Duodote Drug Information

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). DuoDote, a combination of atropine, a cholinergic muscarinic antagonist, and pralidoxime chloride, a cholinesterase reactivator, 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

Because 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 Chloride Pralidoxime 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.

Inadvertent Injection

In 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.

Succinylcholine and Mivacurium

Since 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.

Pregnancy Risk Summary 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.

Pediatric Use Safety 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.

Symptoms Atropine 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. Pralidoxime It 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.

Treatment For 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.