Atropine Sulfate

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

2 DOSAGE AND ADMINISTRATION • Dosage is individualized by use, refer to the full prescribing information for recommended adult and pediatric dosages ( 2.2 , 2.3 ). • Patients with Ischemic Heart Disease: Do not exceed 0.04 mg/kg. ( 2.4 , 5.2 ) 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 Patients Use Initial Dose Continued Treatment Antisialagogue 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 Dose 3 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 Patients Use Initial Dose Continued Treatment Antisialagogue 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 Dose Less than 12 years old:0.5 mg 12 years and older:1 mg Maximum Total Dose Less 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)].

5 WARNINGS AND PRECAUTIONS 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 ) 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.

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Mexiletine : Decreases rate of mexiletine absorption. ( 7.1 ) 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 Summary Limited 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 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 atropine on the fetus. Data Human Data No 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.

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. Most adverse reactions are directly related to atropine’s 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 Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.