ISOPROTERENOL HYDROCHLORIDE

Isoproterenol hydrochloride is 3,4-Dihydroxy-α-[(isopropylamino)methyl] benzyl alcohol hydrochloride, a synthetic sympathomimetic amine that is structurally related to epinephrine but acts almost exclusively on beta receptors. The molecular formula is C 11 H 17 NO 3 • HCl. It has a molecular weight of 247.72 and the following structural formula: Isoproterenol hydrochloride is a racemic compound. Each milliliter of the sterile solution contains: Isoproterenol hydrochloride 0.2 mg Edetate Disodium Dihydrate (EDTA) 0.22 mg Sodium Citrate, Dihydrate 2.07 mg Citric Acid, Anhydrous 2.5 mg Sodium Chloride 7 mg Water for Injection qs to 1 mL The pH is adjusted between 3.5 and 4.5 with hydrochloric acid or sodium hydroxide. The sterile solution is nonpyrogenic and can be administered by the intravenous route. isoproterenol-spl-structure

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 )

• 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 Intravenouos injection Dilute 1 mL (0.2 mg) to 10 mL with Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP 10 mcg to 20 mcg (0.5 mL to 1 mL of diluted solution) The initial dose may be 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.

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 )

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 Gland Pharma at (609)-250‐7990 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 )