INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Isoproterenol Hydrochloride Injection, USP is indicated:o To improve hemodynamic status in patients in distributive shock and shock due to reduced cardiac outputo For bronchospasm occurring during anesthesia. Isoproterenol Hydrochloride Injection, USP is beta-adrenergic agonist indicated:o To improve hemodynamic status in patients in distributive shock and shock due to reduced cardiac output (1)o For treatment of bronchospasm occurring during anesthesia (1).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies in animals to evaluate the carcinogenic potential of isoproterenol hydrochloride have not been done. Mutagenic potential and effect on fertility have not been determined. There is no evidence from human experience that isoproterenol hydrochloride injection may be carcinogenic or mutagenic or that it impairs fertility.

OVERDOSAGE SECTION.

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 patients condition stabilizes. Monitor blood pressure, pulse, respiration, and EKG. It is not known whether isoproterenol hydrochloride is dialyzable.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPLE DISPLAY PANEL: Vial Label (1 mL). NDC 0548-9501-00 Rx onlyIsoproterenol HClInjection, USP0.2 mg/mLIntravenous, Subcutaneous,Intramuscular orIntracardiac Use Only. mL single-dose vialProtectFrom LightAMPHASTARPHARMACEUTICALS, INC.Rancho Cucamonga, CA91730 U.S.A.7395016C/6-17. vial-label-1ml.

SPL UNCLASSIFIED SECTION.

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 precipitate. Discard any unused portion.Diluted solution should be used immediately. Unused material should be discarded.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryProlonged experience with isoproterenol use in pregnant women over several decades, based on published literature, do not identify 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 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 ConsiderationsHypotension associated with shock is 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 DeliveryIsoproterenol 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 SummaryThere 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 ug/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, USP 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. o Cardiac arrhythmias and ischemia may be induced by Isoproterenol Hydrochloride Injection, USP (5.1). 5.1 Cardiac Arrhythmias and Ischemia. Isoproterenol may induce cardiac arrhythmias and myocardial ischemia in patients, especially patients with coronary artery disease, or cardiomyopathy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. NDC NumberContainer ConcentrationFillQuantity 0548-9501-00 Single-dose vial 0.2 mg/mL mL10 1 mL Single-DoseVials 0548-9502-00 Single-dose vial mg/5 mL(0.2 mg/mL) mL10 5 mL Single-DoseVialsProtect from light. Keep in opaque container until used.Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Do not use if the injection is pinkish or darker than slightly yellow or contains precipitate.Discard unused portion.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions have been associated with use of isoproterenol. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to estimate their frequency reliably or to establish causal relationship to drug exposure.Nervous system disorders: Nervousness, headache, dizziness, visual blurringCardiovascular: Tachycardia, tachyarrhythmias, palpitations, angina, ventricular arrhythmias, Adams-Stokes attacks, pulmonary edemaRespiratory: DyspneaOther: 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 Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Isoproterenol is potent nonselective beta-adrenergic agonist with very low affinity for alpha-adrenergic receptors.. 12.2 Pharmacodynamics. Intravenous infusion of isoproterenol in man lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds. Diastolic pressure falls. Renal blood flow is decreased in normotensive subjects but is increased markedly in shock. Systolic blood pressure may remain unchanged or rise, although mean arterial pressure typically falls. Cardiac output is increased because of the positive inotropic and chronotropic effects of the drug in the face of diminished peripheral vascular resistance.Isoproterenol relaxes almost all varieties of smooth muscle when the tone is high, but this action is most pronounced on bronchial and gastrointestinal smooth muscle. It prevents or relieves bronchoconstriction, but tolerance to this effect develops with overuse of the drug.In man, isoproterenol causes less hyperglycemia than does epinephrine. Isoproterenol and epinephrine are equally effective in stimulating the release of free fatty acids and energy production.. 12.3 Pharmacokinetics. AbsorptionIsoproterenol is readily absorbed when given parenterally or as an aerosol.EliminationIsoproterenol is metabolized primarily in the liver and other tissues by COMT. Isoproterenol is relatively poor substrate for MAO and is not taken up by sympathetic neurons to the same extent as are epinephrine and norepinephrine. The duration of action of isoproterenol may therefore be longer than that of epinephrine but is still brief.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Isoproterenol Hydrochloride Injection, USP is contraindicated in patients with:o tachycardiao ventricular arrhythmiaso angina pectoris. Isoproterenol Hydrochloride Injection, USP is contraindicated in patients with:o Tachycardia (4)o Ventricular arrhythmias (4)o Angina pectoris (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Isoproterenol hydrochloride is 3,4-Dihydroxy--[(isopropylamino)methyl] benzyl alcohol hydrochloride, beta-adrenergic agonist and synthetic sympathomimetic amine that is structurally related to epinephrine. The molecular formula is C11H17NO3 HCl. It has molecular weight of 247.72 and the following structural formula:Isoproterenol hydrochloride is racemic compound. Each milliliter of the sterile solution contains: Isoproterenol hydrochloride, USP 0.2 mg Edetate Disodium (EDTA) 0.2 mg Sodium Citrate Dihydrate 2.07 mg Citric Acid, Anhydrous 2.5 mg Sodium Chloride 7.0 mg Water for Injection qs 1.0 mLThe pH is adjusted between 2.5 and 4.5 with hydrochloric acid and/or sodium hydroxide.The sterile solution is nonpyrogenic and can be administered by the intravenous route.. structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Initiate Isoproterenol Hydrochloride Injection, USP at the lowest recommended dose and increase gradually based on patient response (2.2)Recommended initial dosage:o Shock: 0.5 mcg to mcg per minute as an intravenous infusion (2.2)o 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 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 AdministrationPreparation of Dilution+Infusion Rate++ Intravenous infusionDilute mL (1 mg) in 500mL of 5% Dextrose Injection,USP0.5 mcg to mcg perminute (0.25 mL to 2.5 mLof 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 ofAdministrationPreparation ofDilution Initial Dose Subsequent DoseBolus intravenousinjectionDilute mL (0.2mg) to 10 mL withSodium ChlorideInjection, USP,or 5% DextroseInjection, USP10 mcg to 20 mcg(0.5 mL to mL ofdiluted solution)The initial dosemay be repeatedwhen necessaryThere 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 mcg/kg/min.

DOSAGE FORMS & STRENGTHS SECTION.

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

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table 1. Clinically Relevant Interactions with Isoproterenol EpinephrineClinical Impact Both drugs are direct cardiac stimulants, and their combined effects may induce serious arrhythmias upon simultaneous administration.InterventionIsoproterenol hydrochloride injection and epinephrine should not be administered simultaneously.Drugs that may potentiate clinical response of Isoproterenol Clinical ImpactThe effects of isoproterenol may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine.InterventionMonitor 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 ImpactThe cardiostimulating and bronchodilating effects of isoproterenol are antagonized by beta-adrenergic blocking drugs, such as propranolol.InterventionMonitor 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)o Concomitant use of tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium and certain antihistamines; hemodynamic parameters may potentiate clinical response of isoproterenol (7)o Beta-adrenergic blocking drugs may reduce cardiostimulating and bronchodilating effects of isoproterenol (7)See 17 for PATIENT COUNSELING INFORMATION.