Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution:
ATNAA, Duodote: Atropine 2.1 mg/0.7 mL and pralidoxime chloride 600 mg/2 mL [contains benzyl alcohol; prefilled autoinjector]
Pharmacology
Mechanism of Action
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.
Use: Labeled Indications
Organophosphate insecticide or nerve agent poisoning:
ATNAA: Treatment of poisoning in patients who have been exposed to organophosphate nerve agents (eg, sarin, soman, tabun, VX) that have acetylcholinesterase-inhibiting activity for self- or buddy-administration by military personnel
DuoDote: Treatment of poisoning by organophosphate nerve agents (eg, sarin, soman, tabun, VX) or organophosphate insecticides in adult and pediatric patients weighing >41 kg for use by trained emergency medical services personnel
Contraindications
No contraindications exist in the treatment of life-threatening organophosphate insecticide or nerve agent poisoning
Dosage and Administration
Dosing: Adult
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
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
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
Administration
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.
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); avoid freezing. Protect from light.
Note: As of May 2014, for certain lots of DuoDote, the US Food and Drug Administration (FDA) has granted extended expiration dating for up to 3 years 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.
Drug Interactions
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Amantadine: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy
Amezinium: Atropine (Systemic) may enhance the stimulatory effect of Amezinium. Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy
Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy
Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Exceptions: Cannabidiol. Monitor therapy
Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Monitor therapy
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination
EPHEDrine (Systemic): Atropine (Systemic) may enhance the therapeutic effect of EPHEDrine (Systemic). Monitor therapy
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Monitor therapy
Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination
Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination
Macimorelin: Atropine (Systemic) may diminish the diagnostic effect of Macimorelin. Avoid combination
Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Monitor therapy
Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. 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. 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. Monitor therapy
Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. 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. Avoid combination
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy
Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Avoid combination
Ritodrine: Atropine (Systemic) may enhance the adverse/toxic effect of Ritodrine. Monitor therapy
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. 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. Consider therapy modification
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination
Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Adverse Reactions
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)
Warnings/Precautions
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.
- Prostatic hyperplasia: Use with caution in patients with prostatic hyperplasia; may cause urinary retention.
- 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.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions for more detailed information.
Special populations:
- Elderly: 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.
Monitoring Parameters
Respiratory status, ABGs, pulse oximeter; body temperature (especially in warm climates); blood pressure (peak effect occurs ~15 minutes after administration); symptoms of poisoning
Pregnancy
Pregnancy Risk Factor
C
Pregnancy Considerations
Reproduction studies have not been conducted with this combination. Also refer to individual agents. The risk:benefit ratio must be considered in pregnant patients who have been exposed to a nerve agent such as sarin. While adequate studies have not been conducted, survival of the mother may be dependent upon administering atropine and pralidoxime.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience injection site irritation, dry eyes, blurred vision, sensitivity to light, flushing, nausea, vomiting, fatigue, muscle weakness, dry skin, or dry mouth. Have patient report immediately to prescriber fast breathing, severe dizziness, severe headache, confusion, difficult urination, decreased sex drive, passing out, lack of sweating, vision changes, eye pain, severe constipation, abdominal edema, difficulty swallowing, severe abdominal pain, severe eye irritation, sexual dysfunction, unable to pass urine, change in amount of urine passed, abnormal heartbeat, chest pain, or fast heartbeat (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
