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.

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.

hanges 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.

feeding should be considered along with the mother's clinical need for atnaa and any potential adverse effects on the breastfed infant from atnaa or from the underlying maternal condition. 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 .

ral function. reactivation is clinically important because only a small proportion of active acetylcholinesterase is needed to maintain vital functions. 12.2 pharmacodynamics atropine atropine reduces secretions in the mouth and respiratory passages, relieves airway constriction, and may reduce centrally-mediated respiratory paralysis. in severe organophosphorus nerve agent 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 [see warnings and precautions(5.2) ]. pralidoxime chloride pralidoxime chloride has its most critical effect in relieving respiratory muscle paralysis. because pralidoxime chloride 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 chloride has a minor role in relieving muscarinic signs and symptoms, such as salivation or bronchospasm. atnaa temporarily increases blood pressure, a known effect of pralidoxime chloride. in a study of 24 healthy young adults administered a single dose of atropine and pralidoxime chloride auto-injector 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. 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)] figure 1 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 c max (mean ± standard deviation) 13 ± 3 ng/ml 7 ± 3 mcg/ml t max (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 t ½ 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. figure 2 specific populations renal and hepatic impairment the pharmacokinetics of atropine or pralidoxime have not been evaluated in subjects with renal or hepatic impairment. gender atropine: atnaa auc 0-inf and c max values for atropine are 15% higher in females than males. the half-life of atropine is approximately 20 minutes shorter in females than males. pralidoxime chloride: a single atnaa injection produced a mean c max for pralidoxime is about 36% higher in females than males. t max is 23 minutes in females and 32 minutes in males. pralidoxime half-life in males and females are 153 and 107 minutes, respectively. geriatric atropine: half-life of intravenous atropine is 3.0 ± 0.9 hours in adults and 10.0 ± 7.3 hours in geriatric patients (65-75 years of age).

of the components of atnaa following intramuscular administration in healthy subjects pharmacokinetics related to: atropine pralidoxime absorption c max (mean ± standard deviation) 13 ± 3 ng/ml 7 ± 3 mcg/ml t max (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 t ½ 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. figure 2 specific populations renal and hepatic impairment the pharmacokinetics of atropine or pralidoxime have not been evaluated in subjects with renal or hepatic impairment. gender atropine: atnaa auc 0-inf and c max values for atropine are 15% higher in females than males. the half-life of atropine is approximately 20 minutes shorter in females than males. pralidoxime chloride: a single atnaa injection produced a mean c max for pralidoxime is about 36% higher in females than males. t max is 23 minutes in females and 32 minutes in males. pralidoxime half-life in males and females are 153 and 107 minutes, respectively. geriatric atropine: half-life of intravenous atropine is 3.0 ± 0.9 hours in adults and 10.0 ± 7.3 hours in geriatric patients (65-75 years of age).