EPINEPHRINE

Epinephrine Injection, USP is a clear, colorless, sterile solution containing 1 mg/mL epinephrine, packaged as a 30 mL solution in a multiple dose amber vial. In the 30 mL vial, each 1 mL of Epinephrine Injection, USP solution contains 1 mg epinephrine, 0.5 mg citric acid, 1 mg methylparaben (preservative), 8.6 mg sodium chloride, 0.25 mg sodium metabisulfite, hydrochloric acid for pH adjustment and water for injection. The pH range is 2.2-5.0. Solution must be diluted prior to intravenous use. Epinephrine is a sympathomimetic catecholamine. The chemical name of epinephrine is: 1,2-Benzenediol, 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]-, or (-)-3,4-Dihydroxy-α-[2-(methylamino)ethyl]benzyl alcohol. The chemical structure of epinephrine is: The molecular weight of epinephrine is 183.2. Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin. structural formula

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.

• 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 hypotension. After hemodynamic stabilization, wean incrementally over time, such as by decreasing doses of epinephrine every 30 minutes over a 12 to 24 hour period.

None. None. ( 4 )

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

• 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