2.1 Important Administration Information

• Three (3) ATNAA single-dose autoinjectors should be available for use by each service member at risk for organophosphorus nerve agent 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.
• For optimal reactivation of organophosphorus-inhibited cholinesterase, the ATNAA should be administered as soon as possible after appearance of symptoms of organophosphorus nerve agent poisoning.
• ATNAA should be self- or buddy–administered by service members after donning protective mask and hood at the first sign of a chemical attack, and only if some or all of the mild symptoms of organophosphorus nerve agent exposure are present.
• Only administer ATNAA to service members experiencing symptoms of organophosphorus nerve agent poisoning in a situation where exposure is known or suspected. The ATNAA autoinjector is intended as an initial treatment of the symptoms of organophosphorus nerve agent poisoning as soon as symptoms appear; definitive medical care should be sought immediately.
• Close supervision of all treated service members 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

The following instructions should be given to service members for the administration of ATNAA single-dose injections.

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 individuals 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. ATNAA should be used with caution in individuals 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 individuals at risk for acute glaucoma.

5.4 Urinary Retention

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

5.5 Pyloric Stenosis

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

5.6 Exacerbation of Chronic Lung Disease

Atropine 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 ATNAA.

6.1 Atropine

Because ATNAA 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; these are usually seen as skin rashes, and may progress to exfoliation. Anaphylactic reaction and laryngospasm are rare.

6.2 Pralidoxime Chloride

Pralidoxime chloride 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 chloride administration. However, similar behavior has not been reported in subjects given pralidoxime chloride 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 chloride 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 ATNAA is inadvertently administered to service members who are not poisoned with susceptible organophosphorus nerve agents having anticholinesterase activity, the following effects on their ability to function normally may occur.

Atropine 2 mg IM, roughly the equivalent of one ATNAA injection, 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 ATNAA injections, 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 ATNAA injections, 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 male subjects, can be extrapolated to other populations. In the elderly and individuals 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.

Service members who are mistakenly injected with ATNAA should avoid potentially dangerous overheating, avoid vigorous physical activity, and seek medical attention as soon as feasible.

7.1 Succinylcholine and Mivacurium

Since pralidoxime chloride in ATNAA reactivates cholinesterases and succinylcholine and mivacurium are metabolized by cholinesterases, service members poisoned by susceptible organophosphorus nerve agents having anticholinesterase activity who have received ATNAA may exhibit accelerated reversal of the neuromuscular blocking effects of succinylcholine and mivacurium (relative to poisoned service member who has not received pralidoxime). Monitor for neuromuscular effects with concomitant administration.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of ATNAA in pediatric patients have not been established.

8.5 Geriatric Use

Geriatric individuals 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)]. Individuals with severe renal impairment may require less frequent doses after the initial dose.

8.7 Hepatic Impairment

Individuals 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 [see Use in Specific Populations (8.4)]. 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 ATNAA 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 ATNAA Intramuscular Injection in 24 Healthy Adult Subjects [Men (N=12), Women (N=12)]

Pralidoxime Chloride

Pralidoxime chloride is well absorbed after intramuscular injection. ATNAA single dose pharmacokinetic data for pralidoxime chloride 600 mg are provided in Figure 2.

Figure 2. Mean Pralidoxime Plasma Concentrations After a Single ATNAA Intramuscular Injection in 24 Healthy Adult Subjects [Men (N=12), Women (N=12)]

The pharmacokinetic properties of the components of ATNAA are presented in Table 2.

Table 2. Pharmacokinetic Properties of the Components of ATNAA 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 appreciably 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

Store between 20ºC to 25ºC (68 ºF to 77ºF); excursions permitted between 15ºC and 30ºC (between 59ºF and 86ºF) [See USP Controlled Room Temperature]. Not made with natural rubber latex. Keep from freezing. Protect from light.

Use by Military Personnel

ATNAA is intended for use by Military Personnel. See the illustrated Instruction Sheet for Military Personnel.