Isoproterenol Hydrochloride

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 )

• Injection solution: single dose, clear glass vial containing isoproterenol in a clear, colorless solution;
• 5 mL containing 1 mg/5 mL (0.2 mg/mL) DOSAGE FORMS AND STRENGTHS Injection: 1 mg/5 mL (0.2 mg/mL) single dose vial ( 3 )

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 )

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.

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 ADVERSE REACTIONS Common adverse reactions with isoproterenol include tachycardia and palpitations ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact KVK-Tech Inc at 1-800-862-3895 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. DRUG INTERACTIONS

• 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 )

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 2-4% and 15-20%, 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 0.05‑2.7 µg/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.

Isoproterenol is a potent nonselective beta-adrenergic agonist with very low affinity for alpha‑adrenergic receptors.