NDC 16729-512 Atropine Sulfate

Atropine Sulfate

NDC Product Code 16729-512

NDC 16729-512-43

Package Description: 10 CARTON in 1 BOX > 1 VIAL, MULTI-DOSE in 1 CARTON (16729-512-05) > 20 mL in 1 VIAL, MULTI-DOSE

NDC Product Information

Atropine Sulfate with NDC 16729-512 is a a human prescription drug product labeled by Accord Healthcare Inc.. The generic name of Atropine Sulfate is atropine sulfate. The product's dosage form is injection, solution and is administered via endotracheal; intramedullary; intramuscular; intravenous; subcutaneous form.

Labeler Name: Accord Healthcare Inc.

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Atropine Sulfate Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • ATROPINE SULFATE .4 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • BENZYL ALCOHOL (UNII: LKG8494WBH)
  • SULFURIC ACID (UNII: O40UQP6WCF)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Endotracheal - Administration directly into the trachea.
  • Intramedullary - Administration within the marrow cavity of a bone.
  • Intramuscular - Administration within a muscle.
  • Intravenous - Administration within or into a vein or veins.
  • Subcutaneous - Administration beneath the skin; hypodermic. Synonymous with the term SUBDERMAL.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Anticholinergic - [EPC] (Established Pharmacologic Class)
  • Cholinergic Antagonists - [MoA] (Mechanism of Action)
  • Cholinergic Muscarinic Antagonist - [EPC] (Established Pharmacologic Class)
  • Cholinergic Muscarinic Antagonists - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Accord Healthcare Inc.
Labeler Code: 16729
FDA Application Number: ANDA213424 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 03-25-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Atropine Sulfate Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Atropine is indicated for temporary blockade of severe or life threatening muscarinic effects, e.g., as an antisialagogue, an antivagal agent, an antidote for organophosphorus, carbamate, or muscarinic mushroom poisoning, and to treat symptomatic bradycardia.

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 PatientsUseInitial DoseContinued TreatmentAntisialagogue 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 Dose3 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 PatientsUseInitial DoseContinued TreatmentAntisialagogue 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 DoseLess than 12 years old: 0.5 mg


12 years and older: 1 mg


Maximum Total DoseLess 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

Atropine Sulfate Injection, USP, 8 mg per 20 mL (0.4 mg per mL), is a non-pyrogenic, isotonic, clear solution and is supplied in a multiple dose glass vial.

4 Contraindications

None.

5.1 Hypersensitivity

Atropine may cause anaphylaxis.

5.2 Worsening Of Ischemic Heart Disease

In patients with ischemic heart disease, the total dose should be restricted to 2 to 3 mg (maximum 0.03 to 0.04 mg/kg) to avoid atropine-induced tachycardia, increased myocardial oxygen demand and the potential for worsening cardiac ischemia or increasing infarction size.

5.3 Acute Glaucoma

Atropine may precipitate acute glaucoma.

5.4 Pyloric Obstruction

Atropine may convert partial organic pyloric stenosis into complete obstruction.

5.5 Complete Urinary Retention

Atropine may lead to complete urinary retention in patients with prostatic hypertrophy.

5.6 Viscid Plugs

Atropine may cause thickening of bronchial secretions and formation of viscid plugs in patients with chronic lung disease.

5.7 Benzyl Alcohol

The preservative benzyl alcohol has been associated with serious adverse events and death in neonates. The "gasping syndrome"(characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.


Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

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.

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.

8.1 Pregnancy

Risk SummaryLimited 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 ConsiderationsDisease-associated maternal and/or embryo/fetal riskSevere 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.DataHuman DataNo 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 SummaryTrace 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 ConsiderationsMinimizing exposureThe 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.

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.

11 Description

Atropine Sulfate Injection, USP is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. It is administered parenterally by subcutaneous, intramuscular or intravenous injection. Each mL contains atropine sulfate, 0.4 mg (equivalent to 0.33 mg atropine); benzyl alcohol, 9 mg; sodium chloride 9 mg. May contain sulfuric acid for pH adjustment. pH 3.2 (3.0 to 3.8).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.


Atropine Sulfate, USP is chemically designated lα H, 5α H-Tropan-3-α-ol (±)-tropate (ester), sulfate (2:1) (salt) monohydrate, (C


17H


23NO


3)


2 · H


2SO


4 · H


2O, 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.

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 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 I.V. 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

AbsorptionAfter intramuscular administration, atropine is absorbed with peak concentration occurring at 30 min following injection.Effects of exercise:Exercise following intramuscular administration of atropine significantly increases the absorption of atropine due to increased perfusion in the muscle, with an increase in AUC by approximately 20% and Cmax by approximately 80%.
DistributionAtropine is distributed throughout the body. Atropine’s plasma protein binding is about 44% and saturable in the 2 to 20 mcg/mL concentration range.EliminationThe pharmacokinetics of atropine is nonlinear after intravenous administration of 0.5 to 4 mg. Atropine disappears from the blood following injection with a plasma half-life of about 2-4 hours. Much of the drug is destroyed by enzymatic hydrolysis, particularly in the liver, with 13 to 50% is excreted unchanged in the urine.MetabolismThe major metabolites of atropine are noratropine, atropin-n-oxide, tropine, and tropic acid. The metabolism of atropine is inhibited by organophosphate pesticides.
Specific Populations Pregnant WomenAtropine readily crosses the placental barrier and enters the fetal circulation, but is not found in amniotic fluid.Nursing MotherTraces are found in various secretions, including milk.Pediatric and Geriatric PatientsThe 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.

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.

16 How Supplied/Storage And Handling

Atropine Sulfate Injection, USP is a non-pyrogenic, isotonic, clear solution and is supplied as follows:NDC on 8 mg per 20 mL (0.4 mg per mL) Multiple-dose vial: 16729-512-05Presentation
Single Vial Pack
10 Vial Pack NDC#
16729-512-05
16729-512-43 Description
8 mg per 20 mL (0.4 mg per mL) Multiple-dose vial
 8 mg per 20 mL (0.4 mg per mL) Multiple-dose vial, packaged in a carton containing 10 vials.Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. After initial use, store between 20°C to 25°C (68°F to 77°F) and discard within 24 hoursManufactured For:Accord Healthcare, Inc.,


1009, Slater Road,


Suite 210-B,


Durham, NC 27703,


USA.


Manufactured By:Intas Pharmaceuticals Limited,


Plot No.: 457, 458,


Village – Matoda,


Bavla Road, Ta. - Sanand,


Dist.- Ahmedabad – 382 210.


India.


10 3619 0 696327Revised: December 2019

* Please review the disclaimer below.