DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 MexiletineAtropine Sulfate Injection decreased the rate of mexiletine absorption without altering the relative oralbioavailability; this delay in mexiletine absorption was reversed by the combination of atropine andintravenous metoclopramide during pretreatment for anesthesia.. Mexiletine Decreases rate of mexiletine absorption. (7.1) Revised: 11/2020.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Atropine Sulfate Injection, USP is supplied in single-dose syringes as follows:Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F).[See USP Controlled Room Temperature.] Product repackaged by: Henry Schein, Inc., Bastian, VA 24314From Original Manufacturer/Distributors NDC and Unit of SaleTo Henry Schein Repackaged Product NDC and Unit of SaleTotal Strength/Total Volume (Concentration) per unitNDC 0409-9630-05Bundle of 10Ansyr(TM) Plastic SyringeNDC 0404-9823-051 Ansyr(TM) Plastic Syringe in bag(Vial bears NDC 0409-9630-15)Concentration: 0.05 mg/mLFill Volume: mLTotal Atropine Content: 0.25 mgDistributed by Hospira, Inc., Lake Forest, IL 60045 USAAbboject(R) is trademark of Abbott Laboratories.LifeShield(R) is the trademark of ICU Medical, Inc. and is used under license.LAB-1041-4.2. Image2.jpg.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Atropine Sulfate Injection is indicated for temporary blockade of severe or life-threatening muscariniceffects, e.g., as an antisialagogue, an antivagal agent, an antidote for organophosphorus or muscarinicmushroom poisoning, and to treat bradyasystolic cardiac arrest.. Atropine is muscarinic antagonist indicated for temporary blockade of severe or life-threatening muscarinic effects. (1).

NONCLINICAL TOXICOLOGY SECTION.

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

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions have been identified during post-approval use of atropine sulfate.Because these reactions are reported voluntarily from population of uncertain size, it is not alwayspossible to reliably estimate their frequency or establish 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 hypersensitivityreactions have been observed, especially skin rashes which in some instances progressed to exfoliation.. Most adverse reactions are directly related to atropines antimuscarinic action.Dryness of the mouth, blurred vision, photophobia and tachycardia commonlyoccur with chronic administration of therapeutic doses. (6)To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc.at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of ActionAtropine is an antimuscarinic agent since it antagonizes the muscarine-like actions of acetylcholine andother choline esters.Atropine inhibits the muscarinic actions of acetylcholine on structures innervated by postganglioniccholinergic nerves, and on smooth muscles which respond to endogenous acetylcholine but are not soinnervated. As with other antimuscarinic agents, the major action of atropine is competitive orsurmountable antagonism which can be overcome by increasing the concentration of acetylcholine atreceptor sites of the effector organ (e.g., by using anticholinesterase agents which inhibit the enzymaticdestruction of acetylcholine). The receptors antagonized by atropine are the peripheral structures that arestimulated or inhibited by muscarine (i.e., exocrine glands and smooth and cardiac muscle). Responses topostganglionic cholinergic nerve stimulation also may be inhibited by atropine but this occurs less readilythan with responses to injected (exogenous) choline esters.12.2 PharmacodynamicsAtropine-induced parasympathetic inhibition may be preceded by transient phase of stimulation,especially on the heart where small doses first slow the rate before characteristic tachycardia develops dueto paralysis of vagal control. Atropine exerts more potent and prolonged effect on heart, intestine andbronchial muscle than scopolamine, but its action on the iris, ciliary body and certain secretory glands isweaker than that of scopolamine. Unlike the latter, atropine in clinical doses does not depress the centralnervous system but may stimulate the medulla and higher cerebral centers. Although mild vagal excitationoccurs, the increased respiratory rate and (sometimes) increased depth of respiration produced by atropineare more probably the result of bronchiolar dilatation. Accordingly, atropine is an unreliable respiratorystimulant and large or repeated doses may depress respiration.Adequate doses of atropine abolish various types of reflex vagal cardiac slowing or asystole. The drugalso prevents or abolishes bradycardia or asystole produced by injection of choline esters,anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulationof the vagus. Atropine also may lessen the degree of partial heart block when vagal activity is an etiologicfactor. In some patients with complete heart block, the idioventricular rate may be accelerated by atropine;in others, the rate is stabilized. Occasionally large dose may cause atrioventricular (A-V) block andnodal rhythm.Atropine Sulfate Injection in clinical doses counteracts the peripheral dilatation and abrupt decrease inblood pressure produced by choline esters. However, when given by itself, atropine does not exert astriking or uniform effect on blood vessels or blood pressure. Systemic doses slightly raise systolic andlower diastolic pressures and can produce significant postural hypotension. Such doses also slightlyincrease cardiac output and decrease central venous pressure. Occasionally, therapeutic doses dilatecutaneous blood vessels, particularly in the blush area (atropine flush) and may cause atropine feverdue 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 min.) are delayed by to minutes afterdrug administration and both effects are non-linearly related to the amount of drug in the peripheralcompartment. Changes in plasma atropine levels following intramuscular administration (0.5 to4 mg doses) and heart rate are closely overlapped but the time course of the changes in atropine levels andbehavioral impairment indicates that pharmacokinetics is not the primary rate-limiting mechanism for thecentral 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, significantlyincreases the absorption of atropine due to increased perfusion in the muscle and significantly decreasesthe clearance of atropine. The pharmacokinetics of atropine is nonlinear after intravenous administrationof 0.5 to mg. Atropines plasma protein binding is about 44% and saturable in the 2-20 ug/mLconcentration range. Atropine readily crosses the placental barrier and enters the fetal circulation, but isnot found in amniotic fluid. Much of the drug is destroyed by enzymatic hydrolysis, particularly in theliver; from 13 to 50% is excreted unchanged in the urine. Traces are found in various secretions, includingmilk. The major metabolites of atropine are noratropine, atropin-n-oxide, tropine, and tropic acid. Themetabolism 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 andpharmacodynamics (heart rate changes) of atropine.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.

11 DESCRIPTION. Atropine Sulfate Injection, USP is sterile, nonpyrogenic isotonic solution of atropine sulfatemonohydrate in water for injection with sodium chloride sufficient to render the solution isotonic. It isadministered parenterally by intravenous injection.Each milliliter (mL) contains 0.1 mg (adult strength) or 0.05 mg (pediatric strength) of atropine sulfatemonohydrate equivalent to 0.083 mg (adult strength) or 0.042 mg (pediatric strength) of atropine, andsodium chloride, mg. May contain sodium hydroxide and/or sulfuric acid for pH adjustment0.308 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 inamounts 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) andis intended for use only as single-dose injection. When smaller doses are required the unused portionshould be discarded.Atropine Sulfate, USP is chemically designated H, H-Tropan-3--ol (+-)-tropate (ester), sulfate (2:1)(salt) monohydrate, (C17H23NO3)2 H2SO4 H2O, colorless crystals or white crystalline powder verysoluble in water. It has the following structural formula:Atropine, naturally occurring belladonna alkaloid, is racemic mixture of equal parts of d- and1-hyocyamine, whose activity is due almost entirely to the levo isomer of the drug.Sodium Chloride, USP is chemically designated NaCl, white crystalline powder freely soluble in water.The Ansyr(R) syringe is molded from specially formulated polypropylene. Water permeates from insidethe container at an extremely slow rate which will have an insignificant effect on solution concentrationover the expected shelf life. Solutions in contact with the plastic container may leach out certain chemicalcomponents from the plastic in very small amounts; however, biological testing was supportive of thesafety of the syringe material. Formula1.jpg.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 2.1 General AdministrationParenteral drug products should be inspected visually for particulate matter and discoloration prior toadministration, whenever solution and container permit. Do not administer unless solution is clear andseal is intact. Each syringe 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 Dosage2.3 Pediatric DosageDosing 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 mg/kg to 0.04 mg/kg [see Warnings and Precautions (5.1)]. For intravenous administration (2.1)o Titrate according to heart rate, PR interval, blood pressure andsymptoms (2.1)o Adult dosage- Antisialagogue or for antivagal effects: Initial single dose of 0.5 mg to1 mg (2.2)- Antidote for organophosphorus or muscarinic mushroom poisoning:Initial single dose of mg to mg, repeated every 20-30 minutes (2.2)- Bradyasystolic cardiac arrest: mg dose, repeated every 3-5 minutes ifasystole persists (2.2)o Patients with Coronary Artery Disease: Limit the total dose to 0.03 mg/kgto 0.04 mg/kg (2.4). Image1.jpg.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 0.05 mg/mL and 0.1 mg/mL in Ansyr(R) Plastic Syringe.Injection: 0.1 mg/mL in LifeShield(R) Abboject(R) Glass Syringe.Injection: 0.1 mg/mL in Abboject(R) Syringe with Male Luer Lock Adapter.. 0.05 mg/mL injection in Ansyr(R) Plastic Syringe (3)o 0.1 mg/mL injection in Ansyr(R) Plastic Syringe (3)o 0.1 mg/mL injection in LifeShield(R) Abboject(R) Glass Syringe (3)o 0.1 mg/mL injection in Abboject(R) Syringe with Male Luer Lock Adapter (3).

OVERDOSAGE SECTION.

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 exctextent,hallucinations, delirium and coma. Depression and circulatory collapse occur only with severeintoxication. In such cases, blood pressure declines and death due to respiratory failure may ensuefollowing 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, short acting barbiturate or diazepam may be given as needed to controlmarked exctextent and convulsions. Large doses for sedation should be avoided because centraldepressant action may coincide with the depression occurring late in atropine poisoning. Centralstimulants are not recommended.Physostigmine, given as an atropine antidote by slow intravenous injection of to mg (0.5 to mg inpediatric populations), rapidly abolishes delirium and coma caused by large doses of atropine. Sincephysostigmine is rapidly destroyed, the patient may again lapse into coma after one to two hours, andrepeated 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

SAMPLE PACKAGE LABEL. Label1.jpg.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 PregnancyAnimal reproduction studies have not been conducted with atropine. It also is not known whether atropinecan cause fetal harm when given to pregnant woman or can affect reproduction capacity.8.3 Nursing MothersTrace amounts of atropine was found in breast milk. The clinical impact of this is not known.8.4 Pediatric UseRecommendations for use in pediatric patients are not based on clinical trials.8.5 Geriatric UseAn evaluation of current literature revealed no clinical experience identifying differences in responsebetween 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 5.1 TachycardiaWhen the recurrent use of atropine is essential in patients with coronary artery disease, the total doseshould be restricted to to mg (maximum 0.03 to 0.04 mg/kg) to avoid the detrimental effects ofatropine-induced tachycardia on myocardial oxygen demand.5.2 Acute GlaucomaAtropine may precipitate acute glaucoma.5.3 Pyloric ObstructionAtropine may convert partial organic pyloric stenosis into complete obstruction.5.4 Complete Urinary RetentionAtropine may lead to complete urinary retention in patients with prostatic hypertrophy.5.5 Viscid PlugsAtropine may cause inspissation of bronchial secretions and formation of viscid plugs in patients withchronic lung disease.. Tachycardia (5.1)o Glaucoma (5.2)o Pyloric obstruction (5.3)o Worsening urinary retention (5.4)o Viscid bronchial plugs (5.5).