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 INDICATIONS AND USAGE 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 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 Concentrations up to 10 times greater have been used when limitation of volume is essential. Infusion Rate 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. 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) Recommended dosage for adults with bronchospasm occurring during anesthesia: Route of Subsequent Administration Preparation of Dilution Initial Dose Dose Bolus intravenous 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.

3 DOSAGE FORMS AND STRENGTHS Injection solution: single dose, clear glass vials containing isoproterenol hydrochloride injection, USP is clear colorless to slightly yellow colored solution, free from visible particles. 1 mL containing 0.2 mg per 1 mL (0.2 mg per mL) 5 mL containing 1 mg per 5 mL (0.2 mg per mL) Injection: 0.2 mg per mL and 1 mg per 5 mL (0.2 mg per mL) single-dose vial ( 3 )

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

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 Lambda Therapeutics Limited at 1-855-642-2594 or email: safety.nexuspharma@lambda-cro.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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, USP 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.

8 USE IN SPECIFIC POPULATIONS 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. 8.2 Lactation Risk Summary There is no information regarding the presence of isoproterenol in milk or the effects of isoproterenol on the breastfed infant or on milk production. However, due to its short half-life, isoproterenol exposure is expected to be very low in the breastfed infant. 8.4 Pediatric Use Safety and efficacy of isoproterenol in pediatric patients have not been established. Intravenous infusions of isoproterenol in refractory asthmatic children at rates of 0.05 to 2.7 mcg/kg/min have caused clinical deterioration, myocardial necrosis, congestive heart failure and death. The risks of cardiac toxicity appear to be increased by some factors [acidosis, hypoxemia, coadministration of corticosteroids, coadministration of methylxanthines (theophylline, theobromine) or aminophylline] that are especially likely to be present in these patients. If I.V. isoproterenol is used in children with refractory asthma, patient monitoring must include continuous assessment of vital signs, frequent electrocardiography, and daily measurements of cardiac enzymes, including CPK-MB. 8.5 Geriatric Use Clinical studies of Isoproterenol Hydrochloride Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects in clinical circumstances. There are, however, some data that suggest that elderly healthy or hypertensive patients are less responsive to beta-adrenergic stimulation than are younger subjects. In general, dose selection for elderly patients 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 diseases or other drug therapy.

12.1 Mechanism of Action Isoproterenol is a potent nonselective beta-adrenergic agonist with very low affinity for alpha-adrenergic receptors.

11 DESCRIPTION Isoproterenol hydrochloride injection, USP 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. Isoproterenol hydrochloride is white to practically white, crystalline powder and 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, USP is a racemic compound. Each milliliter of the sterile solution contains: Isoproterenolhydrochloride,USP (equivalent to Isoproterenol 0.17 mg) 0.2 mg Edetate Disodium (EDTA) 0.2 mg Sodium Citrate Dihydrate 2.07 mg Citric Acid, Anhydrous 2.5 mg Sodium Chloride 7 mg Water for Injection qs 1 mL The pH is adjusted between 2.5 and 4.5 with hydrochloric acid and/or sodium hydroxide. The sterile solution is nonpyrogenic clear, colorless or practically colorless liquid free from visible particles and can be administered by the intravenous route. isoproterenol-str

10. OVERDOSAGE Overdosage of isoproterenol can cause tachycardia or other arrhythmias, palpitations, angina, hypotension, or hypertension. In case of overdosage, reduce the rate of administration or discontinue isoproterenol hydrochloride injection until patient's condition stabilizes. Monitor blood pressure, pulse, respiration, and EKG. It is not known whether isoproterenol hydrochloride is dialyzable.

16 HOW SUPPLIED/STORAGE AND HANDLING Isoproterenol hydrochloride injection, USP 0.2 mg/mL and 1 mg/5 mL is supplied as a sterile, clear, colorless solution free from visible particulate matter in 3 mL and 5 mL single-dose glass vials respectively. NDC Container Concentration Fill Quantity 69918-731-10 Single-Dose Vial 0.2 mg/mL 1 mL Carton of 10 Single-Dose Vials 69918-735-10 Single-Dose Vial 1 mg/5 mL (0.2 mg/mL) 5 mL Carton of 10 Single-Dose Vials Protect from light. Keep in opaque container until used. Store at 20o to 25oC (68o to 77oF) [See USP Controlled Room Temperature]. Do not use if the injection is pinkish or darker than slightly yellow or contains a precipitate. Discard unused portion. Manufactured for: Nordic Pharma, Inc. Berwyn, PA 19312 USA www.nordicpharmausa.com The Nordic Pharma Logo is a trademark of Nordic Group B.V. Manufactured by: Indoco Remedies Limited Verna, Goa, 403722, India Origin India Revised: 04/2024 2011016 Structural Formula