Atropen

Description

Each prefilled auto-injector provides a dose of the antidote atropine in a self-contained unit, specially designed for self or caregiver administration. Three strengths of AtroPen® (atropine) are available; they are AtroPen® (atropine) 0.5 mg, AtroPen® (atropine) 1 mg, and AtroPen® (atropine) 2 mg. When activated the AtroPen® 0.5 mg dispenses 0.42 mg atropine base (equivalent to 0.5 mg atropine sulfate), the AtroPen® 1 mg dispenses 0.84 mg atropine base (equivalent to 1 mg atropine sulfate), and the AtroPen® 2 mg dispenses 1.67 mg atropine base (equivalent to 2 mg atropine sulfate). Each AtroPen® delivers atropine in 0.7 mL of sterile pyrogen-free solution containing glycerin, phenol, citrate buffer and water for injection. The pH range is 4.0–5.0.

After the AtroPen® (atropine) Auto-injector has been activated, the empty container should be disposed of properly (see DOSAGE AND ADMINISTRATION). It cannot be refilled, nor can the protruding needle be retracted.

Atropine, an anticholinergic agent (muscarinic antagonist), occurs as white crystals, usually needle-like, or as a white, crystalline powder. It is highly soluble in water with a molecular weight of 289.38. Atropine, a naturally occurring belladonna alkaloid, is a racemic mixture of equal parts of d- and l-hyoscyamine, whose activity is due almost entirely to the levo isomer of the drug. Chemically, atropine is designated as 1 H,5 H-Tropan-3 –ol (±) -tropate. Its empirical formula is C₁₇H₂₃NO₃ and its structural formula is:

ATROPEN is indicated for the treatment of poisoning by susceptible organophosphorus nerve agents having cholinesterase activity as well as organophosphorus or carbamate insecticides in adult and pediatric patients.

Dosage And Administration

Important Administration Information

• It is recommended that three ATROPEN autoinjectors be available for use in each patient at risk for organophosphorus or carbamate poisoning; one (1) for mild symptoms plus two (2) more for severe symptoms [see DOSAGE AND ADMINISTRATION]. Different dose strengths of ATROPEN are available depending on the patient’s weight.
• ATROPEN should be used by persons who have had adequate training in the recognition and treatment of nerve agent or insecticide intoxication, but may be administered by a caregiver or self-administration if a trained provider is not available.
• Only administer ATROPEN to patients experiencing symptoms of organophosphorus or carbamate poisoning in a situation where exposure is known or suspected. ATROPEN is a single-dose autoinjector intended as an initial treatment of the muscarinic symptoms of insecticide or nerve agent poisonings (generally breathing difficulties due to increased secretions); definitive medical care should be sought immediately.
• ATROPEN should be administered as soon as symptoms of organophosphorus or carbamate poisoning appear.
• In severe poisonings, it may also be desirable to concurrently administer an anticonvulsant (preferably a benzodiazepine) if seizure is suspected in the unconscious individual since the classic tonic-clonic jerking may not be apparent due to the effects of the poison.
• A cholinesterase reactivator such as pralidoxime may serve as an important adjunct to atropine therapy.
• Close supervision of all treated patients is indicated for at least 48 to 72 hours.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit [see Dosage Forms And Strengths].

Dosage Information

Different dose strengths of ATROPEN are available depending on the patient’s age and weight (see Table 1).

Table 1: Recommended Dose Strength per ATROPEN Injection

Dosage For Mild Symptoms

First Dose

If the patient experiences two or more mild symptoms of nerve agent or insecticide exposure listed in Table 2, administer one (1) ATROPEN injection intramuscularly into the mid-lateral (outer) thigh.

Additional Doses

If, at any time after receiving the first ATROPEN injection, the patient has any of the severe symptoms listed in Table 2, administer two (2) additional ATROPEN injections in rapid succession. If possible, a person other than the patient should administer the second and third ATROPEN injections.

Wait 10 to 15 minutes for ATROPEN to take effect. If after 10 to 15 minutes, the patient does not develop any of the severe symptoms listed in Table 2, no additional ATROPEN injections are recommended.

Dosage For Severe Symptoms

If the patient is either unconscious or has any of the severe symptoms listed in Table 2, immediately administer three (3) ATROPEN injections intramuscularly into the patient’s mid-lateral thigh in rapid succession.

Table 2: Common Symptoms of Organophosphorus or Carbamate Poisoning

Administration Instructions

Directions For The Use Of 2 mg, 1 mg, And 0.5 mg ATROPEN

1. Snap the grooved end of the plastic sleeve down and over the Yellow Safety Release. Remove the ATROPEN autoinjector from the plastic sleeve. Do not place fingers on the Green Tip.
2. Firmly grasp the ATROPEN autoinjector with the Green Tip (needle end) pointed down.
3. With your other hand, pull off the Yellow Safety Release. ATROPEN is now ready to be administered.
4. Aim and firmly jab the Green Tip straight down (at a 90° angle) against the mid-lateral thigh. The ATROPEN device will activate and deliver the medicine when you do this. ATROPEN can inject through clothing, but make sure pockets at the injection site are empty. Very thin people and small children should also be injected in the mid-lateral thigh, but before giving ATROPEN, bunch up the thigh to provide a thicker area for injection.
5. Hold the ATROPEN autoinjector firmly in place for at least 10 seconds to allow the injection to finish.
6. Remove the ATROPEN autoinjector and massage the injection site for several seconds. If the needle is not visible, check to be sure the Yellow Safety Release has been removed, and repeat steps 4 and 5, but press harder.
7. After use, using a hard surface, bend the needle back against the ATROPEN autoinjector and either pin the used ATROPEN autoinjectors to the patient’s clothing or show the used ATROPEN autoinjectors to the first medical person you see. This will allow medical personnel to see the number and dose of ATROPEN autoinjectors administered. Move yourself and the patient away from the contaminated area right away. Try to find medical help.

Directions For The Use Of 0.25 mg ATROPEN

1. Remove the plastic cap from the yellow tube and slide the ATROPEN autoinjector from the tube. Do not place fingers on the Black Tip.
2. Firmly grasp the ATROPEN autoinjector with the Black Tip (needle end) pointed down.
3. With your other hand, pull off the Gray Safety Release. ATROPEN is now ready to be administered.
4. Bunch up the thigh to provide a thicker area for injection. Aim and firmly jab the Black Tip straight down (at a 90° angle) against the mid-lateral thigh. The ATROPEN device will activate and deliver the medicine when you do this.
5. Hold the ATROPEN autoinjector firmly in place for at least 10 seconds to allow the injection to finish.
6. Remove the ATROPEN autoinjector and massage the injection site for several seconds. If the needle is not visible, check to be sure the Gray Safety Release has been removed, and repeat steps 4 and 5, but press harder.
7. After use, using a hard surface, bend the needle back against the ATROPEN autoinjector and either pin the used ATROPEN autoinjectors to the patient’s clothing or show the used ATROPEN autoinjectors to the first medical person you see. This will allow medical personnel to see the number and dose of ATROPEN autoinjectors administered. Move yourself and the patient away from the contaminated area right away. Try to find medical help.

How Supplied

Dosage Forms And Strengths

Injection: Each single-dose ATROPEN autoinjector contains a clear sterile solution of atropine. Four strengths of ATROPEN are available

• 0.25 mg/0.3 mL (yellow label): 0.21 mg atropine (equivalent to 0.25 mg atropine sulfate) in 0.3 mL
• 0.5 mg/0.7 mL (blue label): 0.42 mg atropine (equivalent to 0.5 mg atropine sulfate) in 0.7 mL
• 1 mg/0.7 mL (red label): 0.84 mg atropine (equivalent to 1 mg atropine sulfate) in 0.7 mL
• 2 mg/0.7 mL (green label): 1.67 mg atropine (equivalent to 2 mg atropine sulfate) in 0.7 mL

ATROPEN is a prefilled single-dose autoinjector that contains a clear solution and is supplied in the following package configurations:

Table 3: ATROPEN Package Configurations

Storage And Handling

Store between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F) [See USP Controlled Room Temperature]. Not made with natural rubber latex. Keep from freezing. Protect from light.

After the ATROPEN autoinjector has been activated, the empty container should be disposed of properly. It cannot be refilled, nor can the protruding needle be retracted.

Manufactured by: Meridian Medical Technologies®, Inc. Columbia, MD 21046 A Pfizer Company. Revised: Nov 2020

The following serious adverse reactions are described elsewhere in the labeling:

• Cardiovascular Risks [see WARNINGS AND PRECAUTIONS]
• Heat Injury [see WARNINGS AND PRECAUTIONS]
• Acute Glaucoma [see WARNINGS AND PRECAUTIONS]
• Urinary Retention [see WARNINGS AND PRECAUTIONS]
• Pyloric Stenosis [see WARNINGS AND PRECAUTIONS]
• Exacerbation of Chronic Lung Disease [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity [see WARNINGS AND PRECAUTIONS]

The following adverse reactions associated with the use of atropine were identified in the literature. 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.

Adverse Reactions At Recommended Doses

Common adverse reactions of atropine can be attributed to its antimuscarinic action. These include dryness of the mouth, blurred vision, dry eyes, photophobia, confusion, headache, dizziness, tachycardia, palpitations, flushing, urinary hesitancy or retention, constipation, abdominal pain, abdominal distention, nausea and vomiting, loss of libido, and impotence. Anhidrosis may produce heat intolerance and impairment of temperature regulation in a hot environment. Dysphagia, paralytic ileus, acute angle closure glaucoma, maculopapular rash, petechial rash, and scarlatiniform rash have also been reported. Adverse cardiac reactions, including arrhythmias and myocardial infarction, have been reported with atropine [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Larger doses of atropine may produce central nervous system effects such as restlessness, tremor, fatigue, locomotor difficulties, delirium, hallucinations, depression and ultimately, medullary paralysis and death [see OVERDOSAGE]. 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.

Hypersensitivity

Hypersensitivity reactions will occasionally occur with atropine; these are usually seen as skin rashes and may progress to exfoliation. Anaphylactic reaction and laryngospasm have also occurred.

Pediatric Patients

Adverse events seen in pediatrics are similar to those that occur in adult patients although central nervous system complaints are often seen earlier and at lower doses.

Additional Adverse Reactions To Atropine By Organ System

The following adverse reactions were reported in published literature for atropine in both adults and children:

Cardiovascular

Sinus tachycardia, supraventricular tachycardia, junctional tachycardia, ventricular tachycardia, bradycardia, palpitations, ventricular arrhythmia, ventricular flutter, ventricular fibrillation, atrial arrhythmia, atrial fibrillation, atrial ectopic beats, ventricular premature contractions, bigeminal beats, trigeminal beats, nodal extrasystole, ventricular extrasystole, supraventricular extrasystole, asystole, cardiac syncope, prolongation of sinus node recovery time, cardiac dilation, left ventricular failure, myocardial infarction, intermittent nodal rhythm (no P wave), prolonged P wave, shortened PR segment, R on T phenomenon, shortened RT duration, widening and flattening of QRS complex, prolonged QT interval, flattening of T wave, repolarization abnormalities, altered ST-T waves, retrograde conduction, transient atrioventricular (AV) dissociation, increased blood pressure, decreased blood pressure, labile blood pressure, weak or impalpable peripheral pulses.

Eye

Mydriasis, blurred vision, pupils poorly reactive to light, photophobia, decreased contrast sensitivity, decreased visual acuity, decreased accommodation, cycloplegia, strabismus, heterophoria, cyclophoria, acute angle closure glaucoma, conjunctivitis, keratoconjunctivitis sicca, blindness, tearing, dry eyes/dry conjunctiva, irritated eyes, crusting of eyelid, blepharitis.

Gastrointestinal

Nausea, abdominal pain, paralytic ileus, decreased bowel sounds, distended abdomen, vomiting, delayed gastric emptying, decreased food absorption, dysphagia.

General

Hyperpyrexia, lethargy, somnolence, chest pain, excessive thirst, weakness, syncope, insomnia, tongue chewing, dehydration, feeling hot, injection site reaction.

Immunologic

Anaphylactic reaction.

Special Investigations

Leukocytosis, hyponatremia, elevated blood urea nitrogen (BUN), elevated hemoglobin, elevated erythrocytes, low hemoglobin, hypoglycemia, hyperglycemia, hypokalemia, increase in photic stimulation on electroencephalogram (EEG), signs of drowsiness on EEG, runs of alpha waves on EEG, alpha waves (EEG) blocked upon opening eyes.

Metabolic

Failure to feed.

Central Nervous System

Ataxia, hallucinations (visual or aural), seizures (generally tonic-clonic), abnormal movements, coma, confusion, stupor, dizziness, amnesia, headache, diminished tendon reflexes, hyperreflexia, muscle twitching, opisthotonos, Babinski’s reflex/Chaddock’s reflex, hypertonia, dysmetria, muscle clonus, sensation of intoxication, difficulty concentrating, vertigo, dysarthria.

Psychiatric

Agitation, restlessness, delirium, paranoia, anxiety, mental disorders, mania, withdrawn behavior, behavior changes.

Genitourinary

Difficulty in micturition, urine urgency, distended urinary bladder, urine retention, bed-wetting.

Pulmonary

Tachypnea, slow respirations, shallow respirations, breathing difficulty, labored respirations, inspiratory stridor, laryngitis, laryngospasm, pulmonary edema, respiratory failure, subcostal recession.

Dermatologic

Dry mucous membranes, dry warm skin, flushed skin, oral lesions, dermatitis, petechiae, rash, macular rash, papular rash, maculopapular rash, scarlatiniform rash, erythematous rash, sweating/moist skin, cold skin, cyanosed skin, salivation.

Injection Site

Muscle tightness and pain may occur at the injection site.

Inadvertent Injection

In cases where ATROPEN is inadvertently administered to people who are not poisoned with nerve agent or organophosphorus insecticide, the following effects on their ability to function normally may occur. Patients with cardiac disease may be at risk for serious adverse events, including death.

Atropine 2 mg IM, when given to healthy male volunteers, is associated with minimal effects on visual, motor, and mental functions, though unsteadiness walking and difficulty concentrating may occur. Atropine reduces body sweating and increases body temperature, particularly with exercise and under hot conditions.

Atropine 4 mg IM, when given to healthy male volunteers, is associated with impaired visual acuity, visual near point accommodation, logical reasoning, digital recall, learning, and cognitive reaction time. Ability to read is reduced or lost. Subjects are unsteady and need to concentrate on walking. These effects begin about 15 minutes to one hour or more post-dose.

Atropine 6 mg IM, when given to healthy male volunteers, is associated with the effects described above plus additional central nervous system effects including poor coordination, poor attention span, and visual hallucinations (colored flashes) in many subjects. Frank visual hallucinations, auditory hallucinations, disorientation, and ataxia occur in some subjects. Skilled and labor-intense tasks are performed more slowly and less efficiently. Decision making takes longer and is sometimes impaired.

It is unclear if the above data, obtained from studies of healthy adult subjects, can be extrapolated to other populations. In the elderly and patients with co-morbid conditions, the effects of ≥2 mg atropine on the ability to see, walk, and think properly are unstudied; effects may be greater in susceptible populations.

Patients who are mistakenly injected with ATROPEN should avoid potentially dangerous overheating, avoid vigorous physical activity, and seek medical attention as soon as feasible.

Adverse Reactions Observed In Pediatric Patients After Inappropriate Administration Of ATROPEN

Amitai et el (JAMA 1990) evaluated the safety of ATROPEN 0.5 mg, 1 mg, and 2 mg in a case series of 240 children who received ATROPEN inappropriately (i.e., no nerve agent exposure) during the 1990 Gulf War Period. Overall, severity of atropinization followed a nonlinear correlation with dose. Estimated doses up to 0.045 mg/kg produced no signs of atropinization. Estimated doses between 0.045 mg/kg to 0.175 mg/kg and even greater than 0.175 mg/kg were associated with mild and severe effects, respectively. Actual dosage received by children may have been considerably lower than estimated since incomplete injection in many cases was suspected. Regardless, adverse events reported were generally mild and self-limited. Few children required hospitalization. Adverse reactions reported were dilated pupils (43%), tachycardia (39%), dry membranes (35%), flushed skin (20%), temperature 37.8°C or 100°F (4%), and neurologic abnormalities (5%). There was also local pain and swelling. In 91 children with electrocardiograms (ECGs), no abnormalities were noted other than sinus tachycardia; 22 children had severe tachycardia of 160 bpm to 190 bpm. Neurologic abnormalities consisted of irritability, agitation, confusion, lethargy, and ataxia

Drug Interactions

Pralidoxime

When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone because pralidoxime may potentiate the effect of atropine. Excitement and manic behavior immediately following recovery of consciousness have been reported in several cases. However, similar behavior has occurred in cases of organophosphate poisoning that were not treated with pralidoxime.

Barbiturates

Barbiturates are potentiated by the anticholinesterases; therefore, barbiturates should be used cautiously in the treatment of convulsions resulting from exposure to atropine.

CAUTION! PRIMARY PROTECTION AGAINST EXPOSURE TO CHEMICAL NERVE AGENTS AND INSECTICIDE POISONING IS THE WEARING OF PROTECTIVE GARMENTS INCLUDING MASKS DESIGNED SPECIFICALLY FOR THIS USE.

INDIVIDUALS SHOULD NOT RELY SOLELY UPON ANTIDOTES SUCH AS ATROPINE AND PRALIDOXIME TO PROVIDE COMPLETE PROTECTION FROM CHEMICAL NERVE AGENTS AND INSECTICIDE POISONING.

Patients who have had previous anaphylactic reactions to atropine who have mild symptoms of organophosphorous or nerve agent poisoning should not be treated without adequate medical supervision.

While AtroPen® (atropine) can be administered to all individuals with a life-threatening exposure to organophosphorous nerve agents and insecticides, it should be administered with extreme caution to individuals with the following disorders when the symptoms of nerve agent poisoning are less severe: individuals who are hypersensitive to any component of the product, disorders of heart rhythm such as atrial flutter, severe narrow angle glaucoma, pyloric stenosis, prostatic hypertrophy, significant renal insufficiency, or a recent myocardial infarction.

More than one dose of atropine (AtroPen® (atropine) Auto-injector) may be necessary initially, especially when exposure is massive or symptoms are severe. However, no more than three doses should be administered unless under the supervision of trained medical personnel. High doses of atropine may be required for many hours following high-dose exposure to maintain atropinization. (See DOSAGE AND ADMINISTRATION.)

Children and the elderly may be more susceptible to the pharmacologic effects of atropine.

Severe difficulty in breathing requires artificial respiration in addition to the use of atropine since atropine is not dependable in reversing the weakness or paralysis of the respiratory muscles.

General

The desperate condition of the organophosphorous-poisoned individual will generally mask such minor signs and symptoms of atropine treatment as have been noted in normal subjects.

Atropine should be used with caution in individuals with cardiac disease. Conventional systemic doses may precipitate acute glaucoma in susceptible individuals, convert partial pyloric stenosis into complete pyloric obstruction, precipitate urinary retention in individuals with prostatic hypertrophy, or cause inspissation of bronchial secretions and formation of dangerous viscid plugs in individuals with chronic lung disease.

Laboratory Tests

Treatment of organophosphorous nerve agent and insecticide poisoning should be instituted without waiting for the results of laboratory tests. Red blood cell and plasma cholinesterase, and urinary paranitrophenol measurements (in the case of parathion exposure) may be helpful in confirming the diagnosis and following the course of the illness. A reduction in red blood cell cholinesterase concentration to below 50% of normal has been seen only with organophosphorous ester poisoning.

Information for Patients

Appropriate steps must be taken to insure that users understand the indications for and use of the AtroPen® (atropine) , including review of symptoms of poisoning and operation of the AtroPen® (see DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No reports regarding the potential of atropine for carcinogenesis, mutagenesis, or impairment of fertility have been published in the literature. Since atropine is indicated for short-term emergency use only, no investigations of these aspects have been conducted.

Pregnancy

Teratogenic Effects – Pregnancy Category C: Adequate animal reproduction studies have not been conducted with atropine. It is not known whether atropine can cause fetal harm when administered to a pregnant woman or if these agents can affect reproductive capacity. Atropine should be administered to a pregnant woman only if clearly needed.

Nursing Mothers

Atropine is found in human milk in trace amounts. Caution should be exercised when atropine is administered to a nursing woman.

Pediatric Use

A review of published literature supports the safety and effectiveness of atropine in the setting of organophosphate insecticide poisoning in all pediatric age groups. The starting dose is 0.05 mg/kg IM every 5 to 20 minutes as needed to provide complete atropinization. (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections)

Geriatric Use

In general, dose selection for an elderly individual 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.

Symptoms

Manifestations of atropine overdose are dose-related and include flushing, dry skin and mucous membranes, tachycardia, widely dilated pupils that are poorly responsive to light, blurred vision, and fever (which can sometimes be dangerously elevated). Locomotor difficulties, disorientation, hallucinations, delirium, confusion, agitation, coma, and central depression can occur and may last 48 hours or longer. In instances of severe atropine intoxication, respiratory depression, coma, circulatory collapse, and death may occur.

Treatment

For atropine overdose, supportive treatment should be administered. If respiration is depressed, artificial respiration with oxygen is necessary. Ice bags, a hypothermia blanket, or other methods of cooling may be required to reduce atropine-induced fever, especially in pediatric patients [see Use In Specific Populations]. Catheterization may be necessary if urinary retention occurs. Since atropine elimination takes place through the kidney, urinary output must be maintained and increased if possible: intravenous fluids may be indicated. Because of atropine-induced photophobia, the room should be darkened.

A benzodiazepine may be needed to control marked excitement and convulsions. However, large doses for sedation should be avoided because the central nervous system depressant effect may coincide with the depressant effect occurring late in severe atropine poisoning. Barbiturates are potentiated by the anticholinesterases; therefore, barbiturates should be used cautiously in the treatment of convulsions. Central nervous system stimulants are not recommended.

Contraindications

None.

Mechanism Of Action

Atropine competitively blocks the effects of acetylcholine, including excess acetylcholine due to organophosphorus poisoning, at muscarinic cholinergic receptors on smooth muscle, cardiac muscle, secretory gland cells, and in peripheral autonomic ganglia and the central nervous system.

Pharmacodynamics

Atropine reduces secretions in the mouth and respiratory passages, relieves airway constriction, and may reduce centrally-mediated respiratory paralysis. In severe organophosphorus poisoning, a fully atropinized patient may develop or continue to have respiratory failure and may require artificial respiration and suctioning of airway secretions. Atropine may cause thickening of secretions.

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 increases heart rate and reduces atrioventricular conduction time. Adequate atropine doses can prevent or abolish bradycardia or asystole produced by organophosphorus nerve agents.

Atropine may decrease the degree of partial heart block, which can occur after organophosphorus poisoning. In some patients with complete heart block, atropine may accelerate the idioventricular rate; in others, the rate is stabilized. In some patients with conduction defects, atropine may cause paradoxical atrioventricular block and nodal rhythm.

Atropine will not act on the neuromuscular junction and has no effect on muscle paralysis or weakness, fasciculations or tremors.

Atropine is not dependable in reversing the weakness or paralysis of the respiratory muscles. Severe difficulty in breathing requires artificial respiration in addition to the use of atropine.

Systemic doses of atropine 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. Atropine can dilate cutaneous blood vessels, particularly the “blush” area (atropine flush), may cause atropine “fever” due to suppression of sweat gland activity especially in infants and small children and may inhibit sweating, thereby causing hyperthermia, particularly in a warm environment or with exercise [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Atropine is well absorbed after intramuscular administration. Following 1.67 mg atropine given intramuscularly to adults by the 2 mg ATROPEN delivery system, the peak concentration (Cmax) is 9.6 ± 1.5 (mean ± SEM) ng/mL reached between 3-60 minutes (Tmax). The protein binding of atropine is 14 to 22% in plasma. Atropine is distributed throughout the various body tissues and fluids. Much of the drug is metabolized by enzymatic hydrolysis, particularly in the liver. Atropine has been reported to be excreted in human milk [see Use In Specific Populations]. The unchanged drug excreted by urine is approximately 13 to 50%.

Specific Populations

Gender

The AUC(0-inf) and Cmax values for atropine are 15% higher in females than males. The half-life of atropine is approximately 20 minutes shorter in females than males.

Geriatric

The half-life of intravenous atropine is 3.0 ± 0.9 (mean ± SD) hours in adults and 10.0 ± 7.3 (mean ± SD) hours in geriatric patients (65 to 75 years of age).

Pediatric

The half-life of intravenous atropine in pediatric subjects under 2 years is 6.9 ± 3.3 (mean ± SD) hours; in children over 2 years, the half-life is 2.5 ± 1.2 (mean ± SD) hours.

Renal And Hepatic Impairment

The pharmacokinetics of atropine has not been evaluated in subjects with renal or hepatic impairment.

125 mg/kg) for one week prior to mating and throughout a 5-day mating period with untreated females, a dose-related decrease in fertility was observed. A no-effect dose for male reproductive toxicity was not established. The lowest dose tested was 300 times (on a mg/m² basis) the dose of atropine in a single application of ATROPEN (2 mg).