EPINEPHRINE

1 INDICATIONS AND USAGE Epinephrine 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 ) • For emergency treatment of allergic reactions (Type 1), including anaphylaxis. ( 1.2 ) • For induction and maintenance of mydriasis during intraocular surgery. ( 1.3 ) 1.1 Hypotension associated with Septic Shock Epinephrine Injection USP, 1 mg/mL is indicated to increase mean arterial blood pressure in adult patients with hypotension associated with septic shock. 1.2 Anaphylaxis Emergency treatment of allergic reactions (Type I), including anaphylaxis, which may result from allergic reactions to insect stings, biting insects, foods, drugs, sera, diagnostic testing substances and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. The signs and symptoms associated with anaphylaxis include flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with hypotension, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, airway swelling, laryngospasm, bronchospasm, pruritus, urticaria or angioedema, swelling of the eyelids, lips, and tongue. 1.3 Induction and Maintenance of Mydriasis during Intraocular Surgery Induction and maintenance of mydriasis during intraocular surgery.

2 DOSAGE AND ADMINISTRATION • Hypotension associated with septic shock ( 2.2 ): o Dilute epinephrine in dextrose solution prior to infusion. o Infuse epinephrine into a large vein. o Titrate 0.05 mcg/kg/min to 2 mcg/kg/min to achieve desired blood pressure. o Wean gradually. • Anaphylaxis ( 2.3 ) : Administer intramuscularly or subcutaneously into anterolateral thigh every 5-10 minutes as needed. o Adults and children over 30 kg (66 lb): 0.3-0.5 mg (0.3-0.5 mL) o Children under 30 kg (66 lb): 0.01 mg/kg (0.01 mL/kg) • Intraocular surgery ( 2.4 ) : o Dilute 1 mL with 100 to 1000 mL of an ophthalmic irrigation fluid, for ophthalmic irrigation or intracameral injection. 2.1 General Considerations 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 any unused portion. 2.2 Hypotension associated with Septic Shock Dilute epinephrine in 5 percent dextrose solution or 5 percent dextrose and sodium chloride solution. These dextrose containing fluids provide protection against significant loss of potency by oxidation. Administration in saline solution alone is not recommended . Whole blood or plasma, if indicated to increase blood volume, should be administered separately. Add 1 mL (1 mg) of epinephrine from its vial to 1,000 mL of a 5 percent dextrose containing solution. Each mL of this dilution contains 1 mcg of epinephrine. Correct blood volume depletion as fully as possible before any vasopressor is administered. When, as an emergency measure, intraaortic pressures must be maintained to prevent cerebral or coronary artery ischemia, epinephrine can be administered before and concurrently with blood volume replacement. Whenever possible, give infusions of epinephrine 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. Occlusive vascular diseases (for example, atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger's disease) are more likely to occur in the lower than in the upper extremity; therefore, avoid the veins of the leg in elderly patients or in those suffering from such disorders. There is potential for gangrene in a lower extremity when infusions of catecholamine are given in an ankle vein. To provide hemodynamic support in septic shock associated hypotension in adult patients, the suggested dosing infusion rate of intravenously administered epinephrine 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. Continuous epinephrine infusion is generally required over several hours or days until the patient's hemodynamic status improves. The duration of perfusion or total cumulative dose cannot be predicted. After hemodynamic stabilization, wean incrementally over time, such as by decreasing doses of epinephrine every 30 minutes over a 12- to 24-hour period. 2.3 Anaphylaxis Inject epinephrine intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. When administering to a child, to minimize the risk of injection related injury, hold the leg firmly in place and limit movement prior to and during an injection. The injection may be repeated every 5 to 10 minutes as necessary. For intramuscular administration, use a needle long enough (at least 1/2 inch to 5/8 inch) to ensure the injection is administered into the muscle. Monitor the patient clinically for the severity of the allergic reaction and potential cardiac effects of the drug, with repeat doses titrated to effect. Do not administer repeated injections at the same site, as the resulting vasoconstriction may cau…

5 WARNINGS AND PRECAUTIONS • Monitor patient for acute severe hypertension. ( 5.1 ) • Avoid extravasation into tissues, which can cause local necrosis. ( 5.2 ) • Do not inject into buttocks, digits, hands, or feet. ( 5.3 ) • Potential for pulmonary edema, which may be fatal. ( 5.4 ) • May constrict renal blood vessels and decrease urine formation. ( 5.5 ) • May induce potentially serious cardiac arrhythmias or aggravate angina pectoris, particularly in patients with underlying heart disease. ( 5.6 ) • Presence of sulfite in this product should not deter use. ( 5.10 ) 5.1 Hypertension When Epinephrine Injection is administered intravenously, titrate the infusion while monitoring vital signs. Invasive arterial blood pressure monitoring and central venous pressure monitoring are recommended. Because of varying response to epinephrine, dangerously high blood pressure may occur [see Drug Interactions ( 7 )] . 5.2 Extravasation and Tissue Necrosis with Intravenous Infusion When Epinephrine Injection is administered intravenously, the infusion site should be checked frequently for free flow. Avoid extravasation of epinephrine into the tissues, to prevent local necrosis. 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 superficial slough. Hence, if blanching occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside. 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. 5.3 Incorrect Locations of Injection for Anaphylaxis When Epinephrine Injection is used for the treatment of anaphylaxis, the most appropriate location for administration is into the anterolateral aspect of the thigh (vastus lateralis muscle) because of its location, size, and available blood flow. Injection into (or near) smaller muscles, such as in the deltoid, is not recommended due to possible differences in absorption associated with this use. Do not administer repeated injections of epinephrine at the same site, as the resulting vasoconstriction may cause tissue necrosis. Do not inject into buttock. Injection into the buttock may not provide effective treatment of anaphylaxis and has been associated with the development of Clostridial infections (gas gangrene). Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower this risk. Do not inject into digits, hands, or feet. Epinephrine is a strong vasoconstrictor. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area and has been associated with tissue necrosis. 5.4 Pulmonary Edema When Epinephrine Injection is administered intravenously, there is risk of pulmonary edema because of the peripheral constriction and cardiac stimulation produced. Treatment of pulmonary edema consists of a rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support. 5.5 Renal Impairment Intravenously administered epinephrine initially may produce constriction of renal blood vessels and decrease urine formation. 5.6 Cardiac Arrhythmias and Ischemia Epinephrine may induce cardiac arrhythmias and angina pectoris in patients, especially patients suffering from coronary artery disease, organic heart disease, cerebrovascular disease, hypertension, or patients…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Drugs antagonizing pressor effects of epinephrine • α-blockers, such as phentolamine • Vasodilators, such as nitrates • Diuretics • Antihypertensives • Ergot alkaloids 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 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 ( 5.6 ) 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 Drugs potentiating hypokalemic effects of epinephrine • Potassium depleting diuretics • Corticosteroids • Theophylline Epinephrine should not be used to counteract circulatory collapse or hypotension caused by phenothiazines, as a reversal of the pressor effects of epinephrine may result in further lowering of blood pressure. Epinephrine may antagonize the neuronal blockade produced by guanethidine resulting in decreased antihypertensive effect and requiring increased dosage of the latter. • Drugs that counter the pressor effects of epinephrine include alpha blockers, vasodilators such as nitrates, diuretics, antihypertensives, and ergot alkaloids. ( 7 ) • Drugs that potentiate the effects of epinephrine include sympathomimetics, beta blockers, tricyclic antidepressants, MAO inhibitors, COMT inhibitors, clonidine, doxapram, oxytocin, levothyroxine sodium, and certain antihistamines. ( 7 ) • Drugs that increase the arrhythmogenic potential of epinephrine include beta blockers, cyclopropane and halogenated hydrocarbon anesthetics, quinidine, antihistamines, exogenous thyroid hormones, diuretics, and cardiac glycosides. Observe for development of cardiac arrhythmias. ( 7 ) • Potassium-depleting drugs, including corticosteroids, diuretics, and theophylline, potentiate the hypokalemic effects of epinephrine. ( 7 )

8.1 Pregnancy Risk Summary Prolonged experience with epinephrine use in pregnant women over several decades, based on published literature, does 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 epinephrine use during labor or delivery (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, embryonic lethality, and delayed skeletal ossification) at doses approximately 2 times the maximum recommended daily intramuscular, subcutaneous, or intravenous dose (see Data ). 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 Disease-associated maternal and/or embryo/fetal risk During pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. The prevalence of anaphylaxis occurring during pregnancy is reported to be approximately 3 cases per 100,000 deliveries. Management of anaphylaxis during pregnancy is similar to management in the general population. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in pregnant and non-pregnant patients. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. 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. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of epinephrine on the fetus. 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 may improve maternal hypotension associated with septic shock and 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 2 to 3 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 …

6 ADVERSE REACTIONS Most common adverse reactions to systemically administered epinephrine are headache; anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; peripheral coldness; nausea/vomiting; and/or respiratory difficulties. Arrhythmias, including fatal ventricular fibrillation, rapid rises in blood pressure producing cerebral hemorrhage, and angina have occurred. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Adverse Reactions associated with Epinephrine Infusion (for Hypotension associated with Septic Shock) The following adverse reactions associated with the infusion of epinephrine were identified in the literature. 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, myocardial ischemia, myocardial infarction, limb ischemia, pulmonary edema Gastrointestinal disorders: Nausea, vomiting General disorders and administrative site conditions: Chest pain, extravasation Metabolic: hypoglycemia, hyperglycemia, insulin resistance, hypokalemia, lactic acidosis Nervous system disorders: Headache, nervousness, paresthesia, tremor, stroke, central nervous system bleeding Psychiatric disorders: Excitability Renal disorders: Renal insufficiency Respiratory: Pulmonary edema, rales Skin and subcutaneous tissue disorders: Diaphoresis, pallor, piloerection, skin blanching, skin necrosis with extravasation 6.2 Adverse Reactions associated with Intramuscular or Subcutaneous Use (for Anaphylaxis) Common adverse reactions to systemically administered epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with heart disease, hypertension, or hyperthyroidism [see Warnings and Precautions ( 5.9 )]. Due to the lack of randomized, controlled clinical trials of epinephrine for the treatment of anaphylaxis, the true incidence of adverse reactions associated with the systemic use of epinephrine is difficult to determine. Adverse reactions reported in observational trials, case reports, and studies are listed below by body system: Cardiovascular [see Warnings and Precautions ( 5.6 )] : angina, arrhythmias, hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, and ventricular ectopy. Angina may occur in patients with coronary artery disease. Arrhythmias, including fatal ventricular fibrillation, have occurred, particularly in patients with underlying organic heart disease or patients receiving drugs that sensitize the heart to arrhythmias. Rapid rises in blood pressure associated with epinephrine use have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease. Respiratory: respiratory difficulties. Neurological: dizziness, disorientation, excitability, headache, impaired memory, lightheadedness, nervousness, panic, psychomotor agitation, sleepiness, tingling, tremor, and weakness. Psychiatric: anxiety, apprehensiveness, restlessness. Gastrointestinal: nausea, vomiting. Skin: sweating. Other: Patients with Parkinson's disease may experience psychomotor agitation or a temporary worsening of symptoms [see Warnings and Precautions ( 5.9 )]. Diabetic patients may experience transient increases in blood sugar [see Warnings and Precautions ( 5.9 )]. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [see Warnings and Precautions ( 5.3 )]. Adverse events experienced as a result of an injection into …