with organophosphate poisoning, it was suggested that obidoxime administration may have been a contributing factor (Bentur et al, 1993).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Circumoral paresthesia and hypalgesia have been reported following intramuscular administration of obidoxime, at doses ranging from 2.5 to 10 mg/kg. Duration of effects lasted from 3 minutes to 6 hours post-injection (Sidell & Groff, 1970).
    b) Facial paresthesias, including the circumoral area, were also reported following oral administration of obidoxime at doses ranging from 1 to 9 grams (Sidell & Groff, 1971).
    c) During a clinical study, involving 24 healthy male volunteers, facial paresthesias were reported in 11 individuals who received obidoxime orally, in doses of 2.76 g, 3.68 g, and 4.60 g, given as single doses, and 7.36 g, given as 4 divided doses. Duration of symptoms lasted for 1 to 2 hours (Simon et al, 1976).
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, involving healthy volunteers who received obidoxime orally at doses ranging from 1 to 9 grams, several individuals experienced drowsiness (Sidell & Groff, 1971).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During a clinical study, involving 24 healthy male volunteers, headaches were reported in 6 individuals who received obidoxime orally, at doses of 2.76 g, 3.68 g, and 4.60 g, given as single doses, and 7.36 g, given as 4 divided doses (Simon et al, 1976).
    D) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) During a clinical study, involving 24 healthy male volunteers, generalized weakness was reported in 2 individuals who received 2.76 g and 4.60 g of obidoxime as single oral doses (Simon et al, 1976).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Transient nausea was reported in one patient following intramuscular administration of obidoxime at a dose of 7.5 mg/kg (Sidell & Groff, 1970).
    b) One individual experienced nausea and vomiting approximately 1.5 hours after ingesting one 7 gram dose of obidoxime during a clinical trial (Sidell & Groff, 1971).
    c) During a clinical study, involving 24 healthy male volunteers, nausea and vomiting was reported in one individual after receiving 7.36 grams of obidoxime orally in 4 divided doses (Simon et al, 1976).
    B) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth was reported in all patients who received 7.5 mg/kg (n=3) and 10 mg/kg (n=3) of obidoxime intramuscularly (Sidell & Groff, 1970).
    C) HEARTBURN
    1) WITH THERAPEUTIC USE
    a) During a clinical study, involving 24 healthy male volunteers, heartburn was reported in one individual who ingested 2.76 g of obidoxime as a single dose (Simon et al, 1976).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 20-year-old woman, who presented with organophosphate poisoning, developed transient elevations in liver enzyme levels approximately 4 days after beginning therapy with obidoxime at a dosage regimen of 8 mg/kg administered intravenously every 4 hours for 3 consecutive doses followed by intravenous administration of 4 mg/kg every 6 hours (Bentur et al, 1993).
    b) CASE REPORT - Elevated liver enzyme levels were also reported in a 46-year-old man with organophosphate intoxication who received 250 mg of obidoxime intravenously for 3 doses the first day, followed by 125 mg 3 times/day for the next 5 days, for a total dose of 2625 mg. The liver enzyme levels normalized following discontinuation of obidoxime therapy (De Kort et al, 1988).
    c) Transient increases in hepatic enzymes occurred in several patients who received atropine and obidoxime as antidotal therapy following acute organophosphate poisoning, although a definitive causal relationship was not established (Thiermann et al, 1997).
    B) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Hepatic dysfunction was reported in 5 (9.4%) of 53 adult patients who received the highest cumulative doses of obidoxime as antidotal therapy for acute organophosphate poisoning. Hepatic impairment was reported in 3 of 31 children who also received large cumulative doses of obidoxime. Liver enzyme levels were elevated in 5 patients, and a liver needle biopsy performed in one patient indicated hepatocellular abnormalities (Finkelstein et al, 1989).
    b) Three patients developed hepatitis following high-dose administration of obidoxime, including a loading dose of 8 mg/kg followed by a maintenance dose of 2 mg/kg/hour (duration of therapy not specified), during a clinical trial. Two of the 3 patients subsequently died due to liver failure (Balali-Mood & Shariat, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Facial flushing has been reported following therapeutic administration of obidoxime (Kassa, 2002; Sidell & Groff, 1970).
    B) PAIN
    1) WITH THERAPEUTIC USE
    a) Dull pain may occur at the injection site following intramuscular administration (Kassa, 2002; Sidell & Groff, 1970).
    C) PALE COMPLEXION
    1) WITH THERAPEUTIC USE
    a) During a clinical study, involving 24 healthy male volunteers, pallor was reported in one man who received 3.68 grams of obidoxime as a single oral dose (Simon et al, 1976).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS7683-36-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

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 liver enzymes in symptomatic patients. Hepatitis has been reported following cumulative high-dose exposure to obidoxime.
    D) Obtain an ECG, and institute continuous cardiac monitoring. Dysrhythmias, including torsades de pointes, have been reported with obidoxime therapy.
    4.1.2) SERUM/BLOOD
    A) Monitor liver enzymes in symptomatic patients. Hepatitis has been reported following cumulative high-dose exposure to obidoxime.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG and institute continuous cardiac monitoring. Dysrhythmias, including torsades de pointes, have been reported with obidoxime therapy.

Methods

    A) CHROMATOGRAPHY
    1) A reversed-phase high-performance liquid chromatographic method was described by Grasshoff et al (2001) for determination of obidoxime in urine. The limit of detection and limit of quantification, using this method, were 0.5 mcM and 1 mcM, respectively (Grasshoff et al, 2001).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Symptomatic patients should be observed with frequent monitoring of vital signs.

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 liver enzymes in symptomatic patients. Hepatitis has been reported following cumulative high-dose exposure to obidoxime.
    D) Obtain an ECG, and institute continuous cardiac monitoring. Dysrhythmias, including torsades de pointes, have been reported with obidoxime therapy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Obidoxime is primarily administered parenterally; however, ingestion of obidoxime tablets has occurred. In case of overdose ingestions, decontamination may be beneficial.
    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).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Hepatitis was reported in 3 patients following an obidoxime loading dose of 8 mg/kg followed by a continuous IV infusion of 2 mg/kg/hour. Two of the 3 patients subsequently died due to liver failure.
    B) THERAPEUTIC DOSE: ADULT: As an antidote for organophosphorus pesticide poisoning, 250 mg IM or IV bolus, followed by a continuous IV infusion of 750 mg/24 hours. As an antidote for nerve agent poisoning, 250 mg IV or IM bolus as a single dose (mild toxicity) or 250 mg IV or IM bolus initially, with a second 250 mg dose administered 2 hours later, followed by 250-mg doses every 6 to 12 hours as needed (moderate to severe toxicity). PEDIATRIC: As an antidote for organophosphorus pesticide poisoning, 4 to 8 mg/kg IV bolus dose, followed by an IV infusion of 0.45 mg/kg/hour.

Therapeutic Dose

    7.2.1) ADULT
    A) NERVE AGENT POISONING
    1) INTRAVENOUS (OR INTRAMUSCULAR) BOLUS DOSING
    a) Intravenous (or intramuscular) bolus dosing of obidoxime is a common form of administration for treatment of nerve agent poisoning. The bolus dose may vary depending on the severity of poisoning.
    1) For mild nerve agent poisoning, administer 250 milligrams as a bolus dose. For moderate and severe poisonings, administer 250 milligrams initially, with a second 250 milligram dose administered 2 hours later, followed by 250-milligram doses every 6 to 12 hours as needed (Kassa, 2002).
    2) INTRAVENOUS INFUSION
    a) Obidoxime can also be administered as a continuous intravenous infusion. In order to achieve a 4 microgram/milliliter threshold plasma level of obidoxime for treatment of nerve agent intoxication, the following loading and maintenance doses are suggested (Kassa, 2002).
    1) LOADING DOSE - 0.8 milligram/kilogram, calculated as the therapeutic plasma concentration multiplied by the volume of distribution.
    2) INFUSION RATE - 0.5 milligram/kilogram/hour, calculated as the therapeutic plasma concentration multiplied by the renal clearance.
    B) ORGANOPHOSPHOROUS PESTICIDE POISONING
    1) According to the manufacturer, the recommended dosage regimen is 250 milligrams administered as an intravenous bolus, and may be repeated once or twice at 2-hour intervals, but should not be administered after 6 hours following organophosphate intoxication (Prod Info TOXOGONIN(R) IV injection, 2007).
    2) Another suggested dosage regimen for the treatment of organophosphorous pesticide poisoning is 250 milligrams of obidoxime administered as an intravenous or intramuscular bolus, followed by a continuous intravenous infusion of 750 milligrams/24 hours (Antonijevic & Stojiljkovic, 2007; Thiermann et al, 1997).
    3) CASE REPORT - After ingesting 60 mL of 50% malathion in a suicide attempt, a 42-year-old female was treated with atropine and a total of 3 doses of 250 mg obidoxime IV. Although marked improvement was observed, she could not be weaned from the ventilator. Ten days after admission, she was transferred to another hospital. Plasma and red blood cell cholinesterases were 0.8 Units/mL (normal >2) and 1.6 Units/mL (normal >6), respectively. After more than 9 days, obidoxime (250 mg IV every 6 hours) was restarted and continued for another 4 days. She was weaned from the ventilator approximately 24 hours later and plasma cholinesterase returned to normal (Bentur et al, 2003). The authors suggested that obidoxime treatment should be considered late in the course of untreated or partially treated organophosphate poisoning, particularly when a lipid-soluble compound (e.g., malathion) is the culprit.
    7.2.2) PEDIATRIC
    A) For treatment of organophosphorous pesticide poisoning, children may be administered a 4 to 8 milligrams/kilogram intravenous bolus dose, followed by an intravenous infusion of 0.45 milligram/kilogram/hour (Prod Info TOXOGONIN(R) IV injection, 2007; Antonijevic & Stojiljkovic, 2007).

Minimum Lethal Exposure

    A) In one study of patients with organophosphate poisoning, 6 of 12 patients treated with atropine and obidoxime died, compared with 4 of 43 patients treated with atropine alone, and 0 of 8 patients treated with atropine and pralidoxime. The obidoxime dose used was and 8 mg/kg loading dose followed by 2 mg/kg/hr; the duration of infusion was not stated, but the mean total obidoxime dose was 14.0 g (+/- 7.4 g). Three obidoxime treated patients developed hepatitis, 2 of whom died due to liver failure (Balali-Mood & Shariat, 1998).

Maximum Tolerated Exposure

    A) CASE REPORT: A 20-year-old woman, who presented with organophosphate poisoning, developed transient elevations in liver enzyme levels approximately 4 days after beginning therapy with obidoxime at a dosage regimen of 8 mg/kg administered intravenously every 4 hours for 3 consecutive doses followed by intravenous administration of 4 mg/kg every 6 hours (Bentur et al, 1993).
    B) Circumoral paresthesia and hypalgesia have been reported following intramuscular administration of obidoxime, at doses ranging from 2.5 to 10 mg/kg. Duration of effects lasted from 3 minutes to 6 hours post-injection (Sidell & Groff, 1970).

Workplace Standards

    A) ACGIH TLV Values for CAS7683-36-5 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS7683-36-5 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS7683-36-5 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS7683-36-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAMUSCULAR)MOUSE:
    1) 405 to 480 mcmol/kg (Kassa, 2002)
    B) LD50- (INTRAPERITONEAL)MOUSE:
    1) 285 to 535 mcmol/kg (Kassa, 2002)
    C) LD50- (INTRAMUSCULAR)RAT:
    1) 158 mg/kg (RTECS, 2006)
    D) LD50- (INTRAPERITONEAL)RAT:
    1) 203 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Obidoxime, a bispyridinium aldoxime, reactivates acetylcholinesterase that is inhibited by organophosphorous compound through phosphorylation. At low doses, obidoxime is believed to act upon nicotinic sites only and not able to cross the blood-brain barrier very easily. However, at high doses, when administered intravenously, obidoxime can reach higher peak plasma levels and is able to cross the blood-brain barrier and thereby can reactivate cholinesterase at the muscarinic sites of the CNS (Finkelstein et al, 1989).

Physicochemical

Molecular Weight

    A) 359.2

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