ATNAA ATROPINE AND PRALIDOXIME CHLORIDE AUTO-INJECTOR

Each prefilled ATNAA is a single-dose autoinjector that provides an intramuscular dose of atropine, a cholinergic muscarinic antagonist, and pralidoxime chloride, a cholinesterase reactivator, in a self-contained unit, specifically designed for automatic self- or buddy-administration by military personnel. When activated, each ATNAA injection delivers the following: 2.1 mg of atropine in 0.7 mL of sterile, pyrogen-free solution containing 12.47 mg glycerin, not more than 2.8 mg phenol, 3.05 mg sodium citrate dihydrate, 3.5 mg citric acid monohydrate, and Water for Injection. The pH range is 4.0 – 5.0. 600 mg of pralidoxime chloride equivalent to 476.6 mg of pralidoxime in 2 mL of sterile, pyrogen-free solution containing 40 mg benzyl alcohol, 22.5 mg glycine, and Water for Injection. The pH is adjusted with hydrochloric acid. The pH range is 2.0 – 3.0. After ATNAA has been activated, the empty autoinjector should be disposed of properly [see Dosage and Administration (2.2) ] . It cannot be refilled, nor can the protruding needle be retracted. Atropine occurs as white crystals, usually needle-like, or as a white, crystalline powder. It is slightly soluble in water with a molecular weight of 289.38. Atropine, a naturally occurring belladonna alkaloid, is a racemic mixture of equal parts of d- and l-hyoscyamine, with activity due almost entirely to the levo isomer of the drug. Chemically, atropine is designated as 1αH,5αH-Tropan-3α-ol (±)-tropate. Its empirical formula is C 17 H 23 NO 3 and its structural formula is as follows: Pralidoxime chloride is an odorless, white to pale-yellow crystalline powder, freely soluble in water, with a molecular weight of 172.61. Chemically, pralidoxime chloride is designated as 2-formyl-1-methylpyridinium chloride oxime. Its empirical formula is C 7 H 9 CIN 2 O and its structural formula is indicated above. Chemical Structure

ATNAA is indicated for the treatment of poisoning by susceptible organophosphorus nerve agents having anticholinesterase activity in adults. ATNAA, a combination of atropine, a cholinergic muscarinic antagonist, and pralidoxime chloride, a cholinesterase reactivator, is indicated for the treatment of poisoning by susceptible organophosphorus nerve agents having anticholinesterase activity in adults. ( 1 )

ATNAA is intended as an initial treatment as soon as symptoms appear; definitive medical care should be sought immediately. ( 2.1 ) Dosage for Mild Symptoms: If a service member experiences some or all of the mild symptoms, they should self-administer one injection intramuscularly into the lateral thigh muscle or buttocks. If, at any time after the first dose, the service member develops any of the severe symptoms or if the mild symptoms are not relieved, a buddy should administer two additional injections intramuscularly in rapid succession. ( 2.2 ) Dosage for Severe Symptoms: If a service member has any of the severe symptoms, immediately buddy-administer three injections intramuscularly into the service member's lateral thigh muscle or buttocks in rapid succession. ( 2.2 ) 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 Dosage for Mild Symptoms First Dose : If you experience some or all of the mild symptoms of nerve agent exposure listed in Table 1, self-administer one (1) ATNAA injection intramuscularly into the lateral thigh muscle or buttocks. Wait 10 to 15 minutes for ATNAA to take effect. If, after 10 to 15 minutes, the symptoms of organophosphorus nerve agent poisoning are not relieved, seek someone else to check your symptoms. Another service member must administer the second and third injections. Additional Doses : If you encounter a service member suffering from severe symptoms of organophosphorus nerve agent poisoning listed in Table 1 and one ATNAA has been self-administered, administer two (2) additional ATNAA injections intramuscularly in rapid succession into the casualty's lateral thigh muscle or buttocks. Dosage for Severe Symptoms Casualties with severe symptoms may experience most or all of the mild symptoms of organophosphorus nerve agent poisoning, plus most or all of the severe symptoms listed in Table 1. If a service member is encountered suffering from severe signs of organophosphorus nerve agent poisoning and ATNAA self-aid has not been administered, immediately administer in rapid succession three (3) ATNAA injections into the casualty's lateral thigh muscle or buttocks. Table 1. Common Symptoms of Organophosphorus Nerve Agent Exposure Mild Symptoms Severe Symptoms Unexplained runny nose Unexplained sudden headache Sudden drooling Difficulty in seeing (dimness of vision and miosis) Tightness of chest or difficulty in breathing Wheezing and coughing Localized sweating and muscular twitching in the area of contaminated skin Stomach cramps Nausea, with or without vomiting Tachycardia followed by bradycardia Strange or confused behavior Increased wheezing and increased difficulty in breathing Severely pinpointed pupils Red eyes with tearing Vomiting Severe muscular twitching and general weakness Involuntary urination and defecation Convulsions Unconsciousness Respiratory failure Bradycardia 2.3 Administration Instructions The following instructions should be given to service members for the administration of ATNAA single-dose injections. Self-Aid Administer one (1) ATNAA into your lateral thigh muscle or buttocks as follows: Remove gray safety cap from back end. Place front end on outer thigh and push hard until injector functions. Hold firmly in place for ten seconds. Using a hard surface, bend needle into hook. Push ejected needle through a pocket flap (or other thick and conspicuous part of outer clothing). Wait 10 to 15 minutes for the antidote to take effect. If you are able to ambulate, know who you are, and where you are, you will NOT need a second injection. Giving yourself a second set of injections may cause an overdose of the ATNAA which could result in incapacitation. If symptoms of organophosphorus nerve agent poisoning are not relieved after administering one injection, seek someone else to check your symptoms. A buddy must administer the second and third injections, if needed. Buddy-Aid If you encounter a service member suffering from any of the severe symptoms of organophosphorus nerve agent poisoning, render the following aid: Mask the casualty, if necessary. Do not fasten the hood. If self-aid (one ATNAA injection) has been administered, administer in rapid succession two (2) additional ATNAA injections into the casualty's lateral thigh muscle or buttocks. Use the casualty's own ATNAAs when providing aid. Do not use your own autoinjectors on a casualty. If you do, you may not have any antidote available when needed for self-aid. If self-aid (one ATNAA injection) has not been administered, administer in rapid succession three (3) ATNAA injections into the casualty's lateral thigh muscle or buttocks.

None. None. ( 4 )

The following serious adverse reactions are described elsewhere in the labeling: Cardiovascular Risks [see Warnings and Precautions (5.1) ] Heat Injury [see Warnings and Precautions (5.2) ] Acute Glaucoma [see Warnings and Precautions (5.3) ] Urinary Retention [see Warnings and Precautions (5.4) ] Pyloric Stenosis [see Warnings and Precautions (5.5) ] Exacerbation of Chronic Lung Disease [see Warnings and Precautions (5.6) ] 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. Common adverse reactions of atropine include dryness of mouth, blurred vision, dry eyes, photophobia, confusion, headache, and dizziness among others. ( 6.1 ) The common adverse reactions of pralidoxime chloride include changes in vision, dizziness, headache, drowsiness, nausea, tachycardia, increased blood pressure, muscular weakness, dry mouth, emesis, rash, dry skin, hyperventilation, decreased renal function, excitement, manic behavior, and transient elevation of liver enzymes and creatine phosphokinase. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Meridian Medical Technologies ® , LLC at 1-833-739-0945 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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.

Succinylcholine and Mivacurium: Accelerated reversal of neuromuscular blocking effects may occur; monitor with concomitant administration. ( 7.1 ) 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.

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.