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 its potential 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 always possible 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 hypersensitivity reactions 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 commonly occur 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 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 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 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 due to paralysis of vagal control. Atropine exerts 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) increase 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 and 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 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 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 min.) are delayed by to 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 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 PharmacokineticsAtropine 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 mg. Atropines plasma protein binding is about 44% and saturable in the 2-20 ug/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 PopulationsThe 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Atropine Sulfate Injection, USP is 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 0.1 mg of atropine sulfate monohydrate equivalent to 0.083 mg of atropine, and sodium chloride, mg. May contain sodium hydroxide and/or sulfuric acid for pH adjustment 0.308 m0smol/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 single-dose injection. When smaller doses are required the unused portion should be discarded.Atropine Sulfate, USP is chemically designed 1aH, 5aH-Tropan-3-a-ol(+-)-tropate (ester), sulfate (2:1) (salt) monohydrate, (C17H23NO3)2oH2SO4oH20), colorless crystals or white crystalline powder very soluble in water. It has the following structural formula:Atropine, naturally occurring belladonna alkaloid, is 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 design NaCl, white crystalline powder freely soluble in water.. 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 to administration, whenever solution and container permit. Do not administer unless solution is clear and seal is intact. Discard unused portion.For intravenous administration.Titrate based on heart rate, PR interval, blood pressure and symptoms2.2 Adult Dosage2.3 Pediatric DosageDosing in pediatric populations has not been well studied. Usual initial dose is 0.01 to 0.03 mg/kg.. For intravenous administration. (2.1, 2.3)o Titrate according to heart rate, PR interval, blood pressure and symptoms. (2.1)o Adult dosage- Antisialagogue or for antivagal effects: Initial single dose of 0.5 mg to mg. (2.2)- Antidote for organophosphorus or muscarinic mushroom poising: Initial single dose of mg to mg, repeated every 20-30 minutes. (2.2)- Bradyasystolic cardiac arrest: mg dose, repeated every 3-5 minutes if asystole persists. (2.2)o Patients with Coronary Artery Disease: Total dose should not exceed 0.03 mg/kg to 0.04 mg/kg. (5.1). Image1.jpg.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 0.1 mg/mL in LifeShield(TM) Abboject(TM) Glass Syringes. 0.1 mg/mL injection in LifeShield(TM) Abboject(TM) Glass Syringe (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 MexiletineAtropine 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.. Mexiletine: Decreases rate of mexiletine absorption. (7.1)Revised: 3/2018.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Atropine Sulfate Injection, USP, 0.1 mg/mL, is clear and colorless solution available in mL and 10 mL single-dose glass vials. Each vial is co-packaged with an injector, which together make LifeShield(TM) Abboject(TM) Glass Syringe. It is supplied in the following presentations:Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F). [See USP Controlled Room Temperature.]. Image2.jpg. Image3.jpg.

INDICATIONS & USAGE SECTION.

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

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 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, short acting barbiturate or diazepam may be given as needed to control marked exctextent 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 to mg (0.5 to 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.

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 atropine can 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 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.

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 dose should be restricted to to mg (maximum 0.03 to 0.04 mg/kg) to avoid the detrimental effects of atropine-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 with chronic lung disease.. Tachycardia (5.1)Glaucoma (5.2)Pyloric obstruction (5.3)Worsening urinary retention (5.4)Viscid bronchial plugs (5.5).