Atropine Sulfate

6 ADVERSE REACTIONS 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 in elderly patients. Occasional hypersensitivity reactions have been observed, especially skin rashes which in some instances progressed to exfoliation. 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 American Regent, Inc. at 1-800-734-9236, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

4 CONTRAINDICATIONS None. None. ( 4 )

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 intravenous injection. Each milliliter (mL) contains 0.4 mg or 1 mg of atropine sulfate monohydrate equivalent to 0.332 mg or 0.83 mg 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 5.0). 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. structural formula atropine sulfate

2 DOSAGE AND ADMINISTRATION For intravenous administration. ( 2.1 ). Titrate according to heart rate, PR interval, blood pressure and symptoms. ( 2.1 ) Adult dosage Antisialagogue or for antivagal effects: Initial single dose of 0.5 to 1 mg. ( 2.2 ) Antidote for organophosphorus or muscarinic mushroom poisoning: Initial single dose of 2 to 3 mg, repeated every 20 to 30 minutes. ( 2.2 ) Bradyasystolic cardiac arrest: 1 mg dose, repeated every 3 to 5 minutes if asystole persists. ( 2.2 ) Patients with Coronary Artery Disease: Limit the total dose to 0.03 mg/kg to 0.04 mg/kg. ( 2.4 ) 2.1 General Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless solution is clear and seal is intact. Each vial is intended for single dose only. Discard unused portion. For Intravenous administration. Titrate based on heart rate, PR interval, blood pressure and symptoms. 2.2 Adult Dosage Table 1: Recommended Dosage Use Dose (adults) Repeat Antisialagogue or other antivagal 0.5 to 1 mg 1 to 2 hours Organophosphorus or muscarinic mushroom poisoning 2 to 3 mg 20 to 30 minutes Bradyasystolic cardiac arrest 1 mg 3 to 5 minutes; 3 mg maximum total dose 2.3 Pediatric Dosage Dosing in pediatric populations has not been well studied. Usual initial dose is 0.01 to 0.03 mg/kg. 2.4 Dosing in Patients with Coronary Artery Disease Limit the total dose of atropine sulfate to 0.03 to 0.04 mg/kg [see Warnings and Precautions (5.1) ].

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. Atropine is a muscarinic antagonist indicated for temporary blockade of severe or life threatening muscarinic effects. ( 1 )

10 OVERDOSAGE 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.

7 DRUG INTERACTIONS Mexiletine: Decreases rate of mexiletine absorption. ( 7.1 ) 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.

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics 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 exerts a more potent and prolonged effect on heart, intestine and bronchial muscle than scopolamine, but its action on the iris, ciliary body and certain secretory glands is weaker than that of scopolamine. Unlike the latter, atropine in clinical doses does not depress the central nervous system but may stimulate the medulla and higher cerebral centers. Although mild vagal excitation occurs, the increased respiratory rate and (sometimes) increased depth of respiration produced by atropine are more probably the result of bronchiolar dilatation. Accordingly, atropine is an unreliable respiratory stimulant and large or repeated doses may depress respiration. Adequate doses of atropine abolish various types of reflex vagal cardiac slowing or asystole. The drug also prevents or abolishes bradycardia or asystole produced by injection of choline esters, anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulation of the vagus. Atropine also may lessen the degree of partial heart block when vagal activity is an etiologic factor. In some patients with complete heart block, the idioventricular rate may be accelerated by atropine; in others, the rate is stabilized. Occasionally a large dose may cause atrioventricular (A-V) block and nodal rhythm. Atropine Sulfate Injection, USP in clinical doses counteracts the peripheral dilatation and abrupt decrease in blood pressure produced by choline esters. However, when given by itself, atropine does not exert a striking or uniform effect on blood vessels or blood pressure. Systemic doses 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. Occasionally, therapeutic doses dilate cutaneous blood vessels, particularly in the "blush" area (atropine flush), and may cause atropine "fever" due to suppression of sweat gland activity in infants and small children. The effects of intravenous atropine on heart rate (maximum heart rate) and saliva flow (minimum flow) after intravenous administration (rapid, constant infusion over 3 min.) are delayed by 7 to 8 minutes after drug administration and both effects are non-linearly related to the amount of drug in the peripheral compartment. Changes in plasma atropine levels following intramuscular administration (0.5 to 4 mg doses) and heart rate are closely overlapped but the time course of the changes in atropine levels and behavioral impairment indicates that pharmacokinetics is not the primary rate-limiting mechanism for the central nervous system effect of atropine. 12.3 Pharmacokinetics Atropine disappears rapidly from the blood following injection and is distributed throughout the body. Exercise, both prior to and immediately following intramuscular administration of atropine, significantly increases the absorption of atropine due to increased perfusion in the muscle and significantly decreases the clearance of atropine. The pharmacokinetics of atropine is nonlinear after intravenous administration of 0.5 to 4 mg. Atropine's plasma protein binding is about 44% and saturable in the 2 to 20 mcg/mL concentration range. Atropine readily crosses the placental barrier and enters the fetal circulation, but is not found in amniotic fluid. Much of the drug is destroyed by enzymatic hydrolysis, particularly in the liver; from 13 to 50% is excreted unchanged in the urine. Traces are found in various secretions, including milk. The major metabolites of atropine are noratropine, atropin-n-oxide, tropine, and tropic acid. The metabolism of atropine is inhibited by organophosphate pesticides. Specific Populations The elimination half-life of atropine is more than doubled in children under two years and the elderly (>65 years old) compared to other age groups. There is no gender effect on the pharmacokinetics and pharmacodynamics (heart rate changes) of atropine.

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.

12.2 Pharmacodynamics 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 exerts a more potent and prolonged effect on heart, intestine and bronchial muscle than scopolamine, but its action on the iris, ciliary body and certain secretory glands is weaker than that of scopolamine. Unlike the latter, atropine in clinical doses does not depress the central nervous system but may stimulate the medulla and higher cerebral centers. Although mild vagal excitation occurs, the increased respiratory rate and (sometimes) increased depth of respiration produced by atropine are more probably the result of bronchiolar dilatation. Accordingly, atropine is an unreliable respiratory stimulant and large or repeated doses may depress respiration. Adequate doses of atropine abolish various types of reflex vagal cardiac slowing or asystole. The drug also prevents or abolishes bradycardia or asystole produced by injection of choline esters, anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulation of the vagus. Atropine also may lessen the degree of partial heart block when vagal activity is an etiologic factor. In some patients with complete heart block, the idioventricular rate may be accelerated by atropine; in others, the rate is stabilized. Occasionally a large dose may cause atrioventricular (A-V) block and nodal rhythm. Atropine Sulfate Injection, USP in clinical doses counteracts the peripheral dilatation and abrupt decrease in blood pressure produced by choline esters. However, when given by itself, atropine does not exert a striking or uniform effect on blood vessels or blood pressure. Systemic doses 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. Occasionally, therapeutic doses dilate cutaneous blood vessels, particularly in the "blush" area (atropine flush), and may cause atropine "fever" due to suppression of sweat gland activity in infants and small children. The effects of intravenous atropine on heart rate (maximum heart rate) and saliva flow (minimum flow) after intravenous administration (rapid, constant infusion over 3 min.) are delayed by 7 to 8 minutes after drug administration and both effects are non-linearly related to the amount of drug in the peripheral compartment. Changes in plasma atropine levels following intramuscular administration (0.5 to 4 mg doses) and heart rate are closely overlapped but the time course of the changes in atropine levels and behavioral impairment indicates that pharmacokinetics is not the primary rate-limiting mechanism for the central nervous system effect of atropine.

12.3 Pharmacokinetics Atropine disappears rapidly from the blood following injection and is distributed throughout the body. Exercise, both prior to and immediately following intramuscular administration of atropine, significantly increases the absorption of atropine due to increased perfusion in the muscle and significantly decreases the clearance of atropine. The pharmacokinetics of atropine is nonlinear after intravenous administration of 0.5 to 4 mg. Atropine's plasma protein binding is about 44% and saturable in the 2 to 20 mcg/mL concentration range. Atropine readily crosses the placental barrier and enters the fetal circulation, but is not found in amniotic fluid. Much of the drug is destroyed by enzymatic hydrolysis, particularly in the liver; from 13 to 50% is excreted unchanged in the urine. Traces are found in various secretions, including milk. The major metabolites of atropine are noratropine, atropin-n-oxide, tropine, and tropic acid. The metabolism of atropine is inhibited by organophosphate pesticides. Specific Populations The elimination half-life of atropine is more than doubled in children under two years and the elderly (>65 years old) compared to other age groups. There is no gender effect on the pharmacokinetics and pharmacodynamics (heart rate changes) of atropine.

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3 DOSAGE FORMS AND STRENGTHS Injection: supplied as a clear, colorless solution in a 1 mL glass vial in the following concentrations: 0.4 mg/mL: containing 0.4 mg of atropine sulfate monohydrate equivalent to 0.332 mg of atropine. 1 mg/mL: containing 1 mg atropine sulfate monohydrate equivalent to 0.83 mg of atropine. Injection: 0.4 or 1 mg/mL as a clear, colorless solution in a single-dose vial.

Atropine Sulfate ATROPINE SULFATE SODIUM CHLORIDE SODIUM HYDROXIDE SULFURIC ACID WATER ATROPINE SULFATE ATROPINE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed to evaluate the carcinogenic or mutagenic potential of atropine or its potential to affect fertility adversely.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been performed to evaluate the carcinogenic or mutagenic potential of atropine or its potential to affect fertility adversely.

ANDA216120

Atropine Sulfate

ATROPINE SULFATE

71872-7312

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - Vial Label Rx Only Atropine Sulfate Injection, USP 0.4 mg /mL For Intravenous Use 1 mL Single-Dose Vial Discard Unused Portion 73121.pdp

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.

8.4 Pediatric Use Recommendations for use in pediatric patients are not based on clinical trials.

8.1 Pregnancy Pregnancy Risk Summary There are risks to the mother and fetus associated with untreated severe or life-threatening muscarinic events (see Clinical Considerations). Available data from published observational studies on atropine use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Animal reproduction studies have not been conducted with atropine. 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 because of concerns regarding the effects of atropine on the fetus. Data Human Data Atropine crosses the placenta [see Clinical Pharmacology (12.3)]. 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Risk Summary There are risks to the mother and fetus associated with untreated severe or life-threatening muscarinic events (see Clinical Considerations). Available data from published observational studies on atropine use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Animal reproduction studies have not been conducted with atropine. 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 because of concerns regarding the effects of atropine on the fetus. Data Human Data Atropine crosses the placenta [see Clinical Pharmacology (12.3)]. 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. 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. 8.4 Pediatric Use Recommendations for use in pediatric patients are not based on clinical trials. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Atropine Sulfate Injection, USP 0.4 and 1 mg/mL are supplied in 1 mL, single-dose glass vials as follows: Table 2: How Supplied Concentration (mg/mL) Package Size NDC # 0.4 mg/mL 25 Vials 0517-1004-25 1 mg/mL 25 Vials 0517-1001-25 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C and 30°C (59°F and 86°F). [ See USP Controlled Room Temperature .] IN1004 Rev. 9/2021 AR Logo