epinephrine

1 INDICATIONS AND USAGE Epinephrine in 0.9% Sodium Chloride Injection is a non-selective alpha- and beta-adrenergic agonist indicated to increase mean arterial blood pressure in adult patients with hypotension associated with septic shock. ( 1.1 ) 1.1 Hypotension associated with Septic Shock Epinephrine in 0.9% Sodium Chloride Injection is indicated to increase mean arterial blood pressure in adult patients with hypotension associated with septic shock.

2 DOSAGE AND ADMINISTRATION Hypotension associated with septic shock : • Infuse Epinephrine in 0.9% Sodium Chloride Injection into a large vein. ( 2.2 ) • Intravenous infusion rate of 0.05 mcg/kg/min to 2 mcg/kg/min, titrated to achieve desired mean arterial pressure. ( 2.2 ) • Wean gradually. ( 2.2 ) 2.1 General Considerations Epinephrine in 0.9% Sodium Chloride Injection is a ready to administer product that requires no further dilution prior to infusion. Inspect visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is colored or cloudy, or if it contains particulate matter. Discard all unused drug. 2.2 Hypotension associated with Septic Shock Whenever possible, give infusions of Epinephrine in 0.9% Sodium Chloride Injection into a large vein. Avoid using a catheter tie-in technique, because the obstruction to blood flow around the tubing may cause stasis and increased local concentration of the drug. Avoid the veins of the leg in elderly patients or in those suffering from occlusive vascular diseases. To provide hemodynamic support in septic shock associated hypotension in adult patients, the suggested dosing infusion rate of intravenously administered Epinephrine in 0.9% Sodium Chloride Injection is 0.05 mcg/kg/min to 2 mcg/kg/min and is titrated to achieve a desired mean arterial pressure (MAP). The dosage may be adjusted periodically, such as every 10 to 15 minutes, in increments of 0.05 mcg/kg/min to 0.2 mcg/kg/min, to achieve the desired blood pressure goal. The ideal body weight (IBW) should be used as the weight parameter for dosing epinephrine in adult patients with septic shock associated hypotension. After hemodynamic stabilization, wean incrementally over time, such as by decreasing doses of Epinephrine in 0.9% Sodium Chloride Injection every 30 minutes over a 12 to 24 hour period.

5 WARNINGS AND PRECAUTIONS • Monitor patient for acute severe hypertension. ( 5.1 ) • Potential for pulmonary edema, which may be fatal. ( 5.2 ) • May induce potentially serious cardiac arrhythmias and myocardial ischemia, particularly in patients with underlying heart disease. ( 5.3 ) • Avoid extravasation into tissues, which can cause local necrosis. ( 5.4 ) • Potential for oliguria or renal impairment. ( 5.5 ) • Presence of sulfite in this product should not deter use for hypotension associated with septic shock ( 5.6 ) 5.1 Hypertension Because individual response to epinephrine may vary significantly, monitor blood pressure frequently and titrate to avoid excessive increases in blood pressure. Patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types may experience severe, prolonged hypertension when given epinephrine. 5.2 Pulmonary Edema Epinephrine increases cardiac output and causes peripheral vasoconstriction, which may result in pulmonary edema. 5.3 Cardiac Arrhythmias and Ischemia Epinephrine may induce cardiac arrhythmias and myocardial ischemia in patients, especially patients with coronary artery disease, or cardiomyopathy [see Adverse Reactions and Drug Interactions (7.3) ] . 5.4 Extravasation and Tissue Necrosis with Intravenous Infusion Avoid extravasation of epinephrine into the tissues, to prevent local necrosis. When Epinephrine in 0.9% Sodium Chloride Injection is administered intravenously, check the infusion site frequently for free flow. Blanching along the course of the infused vein, sometimes without obvious extravasation, may be attributed to vasa vasorum constriction with increased permeability of the vein wall, permitting some leakage. This also may progress on rare occasions to a superficial slough. Hence, if blanching occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside. There is potential for gangrene in a lower extremity when infusions of catecholamine are given in an ankle vein. Antidote for Extravasation Ischemia: To prevent sloughing and necrosis in areas in which extravasation has taken place, infiltrate the area with 10 mL to 15 mL of saline solution containing from 5 mg to 10 mg of phentolamine, an adrenergic blocking agent. Use a syringe with a fine hypodermic needle, with the solution being infiltrated liberally throughout the area, which is easily identified by its cold, hard, and pallid appearance. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours. 5.5 Renal Impairment Epinephrine constricts renal blood vessels, which may result in oliguria or renal impairment. 5.6 Allergic Reactions associated with Sulfite Epinephrine in 0.9% Sodium Chloride 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. The presence of sodium metabisulfite in this product should not preclude its use for the treatment of hypotension associated with septic shock even if the patient is sulfite-sensitive, as the alternatives to using epinephrine in a life-threatening situation may not be satisfactory. In susceptible patients, consider using a formulation of epinephrine or another vasoconstrictor that does not contain sodium metabisulfite.

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS • Drugs that counter the pressor effects of Epinephrine in 0.9% Sodium Chloride Injection include alpha blockers, vasodilators such as nitrates, diuretics, antihypertensives, and ergot alkaloids. ( 7.1 ) • Drugs that potentiate the effects of Epinephrine in 0.9% Sodium Chloride Injection include sympathomimetics, beta blockers, tricyclic antidepressants, MAO inhibitors, COMT inhibitors, clonidine, doxapram, oxytocin, levothyroxine sodium, and certain antihistamines. ( 7.2 ) • Drugs that increase the arrhythmogenic potential of Epinephrine in 0.9% Sodium Chloride Injection include beta blockers, cyclopropane and halogenated hydrocarbon anesthetics, quinidine, antihistamines, exogenous thyroid hormones, diuretics, and cardiac glycosides. Observe for development of cardiac arrhythmias. ( 7.3 ) • Potassium-depleting drugs, including corticosteroids, diuretics, and theophylline, potentiate the hypokalemic effects of Epinephrine in 0.9% Sodium Chloride Injection. ( 7.4 ) 7.1 Drugs Antagonizing Pressor Effects of Epinephrine • α-blockers, such as phentolamine • Vasodilators, such as nitrates • Diuretics • Antihypertensives • Ergot alkaloids • Phenothiazine antipsychotics 7.2 Drugs Potentiating Pressor Effects of Epinephrine • Sympathomimetics • β-blockers, such as propranolol • Tricyclic anti-depressants • Monoamine oxidase (MAO) inhibitors • Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone • Clonidine • Doxapram • Oxytocin 7.3 Drugs Potentiating Arrhythmogenic Effects of Epinephrine Patients who are concomitantly receiving any of the following drugs should be observed carefully for the development of cardiac arrhythmias [see Warnings and Precautions (5.5) and Adverse Reactions (6) ] . • β-blockers, such as propranolol • Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane • Antihistamines • Thyroid hormones • Diuretics • Cardiac glycosides, such as digitalis glycosides • Quinidine 7.4 Drugs Potentiating Hypokalemic Effects of Epinephrine • Potassium depleting diuretics • Corticosteroids • Theophylline

8.1 Pregnancy Risk Summary Prolonged experience with epinephrine 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. There are risks to the mother and fetus associated with hypotension associated with shock, and treatment with epinephrine should not be delayed (see Clinical Considerations ) . In animal reproduction studies, epinephrine administered by the subcutaneous route to pregnant rabbits, mice, and hamsters, during the period of organogenesis, resulted in adverse developmental effects (including gastroschisis, and embryonic lethality, and delayed skeletal ossification) at doses approximately 2 times the maximum recommended daily intravenous dose (see Data ) . All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. 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 Disease-associated maternal and/or embryo/fetal risk Hypotension associated with septic shock is a medical emergency in pregnancy which can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic shock may increase the risk of maternal and fetal morbidity and mortality. Do not withhold life-sustaining therapy for a pregnant woman. Labor or Delivery Epinephrine usually inhibits spontaneous or oxytocin induced contractions of the pregnant human uterus and may delay the second stage of labor. Avoid epinephrine during the second stage of labor. In dosage sufficient to reduce uterine contractions, the drug may cause a prolonged period of uterine atony with hemorrhage. Avoid epinephrine in obstetrics when maternal blood pressure exceeds 130/80 mmHg. Although epinephrine improves maternal hypotension associated with anaphylaxis, it may result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia. Data Animal Data In an embryofetal development study with pregnant rabbits dosed during the period of organogenesis (on days 3 to 5, 6 to 7 or 7 to 9 of gestation), epinephrine caused teratogenic effects (including gastroschisis) at doses approximately 15 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 1.2 mg/kg/day for two to three days). Animals treated on days 6 to 7 had decreased number of implantations. In an embryofetal development study, pregnant mice were administered epinephrine (0.1 to 10 mg/kg/day) on Gestation Days 6 to 15. Teratogenic effects, embryonic lethality, and delays in skeletal ossification were observed at approximately 3 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on a mg/m 2 basis at maternal subcutaneous dose of 1 mg/kg/day for 10 days). These effects were not seen in mice at approximately 2 times the maximum recommended daily intramuscular or subcutaneous dose (on a mg/m 2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days). In an embryofetal development study with pregnant hamsters dosed during the period of organogenesis from gestation days 7 to 10, epinephrine produced reductions in litter size and delayed skeletal ossification at doses approximately 2 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day).

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in labeling: • Hypertension [see Warnings and Precautions (5.1) ] • Pulmonary Edema [see Warnings and Precautions (5.2) ] • Cardiac Arrhythmias and Ischemia [see Warnings and Precautions (5.3) ] • Extravasation and Tissue Necrosis with Intravenous Infusion [see Warnings and Precautions (5.4) ] • Renal Impairment [see Warnings and Precautions (5.5) ] • Allergic Reactions associated with Sulfite [see Warnings and Precautions (5.6) ] The following adverse reactions have been associated with use of epinephrine. 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. Cardiovascular disorders : tachycardia, supraventricular tachycardia, ventricular arrhythmias (including fatal ventricular fibrillation), stress cardiomyopathy, myocardial ischemia, myocardial infarction, limb ischemia, pulmonary edema, hypertension Gastrointestinal disorders : nausea, vomiting Metabolic : insulin resistance, hypokalemia, lactic acidosis Nervous system disorders : headache, paresthesia, tremor, stroke, central nervous system bleeding, weakness, dizziness, disorientation, impaired memory, panic, psychomotor agitation, somnolence Psychiatric disorders : anxiety Skin and subcutaneous tissue disorders : diaphoresis, pallor, piloerection, skin blanching, skin necrosis with extravasation. Most common adverse reactions to systemically administered Epinephrine in 0.9% Sodium Chloride Injection are headache; anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; diaphoresis; nausea/vomiting; and/or respiratory difficulties. Arrhythmias, including fatal ventricular fibrillation, rapid rises in blood pressure producing cerebral hemorrhage, and angina have occurred. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-877-725-2747, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.