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.

INDICATIONS AND USAGE

ATROPINEpine 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.

DOSAGE AND ADMINISTRATION

Adult Dosage

IV=intravenous; IM=intramuscular; SC=subcutaneous; ET=endotracheal

*Do not rely on ATROPINEpine 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 ATROPINEpine. ATROPINEpine has no effect on bradycardia in patients with transplanted hearts.

Pediatric Dosage

Table 2: Recommended Dosage in Pediatric Patients

IV=intravenous; IM=intramuscular; SC=subcutaneous; IO=intraosseous; ET=endotracheal;

*Available evidence does not support the routine use of ATROPINEpine in emergency intubation of critically ill infants and children except in specific emergency intubations when there is higher risk of bradycardia

** ATROPINEpine has no effect on bradycardia in patients with transplanted hearts.

Dosing in Patients with Ischemic Heart Disease

Limit the total dose of ATROPINEpine sulfate to 0.03 to 0.04 mg/kg [see Warnings and Precautions (5.2)].

DOSAGE FORMS AND STRENGTHS

ATROPINE, 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.

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Hypersensitivity

ATROPINEpine may cause anaphylaxis.

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 ATROPINEpine-induced tachycardia, increased myocardial oxygen demand and the potential for worsening cardiac ischemia or increasing infarction size.

Acute Glaucoma

ATROPINEpine may precipitate acute glaucoma.

Pyloric Obstruction

ATROPINEpine may convert partial organic pyloric stenosis into complete obstruction.

Complete Urinary Retention

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

Viscid Plugs

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

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.

ADVERSE REACTIONS

DRUG INTERACTIONS

Mexiletine

USE IN SPECIFIC POPULATIONS

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been performed to evaluate the carcinogenic or mutagenic potential of ATROPINEpine or its potential to affect fertility adversely.

Pregnancy

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 Considerations

Disease-associated maternal and/or embryo/fetal risk

Severe 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 ATROPINEpine on the fetus.

Data

Human Data

No adequate and well-controlled studies are available regarding use of ATROPINEpine in pregnant women. In a cohort study of 401 pregnancies in the first trimester and 797 pregnancies in the second or third trimester, ATROPINEpine use was not associated with an increased risk of congenital malformation. In a surveillance study, 381 newborns were exposed to ATROPINEpine 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, ATROPINEpine 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 ATROPINEpine exposure, underlying maternal disease, or concomitant maternal drug use, cannot definitively establish or exclude any drug- associated risk during pregnancy.

Lactation

Risk Summary

Trace amounts of ATROPINEpine have been reported in human milk after oral intake. There are no available data on ATROPINEpine 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 ATROPINEpine to an infant during lactation.

Clinical Considerations

Minimizing exposure

The elimination half-life of ATROPINEpine is more than doubled in children less than 2 years of age [see Clinical Pharmacology (12.3)]. To minimize potential infant exposure to ATROPINE, a woman may pump and discard her milk for 24 hours after use before resuming to breastfeed her infant.

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.

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 ATROPINEpine 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 ATROPINEpine poisoning.

Central stimulants are not recommended.

Physostigmine, given as an ATROPINEpine 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 ATROPINEpine. 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.

ATROPINEpine is not removed by dialysis.

DESCRIPTION

ATROPINE, USP is a sterile, nonpyrogenic, isotonic, clear solution of ATROPINEpine 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 ATROPINEpine sulfate, 0.4 mg; benzyl alcohol, 9 mg; sodium chloride 9 mg. May contain sulfuric acid for pH adjustment.  pH 3.5 (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.

ATROPINEpine Sulfate, USP is chemically designated lα H, 5α H-Tropan-3-α-ol (±)-tropate (ester), sulfate (2:1) (salt) monohydrate, (C₁₇H₂₃NO₃)₂ · H₂SO₄ · H₂O, colorless crystals or white crystalline powder very soluble in water. It has the following structural formula:

ATROPINEpine, 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.

CLINICAL PHARMACOLOGY

Mechanism of Action

Pharmacodynamics

ATROPINEpine-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. ATROPINEpine 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, ATROPINEpine 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 ATROPINEpine are more probably the result of bronchiolar dilatation.

Accordingly, ATROPINEpine is an unreliable respiratory stimulant and large or repeated doses may depress respiration.

Adequate doses of ATROPINEpine 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. ATROPINEpine 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 ATROPINEpine; in others, the rate is stabilized. Occasionally a large dose may cause atrioventricular (A-V) block and nodal rhythm.

ATROPINEpine in clinical doses counteracts the peripheral dilatation and abrupt decrease in blood pressure produced by choline esters. However, when given by itself, ATROPINEpine 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 (ATROPINEpine flush), and may cause ATROPINEpine “fever” due to suppression of sweat gland activity in infants and small children.

The effects of intravenous ATROPINEpine 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 ATROPINEpine levels following intramuscular administration (0.5 to 4 mg doses) and heart rate are closely overlapped but the time course of the changes in ATROPINEpine levels and behavioral impairment indicates that pharmacokinetics is not the primary rate-limiting mechanism for the central nervous system effect of ATROPINEpine.

Pharmacokinetics

      Absorption

After intramuscular administration, ATROPINEpine is absorbed with peak concentration occurring at 30 min following injection.

Effects of exercise:

Exercise following intramuscular administration of ATROPINEpine significantly increases the absorption of ATROPINEpine due to increased perfusion in the muscle, with an increase in AUC by approximately 20% and Cmax by approximately 80%.

Distribution

ATROPINEpine is distributed throughout the body. ATROPINEpine’s plasma protein binding is about 44% and saturable in the 2 to 20 mcg/mL concentration range.

Elimination

The pharmacokinetics of ATROPINEpine is nonlinear after intravenous administration of 0.5 to 4 mg. ATROPINEpine 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.

Metabolism

The major metabolites of ATROPINEpine are norATROPINEpine, ATROPINEpin-n-oxide, tropine, and tropic acid. The metabolism of ATROPINEpine is inhibited by organophosphate pesticides.

Specific Populations

Pregnant Women

ATROPINEpine readily crosses the placental barrier and enters the fetal circulation, but is not found in amniotic fluid.

Nursing Mother

Traces are found in various secretions, including milk.

Pediatric and Geriatric Patients

The elimination half-life of ATROPINEpine is more than doubled in children under two years, and the elderly (> 65 years old) compared to other age groups.

NONCLINICAL TOXICOLOGY

HOW SUPPLIED/STORAGE AND HANDLING

ATROPINE, USP is a non-pyrogenic, isotonic, clear solution and is supplied as follows:

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. After initial use, store between 20° to 25°C (68° to 77°F) and discard within 24 hours.