ATROPINE SULFATE

1 INDICATIONS AND USAGE Atropine Sulfate Injection, USP, is indicated for temporary blockade of severe or life threatening muscarinic effects, e.g., as an antisialagogue, an antivagal agent, an antidote for organophosphorus or muscarinic mushroom poisoning, and to treat bradyasystolic cardiac arrest. These highlights do not include all the information needed to use ATROPINE SULFATE INJECTION safely and effectively. See full prescribing information for ATROPINE SULFATE INJECTION. ATROPINE SULFATE injection, for intravenous use Initial U.S. Approval: 1960

2 DOSAGE AND ADMINISTRATION • Dosage is individualized by use, refer to the full prescribing information for recommended adult and pediatric dosages ( 2.2 , 2.3 ). • Patients with Ischemic Heart Disease: Do not exceed 0.04 mg/kg. ( 2.4 , 5.2 ) 2.1 General Administration Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless solution is clear and seal is intact. After initial use, discard unused portion within 24 hours. Intravenous administration is usually preferred, but subcutaneous, intramuscular, endotracheal, and intraosseous administration are possible. 2.2 Adult Dosage Table 1: Recommended Dosage in Adult Patients Use Initial Dose Continued Treatment Antisialagogue or other antivagal (preanesthesia and during surgery) 0.5 to 1 mg IV/IM/SC 30-60 minutes preoperatively Repeat as needed every 4-6 hours. Maximum Total Dose 3 mg Organophosphorus, carbamate, or muscarinic mushroom poisoning 1 to 6 mg IV/IM/ET depending on severity of symptoms Repeat as needed every 3 to 5 minutes Dose may be doubled with each administration until response (reduced bronchospasm, improved oxygenation and drying of pulmonary secretions). Maintenance Dose: Administer 10% to 20% of the loading dose required for response as a continuous infusion per hour and titrate. Maximum Total Dose: No maximum total dose. Symptomatic bradycardia* 0.5 mg IV/IM or 1 to 2 mg ET by diluting in no more than 10 mL sterile water for injection or 0.9% sodium chloride As needed every 3 to 5 minutes Maximum Total Dose 3 mg IV=intravenous; IM=intramuscular; SC=subcutaneous; ET=endotracheal *Do not rely on atropine in type II second-degree or third-degree AV block with wide QRS complexes because these bradyarrhythmias are not likely to be responsive to reversal of cholinergic effects by atropine. Atropine has no effect on bradycardia in patients with transplanted hearts. 2.3 Pediatric Dosage Table 2: Recommended Dosage in Pediatric Patients Use Initial Dose Continued Treatment Antisialagogue or other antivagal (preanesthesia and during surgery)* 0.02 mg/kg IV/IM/SC 30-60 minutes preoperatively Repeat as needed every 4-6 hours. Maximum Single Dose Less than 12 years old: 0.5 mg 12 years and older: 1 mg Maximum Total Dose Less than 12 years old: 1 mg 12 years and older: 2 mg Organophosphorus, carbamate, or muscarinic mushroom poisoning 0.02 to 0.06 mg/kg IV/IM/IO/ET Repeat as needed every 5 minutes Dose may be doubled with each administration until response (reduced bronchospasm, improved oxygenation and drying of pulmonary secretions). Maintenance Dose: Administer 10% to 20% of the loading dose required for response as a continuous infusion per hour and titrate as needed. Maximum Total Dose: No maximum total dose. Symptomatic bradycardia due to increased vagal tone or primary AV conduction block (not secondary to hypoxia) * * 0.02 mg/kg IV/IO or 0.04 to 0.06 mg/kg via endotracheal tube followed by 1 to 5 mL flush of normal saline followed by 5 ventilations Repeat as needed every 5 minutes Maximum Single Dose Less than12 years old: 0.5 mg 12 years and older: 1 mg IV=intravenous; IM=intramuscular; SC=subcutaneous; IO=intraosseous; ET=endotracheal; *Available evidence does not support the routine use of atropine in emergency intubation of critically ill infants and children except in specific emergency intubations when there is higher risk of bradycardia ** Atropine has no effect on bradycardia in patients with transplanted hearts. 2.4 Dosing in Patients with Ischemic Heart Disease Limit the total dose of atropine sulfate to 0.03 to 0.04 mg/kg [see Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHS Injection: 0.05 mg/mL and 0.1 mg/mL in AnsyrTM Plastic Syringes containing a clear, colorless solution in a polypropylene syringe. Each AnsyrTM 5 mL Plastic Syringe contains 0.25 mg of atropine sulfate (0.05 mg/mL concentration). Each AnsyrTM 5 mL Plastic Syringe contains 0.5 mg of atropine sulfate (0.1 mg/mL concentration). Each AnsyrTM 10 mL Plastic Syringe contains 1 mg of atropine sulfate (0.1 mg/mL concentration). 0.05 mg/mL injection in AnsyrTM Plastic Syringe ( 3 ) 0.1 mg/mL injection in AnsyrTM Plastic Syringe ( 3 )

4 CONTRAINDICATIONS None. CONTRAINDICATIONS None. (4)

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in labeling: Hypersensitivity (5.1) Worsening of Ischemic Heart Disease (5.2) Acute Glaucoma (5.3) Pyloric Obstruction (5.4) Complete Urinary Retention (5.5) Viscid Plugs (5.6) The following adverse reactions have been identified during post-approval use of atropine sulfate. 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. Most of the side effects of atropine are directly related to its antimuscarinic action. Dryness of the mouth, blurred vision, photophobia and tachycardia commonly occur. Anhidrosis can produce heat intolerance. Constipation and difficulty in micturition may occur. Occasional hypersensitivity reactions have been observed, including serious skin rashes. Paralytic ileus may occur. Exacerbation of reflux has been reported. Larger or toxic doses may produce such central effects as restlessness, tremor, fatigue, locomotor difficulties, delirium, followed by hallucinations, depression, and ultimately, medullary paralysis and death. 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. Most adverse reactions are directly related to atropine’s antimuscarinic action. Dryness of the mouth, blurred vision, photophobia and tachycardia commonly occur with chronic administration of therapeutic doses. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS 7.1 Mexiletine Atropine Sulfate Injection decreased the rate of mexiletine absorption without altering the relative oral bioavailability; this delay in mexiletine absorption was reversed by the combination of atropine and intravenous metoclopramide during pretreatment for anesthesia. DRUG INTERACTIONS Mexiletine: Decreases rate of mexiletine absorption. (7.1) Revised: 9/2021

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited available data with Atropine Sulfate Injection use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with untreated severe or life-threatening muscarinic events (see Clinical Considerations). Animal reproduction studies have not been conducted with Atropine Sulfate Injection. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Severe or life-threatening muscarinic events such as acute organophosphate poisoning and symptomatic bradycardia are medical emergencies in pregnancy which can be fatal if left untreated. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of atropine on the fetus. Data Human Data No adequate and well-controlled studies are available regarding use of atropine in pregnant women. In a cohort study of 401 pregnancies in the first trimester and 797 pregnancies in the second or third trimester, atropine use was not associated with an increased risk of congenital malformation. In a surveillance study, 381 newborns were exposed to atropine during the first trimester; 18 major birth defects were observed when 16 were expected. No specific pattern of major birth defects was identified. In another surveillance study of 50 pregnancies in the first trimester, atropine use was not associated with an increased risk of malformations. Methodological limitations of these observational studies including the inability to control for the dosage and timing of atropine exposure, underlying maternal disease, or concomitant maternal drug use, cannot definitively establish or exclude any drug-associated risk during pregnancy. 8.2 Lactation Risk Summary Trace amounts of atropine have been reported in human milk after oral intake. There are no available data on atropine levels in human milk after intravenous injection, the effects on the breastfed infant, or the effects on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of atropine to an infant during lactation. Clinical Considerations Minimizing exposure The elimination half-life of atropine is more than doubled in children less than 2 years of age [see Clinical Pharmacology (12.3)]. To minimize potential infant exposure to Atropine Sulfate Injection, a woman may pump and discard her milk for 24 hours after use before resuming to breastfeed her infant. 8.5 Geriatric Use An evaluation of current literature revealed no clinical experience identifying differences in response between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

12.1 Mechanism of Action Atropine is an antimuscarinic agent since it antagonizes the muscarine-like actions of acetylcholine and other choline esters. Atropine inhibits the muscarinic actions of acetylcholine on structures innervated by postganglionic cholinergic nerves, and on smooth muscles which respond to endogenous acetylcholine but are not so innervated. As with other antimuscarinic agents, the major action of atropine is a competitive or surmountable antagonism which can be overcome by increasing the concentration of acetylcholine at receptor sites of the effector organ (e.g., by using anticholinesterase agents which inhibit the enzymatic destruction of acetylcholine). The receptors antagonized by atropine are the peripheral structures that are stimulated or inhibited by muscarine (i.e., exocrine glands and smooth and cardiac muscle). Responses to postganglionic cholinergic nerve stimulation also may be inhibited by atropine, but this occurs less readily than with responses to injected (exogenous) choline esters.

11 DESCRIPTION Atropine Sulfate Injection, USP is a sterile, nonpyrogenic isotonic solution of atropine sulfate monohydrate in water for injection with sodium chloride sufficient to render the solution isotonic. It is administered parenterally by subcutaneous, intramuscular or intravenous injection. Each milliliter (mL) contains 0.1 mg (adult strength) or 0.05 mg (pediatric strength) of atropine sulfate monohydrate equivalent to 0.083 mg (adult strength) or 0.042 mg (pediatric strength) of atropine, and sodium chloride, 9 mg. May contain sodium hydroxide and/or sulfuric acid for pH adjustment 0.308 mOsmol/mL (calc.). pH (3.0 to 6.5). Sodium chloride added to render the solution isotonic for injection of the active ingredient is present in amounts insufficient to affect serum electrolyte balance of sodium (Na + ) and chloride (Cl - ) ions. The solution contains no bacteriostat, antimicrobial agent or added buffer (except for pH adjustment) and is intended for use only as a single-dose injection. When smaller doses are required the unused portion should be discarded. Atropine Sulfate, USP is chemically designated 1α H, 5α H-Tropan-3-α-ol (±)-tropate (ester), sulfate (2:1) (salt) monohydrate, (C 17 H 23 NO 3 ) 2 ∙ H 2 SO 4 ∙ H 2 O, colorless crystals or white crystalline powder very soluble in water. It has the following structural formula: Atropine, a naturally occurring belladonna alkaloid, is a racemic mixture of equal parts of d- and 1-hyocyamine, whose activity is due almost entirely to the levo isomer of the drug. Sodium Chloride, USP is chemically designated NaCl, a white crystalline powder freely soluble in water. The syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material. structural formula atropine sulfate

10 Overdosage Section Excessive dosing may cause palpitation, dilated pupils, difficulty in swallowing, hot dry skin, thirst, dizziness, restlessness, tremor, fatigue and ataxia. Toxic doses lead to restlessness and excitement, hallucinations, delirium and coma. Depression and circulatory collapse occur only with severe intoxication. In such cases, blood pressure declines and death due to respiratory failure may ensue following paralysis and coma. The fatal adult dose of atropine is not known. In pediatric populations, 10 mg or less may be fatal. In the event of toxic overdosage, a short acting barbiturate or diazepam may be given as needed to control marked excitement and convulsions. Large doses for sedation should be avoided because central depressant action may coincide with the depression occurring late in atropine poisoning. Central stimulants are not recommended. Physostigmine, given as an atropine antidote by slow intravenous injection of 1 to 4 mg (0.5 to 1 mg in pediatric populations), rapidly abolishes delirium and coma caused by large doses of atropine. Since physostigmine is rapidly destroyed, the patient may again lapse into coma after one to two hours, and repeated doses may be required. Artificial respiration with oxygen may be necessary. Ice bags and alcohol sponges help to reduce fever, especially in pediatric populations. Atropine is not removed by dialysis.

16 HOW SUPPLIED/STORAGE AND HANDLING Atropine Sulfate Injection USP, 0.5 mg/5 mL (0.1 mg/mL) is available as a sterile, clear, colorless solution for intravenous administration and supplied in 5 mL single-dose glass syringe as follows: Strength (Concentration) NDC# Unit of Sale Each Atropine Sulfate Injection, USP 0.5 mg/5 mL (0.1 mg/mL) NDC 70121-1705-7 (package of 10, 5 mL single-dose glass syringes) NDC 70121-1705-1 (1 syringe in 1 carton) Atropine Sulfate Injection USP, 1 mg/10 mL (0.1 mg/mL) is available as a sterile, clear, colorless solution for intravenous administration and supplied in 10 mL single-dose glass syringe as follows: Strength (Concentration) NDC# Unit of Sale Each Atropine Sulfate Injection, USP 1 mg/10 mL (0.1 mg/mL) NDC 70121-1706-2 (package of 10, 10 mL single-dose glass syringes in 1 carton) NDC 70121-1706-1 (1 syringe in 1 carton) NDC 70121-1706-4 (package of 24, 10 mL single-dose glass syringes in 1 carton) Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Ahmedabad 382213, INDIA Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 09-2025-03