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PRALIDOXIME

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pralidoxime is a cholinesterase reactivator used as an antidote for the treatment of organophosphate poisoning, anticholinesterase drug overdose, or nerve gas poisoning.

Specific Substances

    1) 2-Formyl-1-methylpyridinium chloride oxime
    2) 2-PAM
    3) 2-PAM chloride
    4) 2-PAMCl
    5) Pralidoxime chloride
    6) Pralidoxima, cloruro de
    7) Pralidoxime, chlorure de
    8) Pralidoximi chloridum
    9) Pyridinium, 2-formyl-1-methyl-, chloride, oxime
    10) 2-Pyridine Aldoxime Methochloride
    11) CAS 51-15-0
    1.2.1) MOLECULAR FORMULA
    1) C7-H9-Cl-N2-O (Prod Info PROTOPAM(R) CHLORIDE injection, 2006)

Available Forms Sources

    A) FORMS
    1) Pralidoxime chloride is available as six 20 milliliters (mL) vials of 1 gram each of sterile pralidoxime chloride white to off-white porous cake, without diluent or syringe; 20 mL of Sterile Water for Injection, USP may be added to prepare the solution. These vials are administered by either intravenous injection or intravenous infusion after further dilution with physiologic saline. If intravenous injection is not possible, the vials may be administered by either intramuscular or subcutaneous routes (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    2) Pralidoxime chloride is also available as prefilled auto-injectors which deliver 600 milligrams (mg) of pralidoxime chloride in 2 milliliters (mL) of a sterile solution containing 20 mg/mL of benzyl alcohol, and 11.26 mg/mL glycine in water for injection, USP (Prod Info PRALIDOXIME, 2002).
    B) USES
    1) Pralidoxime chloride is FDA-approved as an antidote to treat (1) poisoning due to those pesticides and chemicals of the organophosphate class which have anticholinesterase activity and (2) in the control of overdosage by anticholinesterase drugs used in the treatment of myasthenia gravis. The intramuscular auto-injector is used as an adjunct to atropine in the treatment of poisoning by nerve agents having anticholinesterase activity (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    2) Pralidoxime cannot be used to treat poisoning due to phosphorus, inorganic phosphates or organophosphates that do not have anticholinesterase activity (Prod Info PRALIDOXIME, 2002).

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: Pralidoxime chloride is used as an antidote to treat poisoning due to those pesticides and chemicals (eg, nerve agents) of the organophosphate class which have anticholinesterase activity and to control overdosage by anticholinesterase drugs used in the treatment of myasthenia gravis. Atropine and pralidoxime auto-injector is used by emergency medical services personnel to treat nerve agent or insecticide intoxication. Refer to "Anticholinergic poisoning", "Organophosphates", or "Military nerve agents" documents for more information regarding the use of pralidoxime in combination with atropine. Pralidoxime cannot be used to treat poisoning due to phosphorus, inorganic phosphates or organophosphates that do not have anticholinesterase activity.
    B) PHARMACOLOGY: Pralidoxime chloride reactivates cholinesterase (mainly outside CNS) which was inactivated by organophosphate pesticides through phosphorylation. By means of direct chemical reaction, it slows down the process of "aging" of phosphorylated cholinesterase to a permanently inactive form. Pralidoxime also detoxifies certain organophosphates.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) It is difficult to differentiate side effects of pralidoxime from effects of the poison or atropine. Blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, hypertension, hyperventilation, muscular weakness, and elevations in liver enzymes and creatine phosphokinase were observed in healthy volunteers.
    E) WITH POISONING/EXPOSURE
    1) Data are limited. Overdose effects observed in healthy volunteers include dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, and slight tachycardia. In one case report, rapid infusion of pralidoxime resulted in blurred vision, difficulty opening eyes, lateral gaze palsy, hypertension, tachycardia, rigidity of the extremities, and respiratory arrest.
    0.2.20) REPRODUCTIVE
    A) Atropine/pralidoxime chloride and pralidoxime chloride are classified as FDA pregnancy category C. No studies examining the use of atropine/pralidoxime chloride or pralidoxime during pregnancy or breastfeeding are available at this time.
    0.2.21) CARCINOGENICITY
    A) Studies have not been done to evaluate the carcinogenic or mutagenic potential of pralidoxime chloride (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).

Laboratory Monitoring

    A) Monitor vital signs, liver enzymes, and CK levels in symptomatic patients.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) It is difficult to differentiate side effects of pralidoxime from effects of the poison or atropine. Refer to "Anticholinergic poisoning", "Organophosphates", or "Military nerve agents" documents for more information regarding the use of pralidoxime in combination with atropine. 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.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress.
    E) ANTIDOTE
    1) None.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management, and pralidoxime is generally only used in the hospital setting.
    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.
    G) PITFALLS
    1) It is difficult to differentiate side effects of pralidoxime 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.
    H) PHARMACOKINETICS
    1) Metabolism: Hepatic. Distributed throughout extracellular water. It is not bound to plasma protein. Excretion: Renal: Rapid, partly as metabolite and partly unchanged. Elimination half-life: 74 to 77 minutes for a continuous infusion and approximately 3 hours following a single intramuscular injection.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause elevated liver enzymes or hypertension.

Range Of Toxicity

    A) TOXICITY: Range of toxicity has not been established. It is difficult to differentiate side effects of pralidoxime from effects of the poison or atropine. A dose of 14 mg/kg IV was reported to cause CNS toxicity.
    B) THERAPEUTIC DOSE: ADULT: A loading dose of 30 mg/kg (maximum: 2 grams) over 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/hr (up to 650 mg/hr). MAXIMUM DOSE: The maximum recommended dose for pralidoxime is 12 grams in 24 hours for adults. AUTOINJECTOR: Pralidoxime prefilled autoinjector delivers 600 mg IM (adult dosing); may repeat every 15 minutes up to 3 injections if symptoms persist. CHILD: A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride. AUTOINJECTOR: The safety and efficacy of pralidoxime autoinjector for use in nerve agent poisoning have not been established in pediatric patients; however an infusion of 10 to 20 mg/kg/hour of a solution containing 10 to 20 mg of pralidoxime/mL has been used in children with organophosphate poisoning.

Clinical Effects

Summary Of Exposure

    A) USES: Pralidoxime chloride is used as an antidote to treat poisoning due to those pesticides and chemicals (eg, nerve agents) of the organophosphate class which have anticholinesterase activity and to control overdosage by anticholinesterase drugs used in the treatment of myasthenia gravis. Atropine and pralidoxime auto-injector is used by emergency medical services personnel to treat nerve agent or insecticide intoxication. Refer to "Anticholinergic poisoning", "Organophosphates", or "Military nerve agents" documents for more information regarding the use of pralidoxime in combination with atropine. Pralidoxime cannot be used to treat poisoning due to phosphorus, inorganic phosphates or organophosphates that do not have anticholinesterase activity.
    B) PHARMACOLOGY: Pralidoxime chloride reactivates cholinesterase (mainly outside CNS) which was inactivated by organophosphate pesticides through phosphorylation. By means of direct chemical reaction, it slows down the process of "aging" of phosphorylated cholinesterase to a permanently inactive form. Pralidoxime also detoxifies certain organophosphates.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) It is difficult to differentiate side effects of pralidoxime from effects of the poison or atropine. Blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, hypertension, hyperventilation, muscular weakness, and elevations in liver enzymes and creatine phosphokinase were observed in healthy volunteers.
    E) WITH POISONING/EXPOSURE
    1) Data are limited. Overdose effects observed in healthy volunteers include dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, and slight tachycardia. In one case report, rapid infusion of pralidoxime resulted in blurred vision, difficulty opening eyes, lateral gaze palsy, hypertension, tachycardia, rigidity of the extremities, and respiratory arrest.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision, diplopia and impaired accommodation, which may persist up to 2 hours, have been reported in healthy volunteers given pralidoxime, and may be accompanied by a sensation of ocular heaviness (Prod Info PROTOPAM(R) Chloride injection, 2010; Holland et al, 1972; Holland & Parkes, 1976; Swartz & Sidell, 1973).
    B) WITH POISONING/EXPOSURE
    1) Blurred vision, diplopia, and impaired accommodation have been reported in healthy volunteers following pralidoxime overdose (Prod Info PROTOPAM(R) Chloride injection, 2010).
    2) RAPID INFUSION: A 41-year-old man presented to an ED 1.5 hours after ingesting about 250 mL of diethoxy organophosphate pesticide (34% diazinon emulsion). Although he did not have any cholinergic symptoms, he was started on pralidoxime (PAM; a loading dose of 2-g IV infusion of PAM diluted with 150 mL of 0.9% saline over 30 min and then 12 g of PAM diluted with 500 mL of 5% dextrose as a continuous infusion at a rate of 21 mL/hour using an infusion pump). Laboratory analysis revealed a serum pseudocholinesterase concentration of 688 Units/L (reference range, 3400 to 14200 Units/L) on arrival and 3767 Units/L on the second day. While being prepared for discharge about 36 hours after presentation, he inadvertently received about 150 to 200 mL of PAM solution (about 4 to 5 g of pralidoxime) rapidly infused over 10 to 20 min. He rapidly developed blurred vision, difficulty opening his eyes, lateral gaze palsy, hypertension (BP 190/110 mmHg), tachycardia (116 beats/min), and rigidity of the extremities. His condition deteriorated and he developed respiratory arrest, necessitating intubation, mechanical ventilation, and sedation. His condition gradually improved and he was discharged on hospital day 5 (Jeong et al, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been reported in healthy volunteers given pralidoxime (Prod Info PROTOPAM(R) Chloride injection, 2010).
    b) One study reported that a transient increase in heart rate has been seen only after IV administration of the drug (Sidell & Groff, 1971).
    2) WITH POISONING/EXPOSURE
    a) Slight tachycardia has been reported in healthy volunteers following pralidoxime overdose (Prod Info PROTOPAM(R) Chloride injection, 2010).
    b) RAPID INFUSION: A 41-year-old man presented to an ED 1.5 hours after ingesting about 250 mL of diethoxy organophosphate pesticide (34% diazinon emulsion). Although he did not have any cholinergic symptoms, he was started on pralidoxime (PAM; a loading dose of 2-g IV infusion of PAM diluted with 150 mL of 0.9% saline over 30 min and then 12 g of PAM diluted with 500 mL of 5% dextrose as a continuous infusion at a rate of 21 mL/hour using an infusion pump). Laboratory analysis revealed a serum pseudocholinesterase concentration of 688 Units/L (reference range, 3400 to 14200 Units/L) on arrival and 3767 Units/L on the second day. While being prepared for discharge about 36 hours after presentation, he inadvertently received about 150 to 200 mL of PAM solution (about 4 to 5 g of pralidoxime) rapidly infused over 10 to 20 min. He rapidly developed blurred vision, difficulty opening his eyes, lateral gaze palsy, hypertension (BP 190/110 mmHg), tachycardia (116 beats/min), and rigidity of the extremities. His condition deteriorated and he developed respiratory arrest, necessitating intubation, mechanical ventilation, and sedation. His condition gradually improved and he was discharged on hospital day 5 (Jeong et al, 2015).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Increased systolic and diastolic blood pressure has been reported in healthy volunteers given pralidoxime (Prod Info PROTOPAM(R) Chloride injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) RAPID INFUSION: A 41-year-old man presented to an ED 1.5 hours after ingesting about 250 mL of diethoxy organophosphate pesticide (34% diazinon emulsion). Although he did not have any cholinergic symptoms, he was started on pralidoxime (PAM; a loading dose of 2-g IV infusion of PAM diluted with 150 mL of 0.9% saline over 30 min and then 12 g of PAM diluted with 500 mL of 5% dextrose as a continuous infusion at a rate of 21 mL/hour using an infusion pump). Laboratory analysis revealed a serum pseudocholinesterase concentration of 688 Units/L (reference range, 3400 to 14200 Units/L) on arrival and 3767 Units/L on the second day. While being prepared for discharge about 36 hours after presentation, he inadvertently received about 150 to 200 mL of PAM solution (about 4 to 5 g of pralidoxime) rapidly infused over 10 to 20 min. He rapidly developed blurred vision, difficulty opening his eyes, lateral gaze palsy, hypertension (BP 190/110 mmHg), tachycardia (116 beats/min), and rigidity of the extremities. His condition deteriorated and he developed respiratory arrest, necessitating intubation, mechanical ventilation, and sedation. His condition gradually improved and he was discharged on hospital day 5 (Jeong et al, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH THERAPEUTIC USE
    a) Hyperventilation has been reported in healthy volunteers given pralidoxime (Prod Info PROTOPAM(R) Chloride injection, 2010).
    B) RESPIRATORY ARREST
    1) WITH POISONING/EXPOSURE
    a) RAPID INFUSION: A 41-year-old man presented to an ED 1.5 hours after ingesting about 250 mL of diethoxy organophosphate pesticide (34% diazinon emulsion). Although he did not have any cholinergic symptoms, he was started on pralidoxime (PAM; a loading dose of 2-g IV infusion of PAM diluted with 150 mL of 0.9% saline over 30 min and then 12 g of PAM diluted with 500 mL of 5% dextrose as a continuous infusion at a rate of 21 mL/hour using an infusion pump). Laboratory analysis revealed a serum pseudocholinesterase concentration of 688 Units/L (reference range, 3400 to 14200 Units/L) on arrival and 3767 Units/L on the second day. While being prepared for discharge about 36 hours after presentation, he inadvertently received about 150 to 200 mL of PAM solution (about 4 to 5 g of pralidoxime) rapidly infused over 10 to 20 min. He rapidly developed blurred vision, difficulty opening his eyes, lateral gaze palsy, hypertension (BP 190/110 mmHg), tachycardia (116 beats/min), and rigidity of the extremities. His condition deteriorated and he developed respiratory arrest, necessitating intubation, mechanical ventilation, and sedation. His condition gradually improved and he was discharged on hospital day 5 (Jeong et al, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported in healthy volunteers given pralidoxime (Prod Info PROTOPAM(R) Chloride injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Headache has been reported in healthy volunteers following pralidoxime overdose (Prod Info PROTOPAM(R) Chloride injection, 2010).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported in healthy volunteers given pralidoxime (Prod Info PROTOPAM(R) Chloride injection, 2010).
    b) One study reports transient dizziness with IV doses greater than 5 mg/kg (Sidell & Groff, 1971).
    2) WITH POISONING/EXPOSURE
    a) Dizziness has been reported in healthy volunteers following pralidoxime overdose (Prod Info PROTOPAM(R) Chloride injection, 2010).
    C) DROWSY
    1) WITH THERAPEUTIC USE
    a) Drowsiness has been reported in healthy volunteers given pralidoxime (Prod Info PROTOPAM(R) Chloride injection, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea has been reported in healthy volunteers given pralidoxime (Prod Info PROTOPAM(R) Chloride injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Nausea has been reported in healthy volunteers following pralidoxime overdose (Prod Info PROTOPAM(R) Chloride injection, 2010).
    B) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) One study reported that several patients complained of a bitter aftertaste following pralidoxime therapy (Lipson et al, 1969).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) One of 6 normal volunteers given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6 volunteers given 1800 mg intramuscularly experienced elevations in SGOT and/or SGPT enzyme levels (Prod Info PROTOPAM(R) Chloride injection, 2010).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) INCREASED CREATINE KINASE LEVEL
    1) WITH THERAPEUTIC USE
    a) Elevated creatine phosphokinase has been reported in healthy volunteers given pralidoxime (Prod Info PROTOPAM(R) Chloride injection, 2010).
    B) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) Muscle weakness has been reported in healthy volunteers given pralidoxime (Prod Info PROTOPAM(R) Chloride injection, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Atropine/pralidoxime chloride and pralidoxime chloride are classified as FDA pregnancy category C. No studies examining the use of atropine/pralidoxime chloride or pralidoxime during pregnancy or breastfeeding are available at this time.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) ATROPINE/PRALIDOXIME CHLORIDE
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info DuoDote(R) intramuscular injection solution, 2011).
    2) PRALIDOXIME
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info PROTOPAM(R) Chloride injection, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) ATROPINE/PRALIDOXIME CHLORIDE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info DuoDote(R) intramuscular injection solution, 2011).
    2) PRALIDOXIME
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info PROTOPAM(R) Chloride injection, 2010).
    B) PREGNANCY CATEGORY
    1) Atropine/pralidoxime chloride and pralidoxime chloride is classified as FDA pregnancy category C (Prod Info DuoDote(R) intramuscular injection solution, 2011; Prod Info PROTOPAM(R) Chloride injection, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) PRALIDOXIME
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info PROTOPAM(R) Chloride injection, 2010).
    B) BREAST MILK
    1) ATROPINE/PRALIDOXIME CHLORIDE: Atropine has been shown to be excreted into milk; however, it is unknown whether pralidoxime is present in the milk of a nursing woman (Prod Info DuoDote(R) intramuscular injection solution, 2011).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) PRALIDOXIME
    a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info PROTOPAM(R) Chloride injection, 2010).
    B) ANIMAL STUDIES
    1) ATROPINE/PRALIDOXIME CHLORIDE
    a) A dose-related decrease in fertility was observed in male rats administered atropine up to 125 mg/kg one week prior to mating and throughout the 5-day mating period. No studies have been performed with pralidoxime (Prod Info DuoDote(R) intramuscular injection solution, 2011).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS6735-59-7 (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
    3.21.2) SUMMARY/HUMAN
    A) Studies have not been done to evaluate the carcinogenic or mutagenic potential of pralidoxime chloride (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) Studies have not been done to evaluate the carcinogenic or mutagenic potential of pralidoxime chloride (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).

Genotoxicity

    A) Studies have not been done to evaluate the carcinogenic or mutagenic potential of pralidoxime chloride (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, liver enzymes, and CK levels in symptomatic patients.

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) There is no data to support home management, and pralidoxime is generally only used in the hospital setting.
    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) Monitor vital signs, liver enzymes, and CK levels in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: Range of toxicity has not been established. It is difficult to differentiate side effects of pralidoxime from effects of the poison or atropine. A dose of 14 mg/kg IV was reported to cause CNS toxicity.
    B) THERAPEUTIC DOSE: ADULT: A loading dose of 30 mg/kg (maximum: 2 grams) over 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/hr (up to 650 mg/hr). MAXIMUM DOSE: The maximum recommended dose for pralidoxime is 12 grams in 24 hours for adults. AUTOINJECTOR: Pralidoxime prefilled autoinjector delivers 600 mg IM (adult dosing); may repeat every 15 minutes up to 3 injections if symptoms persist. CHILD: A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride. AUTOINJECTOR: The safety and efficacy of pralidoxime autoinjector for use in nerve agent poisoning have not been established in pediatric patients; however an infusion of 10 to 20 mg/kg/hour of a solution containing 10 to 20 mg of pralidoxime/mL has been used in children with organophosphate poisoning.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL: Following organophosphate poisoning, treatment should be initiated as soon as possible. Atropine is the first line agent which should be given once hypoxia, if present, has improved. Initial atropine dose in adults is 2 to 4 mg IV which maybe repeated every 5 to 10 minutes until full atropinization (secretions inhibited or signs of atropine toxicity {delirium, hyperthermia, muscle twitching}). Once the effects of atropine are present, pralidoxime may be given (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    B) A loading dose of 30 mg/kg (maximum: 2 grams) over 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/hr (up to 650 mg/hr) (Howland, 2011). In vitro studies have recommended a target plasma concentration of close to 17 mcg/mL necessary for pralidoxime to be effective, which is higher than the previously suggested concentration of at least 4 mcg/mL (Howland, 2011; Eddleston et al, 2002). ALTERNATE DOSE: An alternate initial dose for adults is 1 to 2 grams diluted in 100 mL of 0.9% sodium chloride infused over 15 to 30 minutes. Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). In patients with serious cholinergic intoxication, a continuous infusion of 500 mg/hr should be considered. In patients with acute lung injury, a 5% solution may be administered by a slow IV injection over at least 5 minutes (Howland, 2006). Intravenous dosing is preferred; however, intramuscular administration may be considered using a 1-g vial of pralidoxime reconstituted with 3 mL of sterile water for injection or 0.9% sodium chloride for injection, producing a solution containing 300 mg/mL (Howland, 2011). An initial intramuscular pralidoxime dose of 1 gram or up to 2 grams in cases of very severe poisoning has also been recommended (Haddad, 1990; S Sweetman , 2002).
    C) MAXIMUM DOSE: The maximum recommended dose for pralidoxime is 12 grams in 24 hours for adults (S Sweetman , 2002); based on WHO, this dose may be exceeded in severely poisoned adults (Tang et al, 2013).
    D) CONTINUOUS INFUSION
    1) A continuous infusion of pralidoxime is generally preferred to intermittent bolus dosing to maintain a target concentration with less variation (Howland, 2011; Eddleston et al, 2008; Roberts & Aaron, 2007; Gallagher et al, 1989; Thompson, 1987). Infusion over a period of several days may be necessary and is generally well tolerated (Namba et al, 1971).
    E) DURATION OF INTRAVENOUS DOSING
    1) Dosing should be continued for at least 24 hours after cholinergic manifestations have resolved (Howland, 2006). Prolonged administration may be necessary in severe cases, especially in the case of poisoning by lipophilic organophosphates (Wadia & Amin, 1988). Observe patients carefully for recurrent cholinergic manifestations after pralidoxime is discontinued.
    F) AUTOINJECTOR
    1) Pralidoxime prefilled autoinjector delivers 600 mg IM (adult dosing); may repeat every 15 minutes up to 3 injections if symptoms persist. The safety and efficacy of pralidoxime auto-injector for use in nerve agent poisoning have not been established in pediatric patients (Prod Info pralidoxime chloride intramuscular auto-imjector solution, 2003).
    2) ATNAA (Antidote Treatment Nerve Agent Autoinjector, Meridian Medical Technologies, Columbia, Maryland) is currently used by the US military and provides atropine injection and pralidoxime chloride injection in a single needle. Each self-contained unit dispenses 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL via intramuscular injection. DOSE: ADULT: One ATNAA into the lateral thigh muscle or buttocks. Wait 10 to 15 minutes for effect (Prod Info ATNAA ANTIDOTE TREATMENT – NERVE AGENT, AUTO-INJECTOR intramuscular injection solution, 2002).
    3) MARK I: This device (Meridian Medical Technologies, Columbia, Maryland) was used by the US military. (Note: the MARK I autoinjector kit was last produced by Meridian Medical Technologies, Columbia, MD in 2008. This product may still be available in some locations.) Each kit contains two autoinjectors: an atropine and a pralidoxime autoinjector. The atropine autoinjector delivers 2.1 mg of atropine in 0.7 mL via intramuscular injection. The pralidoxime autoinjector delivers 600 mg pralidoxime chloride in 2 mL via intramuscular injection (Prod Info DUODOTE(TM) IM injection, 2006).
    4) DuoDote(R) is a dual chambered device (Meridian Medical Technologies, Columbia, Maryland) that delivers 2.1 mg of atropine in 0.7 mL and 600 mg of pralidoxime chloride in 2 mL sequentially using a single needle for use in a civilian or community setting. It should be administered by Emergency Medical Services personnel who have been trained to recognize and treat nerve agent or insecticide intoxication. DOSE: ADULT: Two or more mild symptoms, initial dose, 1 injector (atropine 2.1 mg/pralidoxime chloride 600 mg) IM into the mid-lateral thigh, wait 10 to 15 minutes for effect; subsequent doses, if at any time severe symptoms develop, administer 2 additional injectors in rapid succession IM into the mid-lateral thigh and immediately seek definitive medical care; MAX 3 doses unless definitive medical care is available (Prod Info DuoDote(R) intramuscular injection solution, 2011).
    7.2.2) PEDIATRIC
    A) A loading dose of 20 to 40 mg/kg (maximum: 2 grams/dose) infused over 30 to 60 minutes in 0.9% sodium chloride (Howland, 2006; Schexnayder et al, 1998). Repeat initial bolus dose in 1 hour and then every 3 to 8 hours if muscle weakness or fasciculations persist (continuous infusion preferred). ALTERNATE DOSE: An alternate loading dose of 25 to 50 mg/kg (up to a maximum dose of 2 g), followed via continuous infusion of 10 to 20 mg/kg/hr. In patients with serious cholinergic intoxication, a continuous infusion of 10 to 20 mg/kg/hr up to 500 mg/hr should be considered (Howland, 2006).
    B) AUTOINJECTOR
    1) NERVE AGENT POISONING (AUTO-INJECTOR): The safety and efficacy of pralidoxime auto-injector for use in nerve agent poisoning have not been established in pediatric patients (Prod Info pralidoxime chloride intramuscular auto-imjector solution, 2003); however an infusion of 10 to 20 milligrams/kilogram/hour of a solution containing 10 to 20 milligrams of pralidoxime/milliliter has been used in children with organophosphate poisoning (Farrar et al, 1990; Schexnayder et al, 1998).
    2) Since the AtroPen(R) autoinjector (atropine sulfate; Meridian Medical Technologies, Inc, Columbia, MD) comes in different strengths, certain dose units have been approved for use in children (Prod Info ATROPEN(R) IM injection, 2005).

Maximum Tolerated Exposure

    A) Range of toxicity has not been established. It is difficult to differentiate side effects of pralidoxime from effects of the poison or atropine. A dose of 14 mg/kg IV was reported to cause CNS toxicity (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).
    B) CHILDREN: One study reviewed information on pralidoxime use in children (aged 16 years and younger) using published reports (from 2001 to 2004) and retrospective detailed TESS data. Overall, 81 patients met inclusion criteria and received atropine and pralidoxime for suspected organophosphate exposure. Five cases were identified; 2 patients expired and 3 patients experienced mild adverse effects. It was determined that neither the adverse effects nor death was the direct result of pralidoxime administration (Quail & Shannon, 2007).
    C) ADULT: Following the accidental injection of a pralidoxime chloride autoinjector, an Air Force aviator recovered with no specific treatment (Yamane, 1999).
    D) RAPID INFUSION: A 41-year-old man presented to an ED 1.5 hours after ingesting about 250 mL of diethoxy organophosphate pesticide (34% diazinon emulsion). Although he did not have any cholinergic symptoms, he was started on pralidoxime (PAM; a loading dose of 2-g IV infusion of PAM diluted with 150 mL of 0.9% saline over 30 min and then 12 g of PAM diluted with 500 mL of 5% dextrose as a continuous infusion at a rate of 21 mL/hour using an infusion pump). While being prepared for discharge about 36 hours after presentation, he inadvertently received about 150 to 200 mL of PAM solution (about 4 to 5 g of pralidoxime) rapidly infused over 10 to 20 min. He rapidly developed blurred vision, difficulty opening his eyes, lateral gaze palsy, hypertension (BP 190/110 mmHg), tachycardia (116 beats/min), and rigidity of the extremities. His condition deteriorated and he developed respiratory arrest, necessitating intubation, mechanical ventilation, and sedation. His condition gradually improved and he was discharged on hospital day 5 (Jeong et al, 2015).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Minimum therapeutic concentration: 4 mcg per mL (Prod Info PROTOPAM(R) CHLORIDE injection, 2006)

Workplace Standards

    A) ACGIH TLV Values for CAS6735-59-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS6735-59-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS6735-59-7 :
    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 CAS6735-59-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAMUSCULAR)MOUSE:
    1) 100 mg/kg (RTECS, 2006)
    B) LD50- (INTRAPERITONEAL)MOUSE:
    1) 155 mg/kg (RTECS, 2006)
    C) LD50- (ORAL)MOUSE:
    1) 4100 mg/kg (RTECS, 2006)
    D) LD50- (INTRAMUSCULAR)RAT:
    1) 150 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Pralidoxime chloride reactivates cholinesterase (mainly outside CNS) which was inactivated by organophosphate pesticides through phosphorylation. By means of direct chemical reaction, it slows down the process of "aging" of phosphorylated cholinesterase to a form which is not reactivatable, and it also detoxifies certain organophosphates (Prod Info pralidoxime chloride injection powder for solution, 2002).

Physicochemical

Physical Characteristics

    A) Pralidoxime is an odorless, white, nonhygroscopic, crystalline powder which is soluble in water (Prod Info PROTOPAM(R) CHLORIDE injection, 2006).

Molecular Weight

    A) 172.6 (Prod Info PROTOPAM(R) CHLORIDE injection, 2006)

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