EPINEPHRINE

1 INDICATIONS AND USAGE Epinephrine is a non-selective alpha and beta adrenergic agonist indicated: • For emergency treatment of allergic reactions (Type 1), including anaphylaxis, in adults and pediatric patients. ( 1.1 ) • To increase mean arterial blood pressure in adult patients with hypotension associated with septic shock. ( 1.2 ) 1.1 Anaphylaxis Epinephrine Injection is indicated for emergency treatment of type I allergic reactions, including anaphylaxis, in adults and pediatric patients. 1.2 Hypotension associated with Septic Shock Epinephrine Injection is indicated to increase mean arterial blood pressure in adult patients with hypotension associated with septic shock.

2 DOSAGE AND ADMINISTRATION • Anaphylaxis ( 2.2 ) : • Administer intramuscularly or subcutaneously into anterolateral thigh every 5 to10 minutes as needed. • Adults and pediatric patients 30 kg or greater: 0.3 mg to 0.5 mg (0.3 mL to 0.5 mL) • Pediatric patients under 30 kg: 0.01 mg/kg (0.01 mL/kg) • Hypotension associated with septic shock ( 2.3 ): • Dilute epinephrine in dextrose solution prior to infusion. • Infuse epinephrine into a large vein. • Titrate 0.05 mcg/kg/min to 2 mcg/kg/min to achieve desired blood pressure. • Wean gradually. 2.1 General Considerations Inspect visually for particulate matter and discoloration prior to administration, solution should be clear and colorless. Do not use if the solution is colored or cloudy, or if it contains particulate matter. 2.2 Recommended Dosage and Administration Instructions for Anaphylaxis The recommended dosage of Epinephrine Injection is based on weight and is provided in Table 1 . Administer undiluted Epinephrine Injection intramuscularly or subcutaneously in the anterolateral aspect of the thigh. Table 1 Recommended Dosage of Epinephrine Injection in Adult and Pediatric Patients for Anaphylaxis Dosage Maximum Dosage Adult and Pediatric Patients Weighing 30 kg or Greater 0.3 mg to 0.5 mg (0.3 mL to 0.5 mL) of undiluted Epinephrine Injection 0.5 mg (0.5 mL) per injection Pediatric Patients Weighing Less Than 30 kg 0.01 mg/kg (0.01 mL/kg) of undiluted Epinephrine Injection 0.3 mg (0.3 mL) per injection • In the absence of clinical improvement or if symptoms worsen after the initial treatment, additional doses of Epinephrine Injection may be repeated every 5 to 10 minutes as necessary. • Monitor clinically for cardiac effects. Administration Instructions • 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. • To minimize the risk of injection related injury to a pediatric patient, hold the leg firmly in place and limit movement prior to and during an injection. • Inject Epinephrine Injection intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Do not inject intravenously, and do not inject into buttocks, into digits, hands or feet. • Do not administer repeated injections at the same site, as the resulting vasoconstriction may cause tissue necrosis. 2.3 Recommended Dosage and Administration Instructions for Hypotension associated with Septic Shock Dilute 1 mL (1 mg) of epinephrine from its vial into 1,000 mL of one of the following solutions: 5% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; or 5% Dextrose and 0.2% Sodium Chloride Injection. Each mL of this dilution contains 1 mcg of epinephrine. The diluted solutions can be stored for up to 4 hours at room temperature (20°C to 25°C) or 24 hours under refrigerated conditions (2°C to 8°C). Administration in Sodium Chloride Injection alone is not recommended. If indicated, administer whole blood or plasma separately. 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. Avoid the veins of the leg in elderly patients or in those suffering from occlusive vascular disorders. 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 to15 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 h…

5 WARNINGS AND PRECAUTIONS • Do not inject into buttocks, digits, hands, or feet. ( 5.1 ) • Avoid extravasation into tissues, which can cause local necrosis. ( 5.3 ) • Monitor patient for acute severe hypertension. ( 5.4 ) • Potential for pulmonary edema, which may be fatal. ( 5.5 ) • May constrict renal blood vessels and decrease urine formation. ( 5.6 ) • May induce potentially serious cardiac arrhythmias or aggravate angina • pectoris, particularly in patients with underlying heart disease. ( 5.7 ) • Presence of sulfite in this product should not deter use. ( 5.8 ) 5.1 Injection-Related Complications for Anaphylaxis Injection into the anterolateral aspect of the thigh (vastus lateralis muscle) is the most appropriate location for administration because of its location, size, and available blood flow. Injection into (or near) smaller muscles, such as in the deltoid, is not recommended. Do not administer repeated injections of epinephrine at the same site, as the resulting vasoconstriction may cause tissue necrosis. Do Not Inject Intravenously Large doses or accidental intravenous injection of undiluted epinephrine may result in cerebral hemorrhage due to sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration. 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). 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 tissue necrosis. 5.2 Serious Infections at the Injection Site Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site following epinephrine injection for anaphylaxis. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the epinephrine injection site. 5.3 Extravasation and Tissue Necrosis with Intravenous Infusion Avoid extravasation of epinephrine into the tissues, to prevent local necrosis. When Epinephrine Injection is administered intravenously, the infusion site should be checked 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 superficial slough. Hence, if blanching occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside. There is a 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. 5.4 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. 5.5 Pulmonary Edema Epinephrine increases cardiac output and causes peripheral vas…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS • Drugs that counter the pressor effects of epinephrine include alpha blockers, vasodilators such as nitrates, diuretics, antihypertensives, and ergot alkaloids, phenothiazine antipsychotics. ( 7.1 ) • Drugs that potentiate the effects of epinephrine include sympathomimetics, beta blockers, tricyclic antidepressants, MAO inhibitors, COMT inhibitors, clonidine, doxapram, oxytocin. ( 7.2 ) • 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. ( 7.3 ) • Potassium-depleting drugs, including corticosteroids, diuretics, and theophylline, potentiate the hypokalemic effects of epinephrine. ( 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 Cardiac arrhythmias are more common among patients receiving any of the following drugs [see Warnings and Precautions ( 5.7 ) 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, does 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 anaphylaxis and 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, 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. Treatment of anaphylaxis during pregnancy should not be delayed. 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 is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner for patients in labor or delivery. Hypotension Associated with Septic Shock 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, 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 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…

6 ADVERSE REACTIONS The following adverse reactions associated with the use of epinephrine were identified in clinical use, observational trials, case reports, or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are listed below by body system: Cardiovascular : angina, arrhythmias, cerebral hemorrhage (particularly in elderly patients with cardiovascular disease), hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, ventricular ectopy and stress cardiomyopathy. Gastrointestinal: nausea, vomiting Metabolism and Nutrition Disorders: transient hyperglycemia, sweating Neurological : disorientation, dizziness, headache, impaired memory, panic, psychomotor agitation (particularly in patients with Parkinson's disease), sleepiness, tingling, tremor, weakness. Psychiatric : anxiety, apprehensiveness, restlessness. Respiratory: respiratory difficulties Skin and subcutaneous tissue disorders: skin and soft tissue infections, necrotizing fasciitis, myonecrosis (gas gangrene) 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 ) 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