Isoproterenol Hydrochloride

1 INDICATIONS AND USAGE Isoproterenol hydrochloride injection is indicated: To improve hemodynamic status in patients in distributive shock and shock due to reduced cardiac output For bronchospasm occurring during anesthesia Isoproterenol hydrochloride injection is a beta-adrenergic agonist indicated: To improve hemodynamic status in patients in distributive shock and shock due to reduced cardiac output ( 1 ) For treatment of bronchospasm occurring during anesthesia ( 1 )

2 DOSAGE AND ADMINISTRATION Initiate isoproterenol hydrochloride injection at the lowest recommended dose and increase gradually based on patient response ( 2.2 ) Recommended initial dosage: Shock: 0.5 mcg to 5 mcg per minute as an intravenous infusion (2.2 ) Bronchospasm: 10 mcg to 20 mcg intravenous injection ( 2.2 ) 2.1 General Considerations Inspect visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the injection is pinkish or darker than slightly yellow or contains a precipitate. Discard any unused portion. Diluted solution should be used immediately. Unused material should be discarded. 2.2 Recommended Dosage Dosage should generally be started at the lowest recommended dose and increased gradually based on patient response. Recommended dosage for adults with shock and hypoperfusion states: Route of Administration Preparation of Dilution† Infusion Rate†† Intravenous infusion Dilute 5 mL (1 mg) in 500 mL of 5% Dextrose Injection, USP 0.5 mcg to 5 mcg per minute (0.25 mL to 2.5 mL of diluted solution) †Concentrations up to 10 times greater have been used when limitation of volume is essential. ††Rates over 30 mcg per minute have been used in advanced stages of shock. Adjust the rate of infusion based on heart rate, central venous pressure, systemic blood pressure, and urine flow. If the heart rate exceeds 110 beats per minute, consider decreasing or temporarily discontinuing the infusion. Recommended dosage for adults with bronchospasm occurring during anesthesia: Route of Administration Preparation of Dilution Initial Dose Subsequent Dose Bolus Dilute 1 mL (0.2 mg) to 10 mL with 10 mcg to 20 mcg (0.5 The initial dose may be intravenous injection Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP mL to 1 mL of diluted solution) repeated when necessary There are no well-controlled studies in children to establish appropriate dosing; however, the American Heart Association recommends an initial infusion rate of 0.1 mcg/kg/min, with the usual range being 0.1 mcg/kg/min to 1 mcg/kg/min.

4 CONTRAINDICATIONS Isoproterenol hydrochloride injection is contraindicated in patients with: tachycardia ventricular arrhythmias angina pectoris Isoproterenol hydrochloride injection is contraindicated in patients with: Tachycardia ( 4 ) Ventricular arrhythmias ( 4 ) Angina pectoris ( 4 )

5 WARNINGS AND PRECAUTIONS Cardiac arrhythmias and ischemia may be induced by isoproterenol hydrochloride injection ( 5.1 ) Sulfite: Isoproterenol hydrochloride injection contains metabisulfite, which may cause allergic reaction ( 5.2 ) 5.1 Cardiac Arrhythmias and Ischemia Isoproterenol may induce cardiac arrhythmias and myocardial ischemia in patients, especially patients with coronary artery disease, or cardiomyopathy. 5.2 Allergic Reactions associated with Sulfite Isoproterenol hydrochloride injection contains sodium metabisulfite, which may cause mild to severe allergic reactions including anaphylaxis or asthmatic episodes, particularly in patients with a history of allergies. However, the presence of metabisulfite in this product should not preclude its use for treatment in emergency situations, even if the patient is sulfite-sensitive, as the alternatives to using isoproterenol in a life-threatening situation may not be satisfactory.

7 DRUG INTERACTIONS Table 1. Clinically Relevant Interactions with Isoproterenol Epinephrine Clinical Impact Both drugs are direct cardiac stimulants, and their combined effects may induce serious arrhythmias upon simultaneous administration. Intervention Isoproterenol hydrochloride injection and epinephrine should not be administered simultaneously. Drugs that may potentiate clinical response of Isoproterenol Clinical Impact The effects of isoproterenol may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine. Intervention Monitor hemodynamic parameters in patients who concurrently are taking tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium and certain antihistamines. Adjust doses appropriately. Drugs that may reduce clinical response of Isoproterenol Clinical Impact The cardiostimulating and bronchodilating effects of isoproterenol are antagonized by beta-adrenergic blocking drugs, such as propranolol. Intervention Monitor for hemodynamic response and relief of bronchospasm and adjust dose appropriately. Do not administer isoproterenol hydrochloride injection and epinephrine simultaneously due to combined effects may induce serious arrhythmias ( 7 ) Concomitant use of tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium and certain antihistamines; hemodynamic parameters may potentiate a clinical response of isoproterenol ( 7 ) Beta-adrenergic blocking drugs may reduce cardiostimulating and bronchodilating effects of isoproterenol ( 7 ) See 17 for PATIENT COUNSELING INFORMATION.

6 ADVERSE REACTIONS The following adverse reactions have been associated with use of isoproterenol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Nervous system disorders: Nervousness, headache, dizziness, visual blurring Cardiovascular: Tachycardia, tachyarrhythmias, palpitations, angina, ventricular arrhythmias, Adams-Stokes attacks, pulmonary edema Respiratory: Dyspnea Other: Flushing of the skin, sweating, mild tremors, pallor, nausea Common adverse reactions with isoproterenol include tachycardia and palpitations ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary Prolonged experience with isoproterenol use in pregnant women over several decades, based on published literature, do not identify a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. However, there are risks to the mother and fetus associated with isoproterenol use during labor or delivery (see Clinical Considerations). 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 United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Hypotension associated with shock is a medical emergency in pregnancy which can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with shock may increase the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of isoproterenol on the fetus. Labor and Delivery Isoproterenol usually inhibits spontaneous or oxytocin induced contractions of the pregnant human uterus and may delay the second stage of labor. Avoid isoproterenol during the second stage of labor. Avoid isoproterenol in obstetrics when maternal blood pressure exceeds 130/80 mmHg. Although isoproterenol may improve maternal hypotension associated with shock, it may result in uterine vasoconstriction, decreased uterine blood flow, uterine atony with hemorrhage, and fetal anoxia.