2.1 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 (2.2)]. 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 (3)].

2.2 Dosage Information

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

2.3 Administration Instructions

5.1 Cardiovascular Risks

Cardiovascular adverse reactions reported in the literature for atropine include, but are not limited to, sinus tachycardia, palpitations, premature ventricular contractions, atrial flutter, atrial fibrillation, ventricular flutter, ventricular fibrillation, cardiac syncope, asystole, and myocardial infarction [see Adverse Reactions (6)]. In patients with a recent myocardial infarction and/or severe coronary artery disease, there is a possibility that atropine-induced tachycardia may cause ischemia, extend or initiate myocardial infarcts, and stimulate ventricular ectopy and fibrillation. ATROPEN should be used with caution in patients with known cardiovascular disease or cardiac conduction problems.

5.2 Heat Injury

ATROPEN may inhibit sweating which, in a warm environment or with excessive exercise, can lead to hyperthermia and heat injury. To the extent feasible, avoid excessive exercise and heat exposure [see Adverse Reactions (6), Overdosage (10)].

5.3 Acute Glaucoma

ATROPEN may cause acute glaucoma and should be administered with caution in patients at risk for acute glaucoma or who have severe narrow angle glaucoma. Monitor for signs and symptoms of intraocular pressure, as appropriate.

5.4 Urinary Retention

ATROPEN may cause urinary retention and should be administered with caution to patients with clinically significant bladder outflow obstruction.

5.5 Pyloric Stenosis

ATROPEN may cause complete pyloric obstruction in patients with partial pyloric stenosis. These patients should be monitored for gastrointestinal symptoms following administration of ATROPEN.

5.6 Exacerbation of Chronic Lung Disease

Atropine may cause thickening of bronchial secretions and formation of dangerous viscid plugs in individuals with chronic lung disease. Respiratory status should be monitored in individuals with chronic lung disease following administration of ATROPEN.

5.7 Hypersensitivity

Atropine can cause hypersensitivity reactions, including anaphylactic reactions [see Adverse Reactions (6)]. Medical supervision is necessary in patients who have had previous anaphylactic reactions to atropine and require treatment for organophosphorus or nerve agent poisoning.

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 (5.1), Clinical Pharmacology (12.2)].

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 (10)]. 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.

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.

7.1 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.

7.2 Barbiturates

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

8.1 Pregnancy

8.2 Lactation

8.4 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.

Adverse events seen in pediatric patients treated with atropine are similar to those that occur in adult patients, although central nervous system effects are often seen earlier and at lower doses [see Adverse Reactions (6)].

Overheating (atropine fever) caused by suppression of sweat gland activity may be more pronounced in infants and small children. Extreme hyperthermia in a newborn has been reported with as little as 0.065 mg orally.

8.5 Geriatric Use

Geriatric patients may be more susceptible to the effects of atropine. Because of the longer half-life of atropine in geriatric patients, they may require less frequent doses after the initial dose [see Clinical Pharmacology (12.3)].

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 (8.4)]. 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.

12.1 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.

12.2 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 (5.2)].

12.3 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 (8.2)]. The unchanged drug excreted by urine is approximately 13 to 50%.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

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

16.2 Storage and Handling

Store between 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC and 30ºC (between 59ºF and 86ºF) [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.

Administration Information

Appropriate steps must be taken to ensure that users understand the indications for and use of ATROPEN, including review of symptoms of poisoning and operation of ATROPEN [see Dosage and Administration (2)].

Protection against Organophosphorus Poisoning

Individuals should not rely solely upon atropine to provide complete protection from chemical nerve agents and insecticide poisoning. Primary protection against exposure to chemical nerve agents and insecticide poisoning is the wearing of protective garments including masks designed specifically for this use.

Seek Definitive Medical Care

If feasible and appropriate, advise patients that ATROPEN is an initial emergency treatment, that they need additional care at a healthcare facility.

Avoid Overheating

If feasible and appropriate, advise the patient to avoid a hot environment and excessive physical activity since atropine can inhibit sweating which can lead to overheating and heat injury.

Manufactured by:
Meridian Medical Technologies®, LLC
St. Louis, MO 63146