ATROPEN Auto-Injector

1 INDICATIONS AND USAGE ATROPEN is indicated for the treatment of poisoning by susceptible organophosphorus nerve agents having cholinesterase activity as well as organophosphorus or carbamate insecticides in adult and pediatric patients. ATROPEN is a cholinergic muscarinic antagonist indicated for the treatment of poisoning by susceptible organophosphorus nerve agents having cholinesterase activity as well as organophosphorus or carbamate insecticides in adult and pediatric patients. ( 1 )

2 DOSAGE AND ADMINISTRATION ATROPEN is a single-dose autoinjector intended as an initial treatment of the muscarinic symptoms of insecticide or nerve agent poisonings; definitive medical care should be sought immediately. ( 2.1 ) Dosage is dependent on weight. ( 2.2 ) Dosage for Mild Symptoms: If the patient experiences two or more mild symptoms, administer one injection intramuscularly into the mid-lateral thigh. If, at any time after the first dose, the patient develops any of the severe symptoms, administer two additional injections intramuscularly in rapid succession. ( 2.2 ) Dosage for Severe Symptoms: If the patient is either unconscious or has any of the severe symptoms, immediately administer three injections intramuscularly into the patient's mid-lateral thigh in rapid succession. ( 2.2 ) 2.1 Important Administration Information It is recommended that three ATROPEN autoinjectors be available for use in each patient at risk for organophosphorus or carbamate poisoning; one (1) for mild symptoms plus two (2) more for severe symptoms [see Dosage and Administration ( 2.2 )] . Different dose strengths of ATROPEN are available depending on the patient's weight. ATROPEN should be used by persons who have had adequate training in the recognition and treatment of nerve agent or insecticide intoxication, but may be administered by a caregiver or self-administration if a trained provider is not available. Only administer ATROPEN to patients experiencing symptoms of organophosphorus or carbamate poisoning in a situation where exposure is known or suspected. ATROPEN is a single-dose autoinjector intended as an initial treatment of the muscarinic symptoms of insecticide or nerve agent poisonings (generally breathing difficulties due to increased secretions); definitive medical care should be sought immediately. ATROPEN should be administered as soon as symptoms of organophosphorus or carbamate poisoning appear. In severe poisonings, it may also be desirable to concurrently administer an anticonvulsant (preferably a benzodiazepine) if seizure is suspected in the unconscious individual since the classic tonic-clonic jerking may not be apparent due to the effects of the poison. A cholinesterase reactivator such as pralidoxime may serve as an important adjunct to atropine therapy. 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 Different dose strengths of ATROPEN are available depending on the patient's age and weight (see Table 1 ). Table 1: Recommended Dose Strength per ATROPEN Injection Age and Body Weight Strength of each ATROPEN Injection Adults and pediatric patients weighing over 41 kg (90 pounds) (generally over 10 years of age) ATROPEN 2 mg (green label) Pediatric patients weighing 18 kg to 41 kg (40 pounds to 90 pounds) (generally 4 to 10 years of age) ATROPEN 1 mg (red label) Pediatric patients weighing 7 kg to 18 kg (15 pounds to 40 pounds) (generally 6 months to 4 years of age) ATROPEN 0.5 mg (blue label) Pediatric patients weighing less than 7 kg (15 pounds) (generally less than 6 months of age) ATROPEN 0.25 mg (yellow label) Dosage for Mild Symptoms First Dose: If the patient experiences two or more mild symptoms of nerve agent or insecticide exposure listed in Table 2 , administer one (1) ATROPEN injection intramuscularly into the mid-lateral (outer) thigh. Additional Doses: If, at any time after receiving the first ATROPEN injection, the patient has any of the severe symptoms listed in Table 2 , administer two (2) additional ATROPEN injections in rapid succession. If possible, a person other than the patient should administer the second and third ATROPEN injections. Wait 10 to 15 minutes for ATROPEN to take effect. If after 10 to 15 minutes, the patient does not dev …

3 DOSAGE FORMS AND STRENGTHS Injection: Each single-dose ATROPEN autoinjector contains a clear sterile solution of atropine. Four strengths of ATROPEN are available 0.25 mg/0.3 mL (yellow label): 0.21 mg atropine (equivalent to 0.25 mg atropine sulfate) in 0.3 mL 0.5 mg/0.7 mL (blue label): 0.42 mg atropine (equivalent to 0.5 mg atropine sulfate) in 0.7 mL 1 mg/0.7 mL (red label): 0.84 mg atropine (equivalent to 1 mg atropine sulfate) in 0.7 mL 2 mg/0.7 mL (green label): 1.67 mg atropine (equivalent to 2 mg atropine sulfate) in 0.7 mL Injection: Each prefilled single-dose autoinjector contains atropine in a self-contained unit, and is available in four strengths 0.25 mg/0.3 mL, 0.5 mg/0.7 mL, 1 mg/0.7 mL, and 2 mg/0.7 mL. ( 3 )

4 CONTRAINDICATIONS None. None.

6 ADVERSE REACTIONS 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 )] Hypersensitivity [see Warnings and Precautions ( 5.7 )] The following adverse reactions associated with the use of atropine 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. Mild to moderate pain may be experienced at the site of injection. Common adverse reactions of atropine include dryness of mouth, blurred vision, dry eyes, photophobia, confusion, headache, dizziness, tachycardia, palpitations, flushing, urinary hesitance or retention, constipation, abdominal pain, abdominal distention, nausea, vomiting, loss of libido, and impotency. ( 6 ) 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. Adverse Reactions at Recommended Doses 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 scarlatiniform rash have also been reported. Adverse cardiac reactions, including arrhythmias and myocardial infarction, have been reported with atropine [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.2 )]. Larger doses of atropine may produce central nervous system effects such as restlessness, tremor, fatigue, locomotor difficulties, delirium, hallucinations, depression and ultimately, medullary paralysis and death [see Overdosage ( 10 )] . Large doses can also lead to circulatory collapse. In such cases, blood pressure declines and death due to respiratory failure may ensue following paralysis and coma. Hypersensitivity Hypersensitivity reactions will occasionally occur with atropine; these are usually seen as skin rashes and may progress to exfoliation. Anaphylactic reaction and laryngospasm have also occurred. Pediatric Patients Adverse events seen in pediatrics are similar to those that occur in adult patients although central nervous system complaints are often seen earlier and at lower doses. Additional Adverse Reactions to Atropine by Organ System The following adverse reactions were reported in published literature for atropine in both adults and children: Cardiovascular : Sinus tachycardia, supraventricular tachycardia, junctional tachycardia, ventricular tachycardia, bradycardia, palpitations, ventricular arrhythmia, ventricular flutter, ventricular fibrillation, atrial arrhythmia, atrial fibrillation, atrial ectopic beats, ventricular premature contractions, bigeminal beats, trigeminal beats, nodal extrasystole, ventricular extrasystole, supraventricular extrasystole, asystole, cardiac syncope, prolongation of sinus node recovery time, cardiac dilation, left ventricular failure, myocardial infarction, intermittent nodal rhythm (no P wave), prolonged P wave, shortened PR segment, R on T phenomenon, shortened RT duration, widening and flattening of QRS complex, prolonged QT interval, flattening of T wave, repolarization abnormalities, altered ST-T waves, retrograde conduction, transie …

7 DRUG INTERACTIONS Pralidoxime: The signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected than when atropine is used alone. ( 7.1 ) Barbiturates: Atropine may potentiate the effect of barbiturates. ( 7.2 ) 7.1 Pralidoxime When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone because pralidoxime may potentiate the effect of atropine. Excitement and manic behavior immediately following recovery of consciousness have been reported in several cases. However, similar behavior has occurred in cases of organophosphate poisoning that were not treated with pralidoxime. 7.2 Barbiturates Barbiturates are potentiated by the anticholinesterases; therefore, barbiturates should be used cautiously in the treatment of convulsions resulting from exposure to atropine.

8 USE IN SPECIFIC POPULATIONS Geriatric patients 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 in pregnant women. Adequate animal reproduction studies have not been conducted with atropine. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary Atropine has been reported to be excreted in human milk. There are no data on the effects of atropine on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ATROPEN and any potential adverse effects on the breastfed infant from ATROPEN or from the underlying maternal condition. 8.4 Pediatric Use A review of published literature supports the safety and effectiveness of atropine in the setting of organophosphate insecticide poisoning in all pediatric age groups. Adverse events seen in pediatric patients treated with atropine are similar to those that occur in adult patients, although central nervous system effects are often seen earlier and at lower doses [see Adverse Reactions ( 6 )]. Overheating (atropine fever) caused by suppression of sweat gland activity may be more pronounced in infants and small children. Extreme hyperthermia in a newborn has been reported with as little as 0.065 mg orally. 8.5 Geriatric Use Geriatric patients may be more susceptible to the effects of atropine. Because of the longer half-life of atropine in geriatric patients, they may require less frequent doses after the initial dose [see Clinical Pharmacology ( 12.3 )].

12.1 Mechanism of Action Atropine competitively blocks the effects of acetylcholine, including excess acetylcholine due to organophosphorus poisoning, at muscarinic cholinergic receptors on smooth muscle, cardiac muscle, secretory gland cells, and in peripheral autonomic ganglia and the central nervous system.

11 DESCRIPTION Each prefilled ATROPEN single-dose autoinjector provides an intramuscular dose of atropine, a cholinergic muscarinic antagonist in a self-contained unit, designed for self- or caregiver-administration. When activated, the ATROPEN 0.25 mg autoinjector delivers 0.21 mg atropine base (equivalent to 0.25 mg atropine sulfate) in 0.3 mL of sterile pyrogen-free solution containing citrate buffer, sodium chloride, and Water for Injection. The pH range is 4.0 to 5.0. When activated, the ATROPEN 0.5 mg autoinjector delivers 0.42 mg atropine base (equivalent to 0.5 mg atropine sulfate), the ATROPEN 1 mg autoinjector delivers 0.84 mg atropine base (equivalent to 1 mg atropine sulfate), and the ATROPEN 2 mg autoinjector delivers 1.67 mg atropine base (equivalent to 2 mg atropine sulfate). Each 0.5 mg, 1 mg, and 2 mg ATROPEN autoinjector delivers atropine in 0.7 mL of sterile pyrogen-free solution containing 12.5 mg glycerin, 2.8 mg phenol, citrate buffer, and Water for Injection. The pH range is 4.0 to 5.0. 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 1 αH ,5 αH -Tropan-3α-ol (±) tropate (ester). Its empirical formula is C 17 H 23 NO 3 and its structural formula is as follows: Structural Formula

10 OVERDOSAGE Symptoms Manifestations of atropine overdose are dose-related and include flushing, dry skin and mucous membranes, tachycardia, widely dilated pupils that are poorly responsive to light, blurred vision, and fever (which can sometimes be dangerously elevated). Locomotor difficulties, disorientation, hallucinations, delirium, confusion, agitation, coma, and central depression can occur and may last 48 hours or longer. In instances of severe atropine intoxication, respiratory depression, coma, circulatory collapse, and death may occur. 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 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ATROPEN is a prefilled single-dose autoinjector that contains a clear solution and is supplied in the following package configurations: Table 3: ATROPEN Package Configurations NDC Number Package Configuration Product Description Delivered Dose (atropine) NDC 11704-107-01 Carton of 1 ATROPEN 0.25 mg (yellow label) 0.21 mg/0.3 mL (equivalent to 0.25 mg/0.3 mL of atropine sulfate) NDC 11704-104-01 Carton of 1 ATROPEN 0.5 mg (blue label) 0.42 mg/0.7 mL (equivalent to 0.5 mg/0.7 mL of atropine sulfate) NDC 11704-105-01 Carton of 1 ATROPEN 1 mg (red label) 0.84 mg/0.7 mL (equivalent to 1 mg/0.7 mL of atropine sulfate) NDC 11704-106-01 Carton of 1 ATROPEN 2 mg (green label) 1.67 mg/0.7 mL (equivalent to 2 mg/0.7 mL of atropine sulfate) NDC 11704-101-01 (For military use only) 1 Autoinjector ATROPEN 2 mg 1.67 mg/0.7 mL (equivalent to 2 mg/0. 7 mL of atropine sulfate) 16.2 Storage and Handling Store between 20oC to 25oC (68oF 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. After the ATROPEN autoinjector has been activated, the empty container should be disposed of properly. It cannot be refilled, nor can the protruding needle be retracted.