Atropine and Pralidoxime Chloride

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 )

Injection: Each single-dose ATNAA autoinjector contains the following in two separate chambers: front chamber (visible): a clear, colorless to yellow, sterile solution of atropine (2.1 mg/0.7 mL) back chamber (not visible): a clear, colorless to yellow, sterile solution of pralidoxime chloride (600 mg/2 mL) equivalent to pralidoxime (476.6 mg/2 mL) When activated, ATNAA sequentially administers both drugs intramuscularly through a single needle in one injection. Injection: Each single-dose ATNAA autoinjector contains atropine (2.1 mg/0.7 mL) plus pralidoxime chloride (600 mg/2 mL). ( 3 )

None. None. ( 4 )

Cardiovascular (CV) Risks: Tachycardia, palpitations, premature ventricular contractions, flutter, fibrillation, etc. Use caution in individuals with known CV disease or conduction problems. ( 5.1 ) Heat Injury: May inhibit sweating and lead to hyperthermia; avoid excessive exercising and heat exposure. ( 5.2 ) Acute Glaucoma: May precipitate in susceptible individuals. ( 5.3 ) Urinary Retention : Administer with caution in individuals with bladder outflow obstruction. ( 5.4 ) Pyloric Stenosis: May convert into complete obstruction. ( 5.5 ) Exacerbation of Chronic Lung Disease: Atropine may cause inspiration of bronchial secretions and formation of dangerous viscid plugs in individuals with chronic lung disease; monitor respiratory status. ( 5.6 )

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.

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.

Geriatric individuals may be more susceptible to the effects of atropine. ( 8.5 )

8.1 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 chloride, or the combination in pregnant women. Adequate animal reproduction studies have not been conducted with atropine, pralidoxime chloride, 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.

8.2 Lactation Risk Summary Atropine has been reported to be excreted in human milk. It is not known whether pralidoxime chloride is excreted in human milk. There are no data on the effects of atropine or pralidoxime chloride on the breastfed infant or the effects of the drugs on milk production. The developmental and health benefits of breastfeeding 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 .

Atropine Atropine competitively blocks the effects of acetylcholine, including excess acetylcholine due to organophosphorus nerve agent poisoning, at muscarinic cholinergic receptors on smooth muscle, cardiac muscle, secretory gland cells, and in peripheral autonomic ganglia and the central nervous system. Pralidoxime Chloride Pralidoxime chloride reactivates acetylcholinesterase which has been inactivated by phosphorylation due to susceptible organophosphorus nerve agents having anticholinesterase activity . However, pralidoxime chloride does not reactivate acetylcholinesterase inactivated by all organophosphorus nerve agents (e.g. soman). Pralidoxime chloride cannot reactivate phosphorylated acetylcholinesterases that have undergone a further chemical reaction known as "aging." Reactivated acetylcholinesterase hydrolyzes excess acetylcholine resulting from organophosphorus nerve agent poisoning to help restore impaired cholinergic neural function. Reactivation is clinically important because only a small proportion of active acetylcholinesterase is needed to maintain vital functions.