2.1 Important Administration Information

• Three (3) single-dose DuoDote autoinjectors should be available for use in each patient (including healthcare providers) at risk for organophosphorus poisoning; one (1) for mild symptoms plus two (2) more for severe symptoms [see Dosage and Administration (2.2)]. Note that individuals may not have all symptoms included under the mild or severe symptom category.
• Only administer DuoDote to patients experiencing symptoms of organophosphorus poisoning in a situation where exposure is known or suspected. The DuoDote autoinjector is intended as an initial treatment of the symptoms of organophosphorus nerve agent or insecticide poisonings as soon as symptoms appear; definitive medical care should be sought immediately.
• The DuoDote autoinjector should be administered by healthcare providers who have had adequate training in the recognition and treatment of nerve agent or insecticide intoxication.
• Close supervision of all treated patients is indicated for at least 48 to 72 hours.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit [see Dosage Forms and Strengths (3)].

2.2 Dosage Information

2.3 Administration Instructions

*Do Not Remove Gray Safety Release until ready to use.

*Never touch the Green Tip (Needle End)!

1)

Tear open the plastic pouch at any of the notches. Remove the DuoDote autoinjector from the pouch.

2)

Place the DuoDote autoinjector in your dominant hand. (If you are right-handed, your right hand is dominant.) Firmly grasp the center of the DuoDote autoinjector with the Green Tip (needle end) pointing down.

3)

With your other hand, pull off the Gray Safety Release. DuoDote is now ready to be administered.

4)

The injection site is the mid-lateral thigh area. The DuoDote autoinjector can inject through clothing. However, make sure pockets at the injection site are empty. People who may not have a lot of fat at the injection site should also be injected in the mid-lateral thigh, but before giving the injection, bunch up the thigh to provide a thicker area for injection.

5)

Firmly push the Green Tip straight down (a 90° angle) against the mid-lateral thigh. Continue to firmly push until you feel the DuoDote autoinjector trigger. After the autoinjector triggers, hold the DuoDote autoinjector firmly in place against the injection site for approximately 10 seconds.

6)

Remove the DuoDote autoinjector from the thigh and look at Green Tip. If the needle is visible, the drug has been administered. If the needle is not visible, check to be sure the Gray Safety Release has been removed, and then repeat above steps beginning with Step 4, but push harder in Step 5.

7)

After the drug has been administered, push the needle against a hard surface to bend the needle back against the DuoDote autoinjector.

8)

Put the used DuoDote autoinjector back into the plastic pouch, if available. Leave used DuoDote autoinjector(s) with the patient to allow other medical personnel to see the number of DuoDote autoinjector(s) administered.

9)

Immediately move yourself and the patient away from the contaminated area and seek definitive medical care for the patient.

5.1 Cardiovascular Risks

Cardiovascular 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.

5.2 Heat Injury

Atropine 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 [see Overdosage (10.2)].

5.3 Acute Glaucoma

Atropine should be administered with caution in patients at risk for acute glaucoma.

5.4 Urinary Retention

Atropine should be administered with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

5.5 Pyloric Stenosis

Atropine should be administered with caution in patients with partial pyloric stenosis because of the risk of complete pyloric obstruction.

5.6 Exacerbation of Chronic Lung Disease

Atropine may cause inspissation 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.

6.1 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 [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

Larger doses of atropine may produce central nervous system effects such as restlessness, tremor, fatigue, locomotor difficulties, delirium, and hallucinations [see Overdosage (10.1)].

Hypersensitivity reactions will occasionally occur, are usually seen as skin rashes, and may progress to exfoliation. Anaphylactic reaction and laryngospasm are rare.

6.2 Pralidoxime Chloride

Pralidoxime can cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure [see Clinical Pharmacology (12.2)], 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.

6.3 Injection Site

Muscle tightness and pain may occur at the injection site.

6.4 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.

7.1 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.

8.1 Pregnancy

8.2 Lactation

8.4 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 [see Adverse Reactions (6.1)].

Safety and effectiveness of DuoDote in pediatric patients weighing less than or equal to 41 kg (90 pounds) have not been established.

8.5 Geriatric Use

Geriatric patients may be more susceptible to the effects of atropine [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Pralidoxime chloride can cause decreased renal function [see Adverse Reactions (6.2)]. Patients with severe renal impairment may require less frequent doses after the initial dose.

8.7 Hepatic Impairment

Patients with severe hepatic impairment may require less frequent doses after the initial dose.

10.1 Symptoms

10.2 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.

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Atropine:
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:
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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Seek Definitive Medical Care
If feasible and appropriate, advise patients that DuoDote is an initial emergency treatment, that they need additional care at a healthcare facility.

Avoid Overheating
If 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.

Manufactured by:
Meridian Medical Technologies®, LLC
St. Louis, MO 63146