Manifestations of atropine overdose are dose-related and include flushing, dry skin and mucous membranes, tachycardia, widely dilated pupils that are poorly responsive to light, blurred vision, and fever (which can sometimes be dangerously elevated). Locomotor difficulties, disorientation, hallucinations, delirium, confusion, agitation, coma, and central depression can occur and may last 48 hours or longer. In instances of severe atropine intoxication, respiratory depression, coma, circulatory collapse, and death may occur.
PralidoximeIt may be difficult to differentiate adverse events caused by pralidoxime from those caused by organophosphorus poisoning. Symptoms of pralidoxime overdose may include dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, and tachycardia. Transient hypertension caused by pralidoxime may last several hours.
TreatmentFor atropine overdose, supportive treatment should be administered. If respiration is depressed, artificial respiration with oxygen is necessary. Ice bags, a hypothermia blanket, or other methods of cooling may be required to reduce atropine-induced fever, especially in pediatric patients. Catheterization may be necessary if urinary retention occurs. Since atropine elimination largely takes place through the kidney, urinary output must be maintained and increased if possible; intravenous fluids may be indicated. Because of atropine-induced photophobia, the room should be darkened.
A benzodiazepine may be needed to control marked excitement and convulsions. However, large doses for sedation should be avoided because the central nervous system depressant effect may coincide with the depressant effect occurring late in severe atropine poisoning. Barbiturates are potentiated by the anticholinesterases; therefore, barbiturates should be used cautiously in the treatment of convulsions. Central nervous system stimulants are not recommended.
None.
The following serious adverse reactions are described elsewhere in the labeling:
The following adverse reactions associated with the use of atropine and pralidoxime chloride were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
AtropineBecause DuoDote contains pralidoxime chloride, which may potentiate the effect of atropine, signs of atropinization may occur earlier than might be expected when atropine is used alone.
Common adverse reactions of atropine can be attributed to its antimuscarinic action. These include dryness of the mouth, blurred vision, dry eyes, photophobia, confusion, headache, dizziness, tachycardia, palpitations, flushing, urinary hesitancy or retention, constipation, abdominal pain, abdominal distention, nausea and vomiting, loss of libido, and impotence. Anhidrosis may produce heat intolerance and impairment of temperature regulation in a hot environment. Dysphagia, paralytic ileus, acute angle closure glaucoma, maculopapular rash, petechial rash, and scarletiniform rash have also been reported. Adverse cardiac reactions, including arrhythmias and myocardial infarction, have been reported with atropine.
Larger doses of atropine may produce central nervous system effects such as restlessness, tremor, fatigue, locomotor difficulties, delirium, and hallucinations.
Hypersensitivity reactions will occasionally occur, are usually seen as skin rashes, and may progress to exfoliation. Anaphylactic reaction and laryngospasm are rare.
Pralidoxime ChloridePralidoxime can cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure , muscular weakness, dry mouth, emesis, rash, dry skin, hyperventilation, decreased renal function, and decreased sweating when given parenterally to normal adult volunteers who have not been exposed to anticholinesterase poisons.
In several cases of organophosphorus poisoning, excitement and manic behavior have occurred immediately following recovery of consciousness, in either the presence or absence of pralidoxime administration. However, similar behavior has not been reported in subjects given pralidoxime in the absence of organophosphorus poisoning.
Elevations in AST and/or ALT enzyme levels were observed in 1 of 6 normal adult volunteers given 1200 mg of pralidoxime intramuscularly, and in 4 of 6 adult volunteers given 1800 mg intramuscularly. Levels returned to normal in about two weeks. Transient elevations in creatine kinase were observed in all normal volunteers given the drug.
Injection SiteMuscle tightness and pain may occur at the injection site.
Inadvertent InjectionIn cases where DuoDote is inadvertently administered to people who are not poisoned with nerve agent or organophosphorus insecticide, the following effects on their ability to function normally may occur.
Atropine 2 mg IM, roughly the equivalent of one DuoDote autoinjector, when given to healthy male volunteers, is associated with minimal effects on visual, motor, and mental functions, though unsteadiness walking and difficulty concentrating may occur. Atropine reduces body sweating and increases body temperature, particularly with exercise and under hot conditions.
Atropine 4 mg IM, roughly the equivalent of two DuoDote autoinjectors, when given to healthy male volunteers, is associated with impaired visual acuity, visual near point accommodation, logical reasoning, digital recall, learning, and cognitive reaction time. Ability to read is reduced or lost. Subjects are unsteady and need to concentrate on walking. These effects begin about 15 minutes to one hour or more post-dose.
Atropine 6 mg IM, roughly the equivalent of three DuoDote autoinjectors, when given to healthy male volunteers, is associated with the effects described above plus additional central effects including poor coordination, poor attention span, and visual hallucinations (colored flashes) in many subjects. Frank visual hallucinations, auditory hallucinations, disorientation, and ataxia occur in some subjects. Skilled and labor-intense tasks are performed more slowly and less efficiently. Decision making takes longer and is sometimes impaired.
It is unclear if the above data, obtained from studies of healthy adult subjects, can be extrapolated to other populations. In the elderly and patients with co-morbid conditions, the effects of ≥2 mg atropine on the ability to see, walk, and think properly are unstudied; effects may be greater in susceptible populations.
Patients who are mistakenly injected with DuoDote should avoid potentially dangerous overheating, avoid vigorous physical activity, and seek medical attention as soon as feasible.
DuoDote is indicated for the treatment of poisoning by organophosphorus nerve agents as well as organophosphorus insecticides in adults and pediatric patients weighing more than 41 kg (90 pounds).
Atropine reduces secretions in the mouth and respiratory passages, relieves airway constriction, and may reduce centrally-mediated respiratory paralysis. In severe organophosphorus poisoning, a fully atropinized patient may develop or continue to have respiratory failure and may require artificial respiration and suctioning of airway secretions. Atropine may cause thickening of secretions.
Atropine-induced parasympathetic inhibition may be preceded by a transient phase of stimulation, especially on the heart where small doses first slow the rate before characteristic tachycardia develops due to paralysis of vagal control. Atropine increases heart rate and reduces atrioventricular conduction time. Adequate atropine doses can prevent or abolish bradycardia or asystole produced by organophosphorus nerve agents.
Atropine may decrease the degree of partial heart block which can occur after organophosphorus poisoning. In some patients with complete heart block, atropine may accelerate the idioventricular rate; in others, the rate is stabilized. In some patients with conduction defects, atropine may cause paradoxical atrioventricular (A-V) block and nodal rhythm.
Atropine will not act on the neuromuscular junction and has no effect on muscle paralysis or weakness, fasciculations or tremors; pralidoxime is intended to treat these symptoms.
Systemic doses of atropine slightly raise systolic and lower diastolic pressures and can produce significant postural hypotension. Such doses also slightly increase cardiac output and decrease central venous pressure. Atropine can dilate cutaneous blood vessels, particularly the “blush” area (atropine flush), and may inhibit sweating, thereby causing hyperthermia, particularly in a warm environment or with exercise.
Pralidoxime ChloridePralidoxime chloride has its most critical effect in relieving respiratory muscle paralysis. Because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Pralidoxime has a minor role in relieving muscarinic signs and symptoms, such as salivation or bronchospasm.
DuoDote temporarily increases blood pressure, a known effect of pralidoxime. In a study of 24 healthy young adults administered a single dose of atropine and pralidoxime autoinjector intramuscularly (approximately 9 mg/kg pralidoxime chloride), diastolic blood pressure increased from baseline by 11 ± 14 mm Hg (mean ± SD), and systolic blood pressure increased by 16 ± 19 mm Hg, at 15 minutes post-dose. Blood pressures remained elevated at these approximate levels through one hour post-dose, began to decrease at two hours post-dose and were near pre-dose baseline at four hours post-dose.
Atropine is well absorbed after intramuscular administration. Single dose DuoDote pharmacokinetic data for atropine are shown in Figure 1. The intramuscular injection site was the antero-lateral thigh.
Mean atropine plasma concentrations shown in Figure 1 indicate a plateau beginning at about 5 minutes post-dose and extending through 60 minutes post-dose.
Figure 1: Mean Atropine Plasma Concentrations After a
Single DuoDote Intramuscular Injection, Which Delivers 2.1 mg of Atropine Base
and 600 mg Pralidoxime Chloride, N=24 Healthy Adult Subjects [Men (n=12), Women
(n=12)].
Pralidoxime chloride is rapidly absorbed after intramuscular injection. DuoDote single dose pharmacokinetic data for pralidoxime chloride 600 mg are provided in Figure 2.
Figure 2: Mean Pralidoxime Plasma Concentrations After
a Single DuoDote Intramuscular Injection, Which Delivers 2.1 mg of Atropine and
600 mg Pralidoxime Chloride, N=24 Healthy Adult Subjects.
The pharmacokinetic properties of the components of DuoDote are presented in Table 2.
Table 2: Pharmacokinetic Properties of the Components
of DuoDote Following Intramuscular Administration in Healthy Subjects
| Pharmacokinetics related to: | Atropine | Pralidoxime |
| Absorption | ||
| Cmax (mean ± standard deviation) | 13 ± 3 ng/mL | 7 ± 3 mcg/mL |
| Tmax (mean ± standard deviation) | 31 ± 30 minutes | 28 ± 15 minutes |
| Distribution | ||
| Protein binding | 14 to 22% to plasma proteins | Not appreciable bound to serum proteins |
| Elimination | ||
| T½ | 2.4 ± 0.3 hours | 2 ± 1 hours |
| Major route of excretion | Urinary | Urinary |
| Percentage of dose excreted in urine | 50 to 60% as unchanged drug. About 17 to 28% eliminated in the first 100 minutes. | 72 to 94% as unchanged drug. About 57 to 70% eliminated in the first 30 minutes, partly as metabolite. |
Atropine readily crosses the placental barrier and enters fetal circulation. There are no adequate data on the developmental risk associated with the use of atropine, pralidoxime, or the combination in pregnant women. Adequate animal reproduction studies have not been conducted with atropine, pralidoxime, or the combination. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Each single-dose DuoDote autoinjector contains the following in two separate chambers:
When activated, DuoDote sequentially administers both drugs intramuscularly through a single needle in one injection.
Storage And HandlingEach single-dose DuoDote (atropine and pralidoxime chloride) autoinjector contains atropine (2.1 mg/0.7 mL; colorless to yellow solution, visible in front chamber) and pralidoxime chloride (600 mg/2 mL; colorless to yellow solution, not visible in rear chamber) and is available in a single unit carton, NDC-11704-620-01.
Each DuoDote autoinjector is supplied in a pouch that provides protection from light.
Store at 25°C (77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F). Not made with natural rubber latex. Keep from freezing. Protect from light.
Manufactured by: Meridian Medical Technologies™, Inc. Columbia, MD 21046. Revised: Oct 2017
Included as part of the PRECAUTIONS section.
PRECAUTIONS Cardiovascular RisksCardiovascular adverse reactions reported in the literature for atropine include, but are not limited to, sinus tachycardia, palpitations, premature ventricular contractions, atrial flutter, atrial fibrillation, ventricular flutter, ventricular fibrillation, cardiac syncope, asystole, and myocardial infarction. In patients with a recent myocardial infarction and/or severe coronary artery disease, there is a possibility that atropine-induced tachycardia may cause ischemia, extend or initiate myocardial infarcts, and stimulate ventricular ectopy and fibrillation. DuoDote should be used with caution in patients with known cardiovascular disease or cardiac conduction problems.
Heat InjuryAtropine may inhibit sweating which, in a warm environment or with excessive exercise, can lead to hyperthermia and heat injury. To the extent feasible, avoid excessive exercise and heat exposure.
Acute GlaucomaAtropine should be administered with caution in patients at risk for acute glaucoma.
Urinary RetentionAtropine should be administered with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
Pyloric StenosisAtropine should be administered with caution in patients with partial pyloric stenosis because of the risk of complete pyloric obstruction.
Exacerbation Of Chronic Lung DiseaseAtropine may cause inspiration of bronchial secretions and formation of dangerous viscid plugs in individuals with chronic lung disease. Respiratory status should be monitored in individuals with chronic lung disease following administration of DuoDote.
Patient Counseling Information Use By Healthcare ProvidersDuoDote is intended for use by Healthcare Providers. See the illustrated Instruction Sheet for Healthcare Providers.
Seek Definitive Medical CareIf feasible and appropriate, advise patients that DuoDote is an initial emergency treatment, that they need additional care at a healthcare facility.
Avoid OverheatingIf feasible and appropriate, advise the patient to avoid a hot environment and excessive physical activity since DuoDote can inhibit sweating which can lead to overheating and heat injury.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenesisDuoDote is indicated for short-term emergency use only, and no adequate studies regarding the carcinogenic potential of atropine or pralidoxime chloride have been conducted.
MutagenesisStudies to assess the mutagenic potential of atropine or pralidoxime chloride have not been conducted.
Impairment Of FertilityAtropine
In studies in which male rats were orally administered atropine (62.5 to 125 mg/kg) for one week prior to mating and throughout a 5-day mating period with untreated females, a dose-related decrease in fertility was observed. A no-effect dose for male reproductive toxicity was not established. The lowest dose tested was 290 times (on a mg/m² basis) the dose of atropine in a single application of DuoDote (2.1 mg).
Fertility studies of atropine in females have not been conducted.
Pralidoxime Chloride
The effects of pralidoxime chloride on fertility have not been assessed.
Use In Specific Populations Pregnancy Risk SummaryAtropine readily crosses the placental barrier and enters fetal circulation. There are no adequate data on the developmental risk associated with the use of atropine, pralidoxime, or the combination in pregnant women. Adequate animal reproduction studies have not been conducted with atropine, pralidoxime, or the combination. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Lactation Risk SummaryAtropine has been reported to be excreted in human milk. It is not known whether pralidoxime is excreted in human milk. There are no data on the effects of atropine or pralidoxime on the breastfed infant or the effects of the drugs on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DuoDote and any potential adverse effects on the breastfed infant from DuoDote or from the underlying maternal condition.
Pediatric UseSafety and effectiveness of atropine in DuoDote in patients weighing more than 41 kg (90 pounds) is supported by published literature. Safety and effectiveness of pralidoxime chloride in DuoDote in patients more than 41 kg (90 pounds) is supported by data from pharmacokinetic studies in adults and experience in the pediatric population. Adverse events seen in pediatric patients treated with atropine are similar to those that occur in adult patients, although central nervous system complaints are often seen earlier and at lower doses.
Safety and effectiveness of DuoDote in pediatric patients weighing less than or equal to 41 kg (90 pounds) have not been established.
Geriatric UseGeriatric patients may be more susceptible to the effects of atropine.
Renal ImpairmentPralidoxime chloride can cause decreased renal function . Patients with severe renal impairment may require less frequent doses after the initial dose.
Hepatic ImpairmentPatients with severe hepatic impairment may require less frequent doses after the initial dose.
First Dose
If the patient experiences two or more mild symptoms of nerve agent or insecticide exposure listed in Table 1, administer one (1) DuoDote injection intramuscularly into the mid-lateral thigh.
Additional Doses
If, at any time after the first dose, the patient develops any of the severe symptoms listed in Table 1, administer two (2) additional DuoDote injections intramuscularly in rapid succession.
Wait 10 to 15 minutes for DuoDote to take effect. If, after 10 to 15 minutes, the patient does not develop any of the severe symptoms listed in Table 1, no additional DuoDote injections are recommended.
Dosage For Severe Symptoms In Adults And Pediatric Patients Weighing More Than 41 kg (90 Pounds)If a patient has any of the severe symptoms listed in Table 1, immediately administer three (3) DuoDote injections intramuscularly into the patient's mid-lateral thigh in rapid succession
Table 1: Common Symptoms of Organophosphorus Exposure
| Mild Symptoms | Severe Symptoms |
|
|
*Do Not Remove Gray Safety Release until ready to use.
*Never touch the Green Tip (Needle End)!
The following serious adverse reactions are described elsewhere in the labeling:
The following adverse reactions associated with the use of atropine and pralidoxime chloride were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
AtropineBecause DuoDote contains pralidoxime chloride, which may potentiate the effect of atropine, signs of atropinization may occur earlier than might be expected when atropine is used alone.
Common adverse reactions of atropine can be attributed to its antimuscarinic action. These include dryness of the mouth, blurred vision, dry eyes, photophobia, confusion, headache, dizziness, tachycardia, palpitations, flushing, urinary hesitancy or retention, constipation, abdominal pain, abdominal distention, nausea and vomiting, loss of libido, and impotence. Anhidrosis may produce heat intolerance and impairment of temperature regulation in a hot environment. Dysphagia, paralytic ileus, acute angle closure glaucoma, maculopapular rash, petechial rash, and scarletiniform rash have also been reported. Adverse cardiac reactions, including arrhythmias and myocardial infarction, have been reported with atropine.
Larger doses of atropine may produce central nervous system effects such as restlessness, tremor, fatigue, locomotor difficulties, delirium, and hallucinations.
Hypersensitivity reactions will occasionally occur, are usually seen as skin rashes, and may progress to exfoliation. Anaphylactic reaction and laryngospasm are rare.
Pralidoxime ChloridePralidoxime can cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure , muscular weakness, dry mouth, emesis, rash, dry skin, hyperventilation, decreased renal function, and decreased sweating when given parenterally to normal adult volunteers who have not been exposed to anticholinesterase poisons.
In several cases of organophosphorus poisoning, excitement and manic behavior have occurred immediately following recovery of consciousness, in either the presence or absence of pralidoxime administration. However, similar behavior has not been reported in subjects given pralidoxime in the absence of organophosphorus poisoning.
Elevations in AST and/or ALT enzyme levels were observed in 1 of 6 normal adult volunteers given 1200 mg of pralidoxime intramuscularly, and in 4 of 6 adult volunteers given 1800 mg intramuscularly. Levels returned to normal in about two weeks. Transient elevations in creatine kinase were observed in all normal volunteers given the drug.
Injection SiteMuscle tightness and pain may occur at the injection site.
Inadvertent InjectionIn cases where DuoDote is inadvertently administered to people who are not poisoned with nerve agent or organophosphorus insecticide, the following effects on their ability to function normally may occur.
Atropine 2 mg IM, roughly the equivalent of one DuoDote autoinjector, when given to healthy male volunteers, is associated with minimal effects on visual, motor, and mental functions, though unsteadiness walking and difficulty concentrating may occur. Atropine reduces body sweating and increases body temperature, particularly with exercise and under hot conditions.
Atropine 4 mg IM, roughly the equivalent of two DuoDote autoinjectors, when given to healthy male volunteers, is associated with impaired visual acuity, visual near point accommodation, logical reasoning, digital recall, learning, and cognitive reaction time. Ability to read is reduced or lost. Subjects are unsteady and need to concentrate on walking. These effects begin about 15 minutes to one hour or more post-dose.
Atropine 6 mg IM, roughly the equivalent of three DuoDote autoinjectors, when given to healthy male volunteers, is associated with the effects described above plus additional central effects including poor coordination, poor attention span, and visual hallucinations (colored flashes) in many subjects. Frank visual hallucinations, auditory hallucinations, disorientation, and ataxia occur in some subjects. Skilled and labor-intense tasks are performed more slowly and less efficiently. Decision making takes longer and is sometimes impaired.
It is unclear if the above data, obtained from studies of healthy adult subjects, can be extrapolated to other populations. In the elderly and patients with co-morbid conditions, the effects of ≥2 mg atropine on the ability to see, walk, and think properly are unstudied; effects may be greater in susceptible populations.
Patients who are mistakenly injected with DuoDote should avoid potentially dangerous overheating, avoid vigorous physical activity, and seek medical attention as soon as feasible.
DRUG INTERACTIONS Succinylcholine And MivacuriumSince pralidoxime in DuoDote reactivates cholinesterases and succinylcholine and mivacurium are metabolized by cholinesterases, patients with organophosphorus nerve agent or organophosphorus insecticide poisoning who have received DuoDote may exhibit accelerated reversal of the neuromuscular blocking effects of succinylcholine and mivacurium (relative to poisoned patients who have not received pralidoxime). Monitor for neuromuscular effects with concomitant administration.
