Version May 2024
Organophosphate insecticide or nerve agent poisoning: Note: If exposure is known or suspected, antidotal therapy should be given immediately as soon as symptoms appear (critical to administer immediately in case of soman exposure since its adverse effects develop within minutes). Only health care providers who have had adequate training in the recognition and treatment of nerve agent or insecticide intoxication should administer.
Children and Adolescents weighing >41 kg: DuoDote (atropine 2.1 mg/pralidoxime 600 mg per autoinjector):
Mild symptoms (≥2 mild symptoms): IM: 1 injection (wait 10 to 15 minutes for effect); if after 10 to 15 minutes no severe symptoms emerge, no further injections are indicated; if any severe symptoms emerge at any point following initial injection, repeat dose by giving 2 additional injections in rapid succession. Transport to medical care facility.
Severe symptoms (≥1 severe symptom): IM: 3 injections in rapid succession. Transport to medical care facility.
Maximum cumulative dose: 3 injections unless medical care support (eg, hospital, respiratory support) is available
Symptoms of organophosphate insecticide or nerve agent poisoning, as provided by manufacturer in the DuoDote product labeling to guide therapy:
Mild symptoms: Airway secretions increased, blurred vision, bradycardia, breathing difficulties, chest tightness, drooling, miosis, nausea, vomiting, runny nose, salivation, stomach cramps (acute onset), tachycardia, teary eyes, tremors/muscular twitching, wheezing/coughing
Severe symptoms: Breathing difficulties (severe), confused/strange behavior, convulsions, copious secretions from lung or airway, involuntary urination/defecation, muscular twitching/generalized weakness (severe), unconsciousness
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; pralidoxime can cause kidney impairment.
There are no dosage adjustments provided in manufacturer's labeling. Use with caution in severe impairment.
(For additional information see "Atropine and pralidoxime: Drug information")
Organophosphate insecticide or nerve agent poisoning: IM: Note: If exposure is suspected, antidotal therapy should be given immediately as soon as symptoms appear (critical to administer immediately in case of soman exposure since its adverse effects develop within minutes). Definitive medical care should be sought after any injection given. One injection only may be given as self-aid. If repeat injections are needed, administration must be done by another trained individual. Emergency medical personnel who have self-administered a dose must determine their capacity to continue to provide care.
ATNAA:
Mild symptoms (some or all mild symptoms): Self-Aid or Buddy-Aid: 1 injection (wait 10 to 15 minutes for effect); if the patient is able to ambulate, and knows who and where they are, then no further injections are needed. If symptoms are still present: Buddy-Aid: May repeat 1 to 2 more injections
Severe symptoms (if most or all): Buddy-Aid: If no self-aid given, 3 injections in rapid succession; if 1 self-aid injection given, 2 injections in rapid succession
Maximum cumulative dose: 3 injections
Symptoms of organophosphate insecticide or nerve agent poisoning, as provided by manufacturer in the ATNAA product labeling to guide therapy:
Mild symptoms: Breathing difficulties, chest tightness, coughing, difficulty in seeing, drooling, headache, localized sweating and muscular twitching, miosis, nausea (with or without vomiting), runny nose, stomach cramps, tachycardia (followed by bradycardia), wheezing
Severe symptoms: Bradycardia, confused/strange behavior, convulsions, increased wheezing and breathing difficulties, involuntary urination/defecation, miosis (severe), muscular twitching/generalized weakness (severe), red/teary eyes, respiratory failure, unconsciousness, vomiting
DuoDote:
Mild symptoms (≥2 mild symptoms): 1 injection (wait 10 to 15 minutes for effect); if after 10 to 15 minutes no severe symptoms emerge, no further injections are indicated; if any severe symptoms emerge at any point following initial injection, repeat dose by giving 2 additional injections in rapid succession. Transport to medical care facility.
Severe symptoms (≥1 severe symptom): 3 injections in rapid succession. Transport to medical care facility.
Maximum cumulative dose: 3 injections unless medical care support (eg, hospital, respiratory support) is available
Symptoms of organophosphate insecticide or nerve agent poisoning, as provided by manufacturer in the DuoDote product labeling to guide therapy:
Mild symptoms: Airway secretions increased, blurred vision, bradycardia, breathing difficulties, chest tightness, drooling, miosis, nausea, vomiting, runny nose, salivation, stomach cramps (acute onset), tachycardia, teary eyes, tremors/muscular twitching, wheezing/coughing
Severe symptoms: Breathing difficulties (severe), confused/strange behavior, convulsions, copious secretions from lung or airway, involuntary urination/defecation, muscular twitching/generalized weakness (severe), unconsciousness
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no specific dosage adjustments provided in the manufacturer's labeling. Use with caution; pralidoxime may cause decreased renal function.
There are no specific dosage adjustments provided in the manufacturer's labeling; use with caution in patients with severe impairment.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined. Reactions reported with Duodote. Also see individual agents.
Cardiovascular: Transient increase of blood pressure (usually occurring 15 minutes after administration and returning to baseline 4 hours post-dose)
Central nervous system: Hypertonia (at injection site; mild-to-moderate)
Local: Pain at injection site (mild-to-moderate)
No contraindications exist in the treatment of life-threatening organophosphate insecticide or nerve agent poisoning
Concerns related to adverse effects:
• Atropinization: Signs of atropinization (eg, flushing, mydriasis, tachycardia, dryness of mouth or nose) may occur earlier than expected with the use of a combination product as compared to atropine alone. Monitor effects closely when administering subsequent injections as necessary. The presence of these effects is not indicative of the success of therapy. Reversal of bronchial secretions is the preferred indicator of success.
• Hyperthermia: Atropine may inhibit sweating and possibly lead to heat-related injury or hyperthermia in patients exposed to warm environments or exercise.
Disease-related concerns: The following diseases are relative precautions only when symptoms of poisoning are not severe:
• Cardiovascular disease: Use with caution in patients with heart disease, arrhythmias (eg, atrial flutter), severe CAD, or history of recent MI; treatment-related blood pressure increases and tachycardia may lead to ischemia, precipitate an MI, or increase arrhythmogenic potential.
• Chronic lung disease: Use with caution in patients with chronic lung disease; may cause inspiration of bronchial secretions and formation of dangerous viscid plugs.
• Hepatic impairment: Use with caution in patients with hepatic impairment; effects of atropine may be prolonged in severe hepatic impairment.
• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may precipitate myasthenic crisis.
• Narrow-angle glaucoma: Use with caution in patients with severe narrow-angle glaucoma; may precipitate acute glaucoma.
• Pyloric stenosis: Use with caution in patients with pyloric stenosis; may cause complete pyloric obstruction.
• Renal impairment: Use with caution in renal impairment; pralidoxime is excreted renally and the effects of atropine may be prolonged in severe renal impairment.
• Urinary obstruction: Use with caution in patients with urinary obstruction; may cause urinary retention.
Special populations:
• Older adult: May be more sensitive to the anticholinergic effects of atropine.
• Pediatric: May be more sensitive to the anticholinergic effects of atropine.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use: Clinical symptoms consistent with highly-suspected organophosphate insecticide or nerve agent poisoning should be treated with antidote immediately; administration should not be delayed for confirmatory laboratory tests. Treatment should always include proper evacuation and decontamination procedures; medical personnel should protect themselves from inadvertent contamination. Antidotal administration is intended only for initial management; definitive and more extensive medical care is required following administration. Individuals should not rely solely on antidote for treatment, as other supportive measures (eg, artificial respiration) may still be required. Continued administration of additional doses in asymptomatic patients may result in atropine toxicity.
CNS effects (eg, restlessness, tremor, fatigue, locomotor difficulties, delirium, hallucinations) of atropine are often seen earlier and at lower doses in pediatric patients compared to adults.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution:
ATNAA, Duodote [DSC]: Atropine 2.1 mg/0.7 mL and pralidoxime chloride 600 mg/2 mL [contains benzyl alcohol; prefilled autoinjector]
No
Solution Auto-injector (DuoDote Intramuscular)
2.1-600 mg (per mL): $22.58
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Evacuation and decontamination procedures should be undertaken as soon as possible. Medical personnel need to protect themselves from accidental exposure. Primary prophylaxis against organophosphate nerve agents should always consist of appropriate protective garments and masks. Organophosphate agents are well absorbed through skin, lungs, and GI tract. They are usually described as having a petroleum or garlic like odor. Once absorbed, organophosphate agents bind to acetylcholinesterase (also known as RBC acetylcholinesterases) and inactivate the enzyme. Acetylcholinesterases catalyze the hydrolysis of acetylcholine to choline and acetic acid; therefore, once inactivated excess acetylcholine accumulates.
Clinical symptoms of toxicity are associated with cholinergic excess and involve the autonomic nervous system, CNS, and neuromuscular junction. Clinical features of acute cholinergic toxicity include bradycardia, miosis, lacrimation, salivation, bronchorrhea, bronchospasm, emesis and diarrhea. At times, mydriasis and tachycardia may be observed. 100% oxygen and fluid resuscitation are important initial steps in management. Onset and duration of clinical features consistent with poisoning vary depending on agent and route of exposure; therefore, every effort should be made to identify poisoning agent. In addition, time interval to “aging” process (irreversible binding between organophosphates and acetylcholinesterase) vary depending on nerve agent. Once “aging” has occurred, oxime therapy (eg, pralidoxime) is ineffective, thus making timing of antidote administration critical, particularly in the case of soman exposure where “aging” process occurs within minutes of exposure.
ATNAA (Antidote Treatment-Nerve Agent Auto-Injector) is only available for use by US Armed Forces military personnel. Information on distribution is available at Defense Services Supply Center-Philadelphia at 215-737-2341.
Duodote is only available for use by trained emergency medical services personnel to treat civilians. Distribution is limited to directly from manufacturer (Meridian Medical Technologies, Inc) to emergency medical service organizations or their suppliers.
IM:
DuoDote: Administer IM into the mid-lateral thigh. Hold the device firmly at the center with the green tip (needle end) pointing down; remove the gray safety release with the other hand; do not touch the green tip at any time. The device is now ready for administration into the mid-lateral thigh; removal of clothing is not necessary, but pockets should be empty. If patient does not have a lot of fat at the injection site, bunch up thigh tissue for a thicker injection area. Firmly push the green tip against the mid-lateral thigh. Hold firmly in place until auto-injector triggers and continue to hold for 10 seconds after the device has triggered. The needle does not retract; after administration, the needle should be visible; if the needle is not visible, repeat the above steps. After use, bend the needle against a hard surface to avoid accidental injury.
IM:
ATNAA: May be administered in the lateral thigh muscle or buttocks. The first dose may be self-administered; subsequent doses must be administered by a buddy. Remove the gray safety cap from the back end; place the front end on the outer thigh or buttocks and push hard to activate the injector. Hold firmly in place for 10 seconds. After use, bend the needle into a hook shape against a hard surface.
DuoDote: Self-administration: Hold the device firmly at the center with the green tip (needle end) pointing down; remove the gray safety release with the other hand. Do not touch the green tip at any time. Removal of clothing is not necessary, but pockets should be empty. Firmly push green tip straight down (90° angle) against the mid-lateral thigh. Hold firmly in place until auto-injector triggers and for ~10 seconds after device has triggered. After administration, the needle will be visible; if the needle is not visible, repeat the above steps. After use, bend the needle against a hard surface (needle does not retract) to avoid accidental injury.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); avoid freezing. Protect from light.
Note: FDA has granted extended expiration dating for certain lots of Duodote beyond the manufacturer's labeled expiration dating. Further information may be found at http://www.fda.gov/drugs/drugsafety/ucm376367.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery.
DuoDote: Treatment of poisoning by organophosphate nerve agents (eg, tabun, sarin, soman) or organophosphate insecticides for use by trained emergency medical services personnel (FDA approved in pediatric patients weighing >41 kg and adults).
ATNAA: Treatment of poisoning in patients who have been exposed to organophosphate nerve agents (eg, tabun, sarin, soman) that have acetylcholinesterase-inhibiting activity for self- or buddy-administration by military personnel (FDA approved in adults).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Alpha1-Agonists: Atropine (Systemic) may enhance the hypertensive effect of Alpha1-Agonists. Risk C: Monitor therapy
Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Amezinium: Atropine (Systemic) may enhance the stimulatory effect of Amezinium. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy
Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapy
Chlorprothixene: Anticholinergic Agents may enhance the anticholinergic effect of Chlorprothixene. Risk C: Monitor therapy
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Risk X: Avoid combination
CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
EPHEDrine (Systemic): Atropine (Systemic) may enhance the therapeutic effect of EPHEDrine (Systemic). Risk C: Monitor therapy
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor therapy
Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid combination
Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Risk C: Monitor therapy
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination
Macimorelin: Atropine (Systemic) may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy
Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Risk C: Monitor therapy
Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor therapy
Opioid Agonists: Anticholinergic Agents may enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy
Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid combination
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium citrate. Risk X: Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination
Ritodrine: Atropine (Systemic) may enhance the adverse/toxic effect of Ritodrine. Risk C: Monitor therapy
Rivastigmine: Anticholinergic Agents may diminish the therapeutic effect of Rivastigmine. Rivastigmine may diminish the therapeutic effect of Anticholinergic Agents. Management: Use of rivastigmine with an anticholinergic agent is not recommended unless clinically necessary. If the combination is necessary, monitor for reduced anticholinergic effects. Risk D: Consider therapy modification
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider therapy modification
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination
Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination
Atropine crosses the placenta.
Information related to the use of atropine/pralidoxime following organophosphate poisoning in pregnant patients is limited (Bailey 2003; Kamha 2005; Sun 2015). In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).
Refer to individual monographs for additional information.
Respiratory status, ABGs, pulse oximeter; body temperature (especially in warm climates); blood pressure (peak effect occurs ~15 minutes after administration); symptoms of poisoning.
Direct measurement of RBC acetylcholinesterase activity provides a measure of degree of toxicity, although symptoms may not correlate with degree of inactivation unless activity reduced to <50%. Sequential measurement (if rapidly available) may help to determine the effectiveness of oxime therapy. Plasma (or pseudo) cholinesterase activity is more easily performed, but does not correlate well with the severity and should not be used to guide therapy.
Atropine: Functions as a competitive antagonist of acetylcholine at muscarinic receptors in the peripheral and central nervous system, thus reducing the symptoms of parasympathetic overstimulation resulting from excess acetylcholine caused by organophosphate insecticide or nerve agent poisoning. The parasympatholytic action of atropine decreases oral and respiratory secretions, relieves airway constriction, and attenuates the bradycardia induced by organophosphate insecticides and nerve agents. Antagonizes acetylcholine accumulation at respiratory center and may reduce centrally-mediated respiratory paralysis.
Pralidoxime: An oxime which functions by way of nucleophilic attack on the ester site of the acetylcholinesterase enzyme which has been deactivated by phosphorylation. Displacement of the phosphoryl group allows reactivation of acetylcholinesterase’s hydrolytic activity, thus permitting renewed catalysis of accumulated acetylcholine. Destruction of accumulated acetylcholine allows for restoration of normal functioning at neuromuscular junctions and relief from respiratory muscle paralysis.
See individual agents.
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