epinephrine

1 INDICATIONS & USAGE AUVI-Q® is indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitoes), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. AUVI-Q is intended for immediate administration in patients who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Anaphylactic reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema. AUVI-Q is intended for immediate self-administration as emergency supportive therapy only and is not a substitute for immediate medical care.

2 DOSAGE AND ADMINISTRATION Anaphylaxis : o Adults and Children 30 kg (66 lbs) or more : 0.3 mg to 0.5 mg (0.3 mL to 0.5 mL) intramuscularly or subcutaneously into anterolateral aspect of the thigh every 5 to 10 minutes as necessary ( 2.2 ) o Children 30 kg (66 lbs) or less : 0.01 mg/kg (0.01 mL/kg), up to 0.3 mg (0.3 mL), intramuscularly or subcutaneously into anterolateral aspect of the thigh every 5 to 10 minutes as necessary ( 2.2 ) Hypotension associated with septic shock: o Dilute epinephrine in dextrose solution prior to infusion ( 2.3 ) o Infuse epinephrine into a large vein ( 2.3 ) o Intravenous infusion rate of 0.05 mcg/kg/min to 2 mcg/kg/min, titrated to achieve desired mean arterial pressure ( 2.3 ) o Wean gradually ( 2.3 ) o See Full Prescribing Information for instructions on dilution and administration of the injection. 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 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 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, and repeat as needed. Do not administer repeated injections at the same site, as the resulting vasoconstriction may cause tissue necrosis. Adults and Children 30 kg (66 lbs) or more : 0.3 to 0.5 mg (0.3 to 0.5 mL) of undiluted epinephrine administered intramuscularly or subcutaneously in the anterolateral aspect of the thigh, up to a maximum of 0.5 mg (0.5 mL) per injection, repeated every 5 to 10 minutes as necessary. Monitor clinically for reaction severity and cardiac effects. Children less than 30 kg (66 lbs) : 0.01 mg/kg (0.01 mL/kg) of undiluted epinephrine administered intramuscularly or subcutaneously in the anterolateral aspect of the thigh, up to a maximum of 0.3 mg (0.3 mL) per injection, repeated every 5 to 10 minutes as necessary. Monitor clinically for reaction severity and cardiac effects. 2.3 Hypotension associated with Septic Shock Dilute 1 mL (1 mg) of epinephrine from its ampule to 1,000 mL of a 5% dextrose or 5% dextrose and sodium chloride solution to produce a 1 mcg per mL dilution. Administration in saline solution 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 diseases. To provide hemodynamic support in septic shock associated hypotension in adult patients, the suggested dosing infusion rate of intravenously administered epinephrine is 0.05 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 to 0.2 mcg/kg/min, to achieve the desired blood pressure goal. After hemodynamic stabilization, wean incrementally over time, such as by decreasing doses of epinephrine every 10 minutes to determine if the patient can tolerate gradual withdrawal. Epinephrine diluted in 5% dextrose solutions or 5% dextrose and sodium chloride solutions are stable for 4 hours at room temperature or 24 hours under refrigerated conditions.

3 DOSAGE FORMS AND STRENGTHS Injection: 4 mg Epinephrine in 250 mL 0.9% Sodium Chloride Injection (16 mcg/mL), is a clear, colorless, premixed solution in a ready to use, single-dose VIAFLO container. Injection: 16 mg Epinephrine in 250 mL 0.9% Sodium Chloride Injection (64 mcg/mL), is a clear, colorless, premixed solution in a ready to use, single-dose VIAFLO container. • Injection: 4 mg Epinephrine in 250 mL 0.9% Sodium Chloride Injection (16 mcg/mL), in single-dose VIAFLO container. ( 3 ) • Injection: 16 mg Epinephrine in 250 mL 0.9% Sodium Chloride Injection (64 mcg/mL), in single-dose VIAFLO container. ( 3 )

4 CONTRAINDICATIONS None ( 4 ) None ( 4 )

6 ADVERSE REACTIONS Due to 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. Common adverse reactions to systemically administered epinephrine include anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism [see WARNINGS AND PRECAUTIONS ( 5- 5.5)]. Arrhythmias, including fatal ventricular fibrillation, have been reported, particularly in patients with underlying cardiac disease or those receiving certain drugs [see WARNINGS AND PRECAUTIONS (5.5) and DRUG INTERACTIONS ( 7 )]. Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease [see WARNINGS AND PRECAUTIONS ( 5- 5.5)]. Angina may occur in patients with coronary artery disease [see WARNINGS AND PRECAUTIONS ( 5- 5.5)]. Rare cases of stress cardiomyopathy have been reported in patients treated with epinephrine. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [see WARNINGS AND PRECAUTIONS ( 5- 5.2)]. Adverse events experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury. Injection of epinephrine into the buttock has resulted in cases of gas gangrene [see WARNINGS AND PRECAUTIONS ( 5- 5.2)]. 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 in the thigh [see WARNINGS AND PRECAUTIONS ( 5- 5.2)].

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 USE IN SPECIFIC POPULATIONS Elderly patients and pregnant women may be at greater risk of developing adverse reactions when epinephrine is administered parenterally ( 8.1, 8.5 ) Pregnancy: May cause fetal harm ( 8.1 ) 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. 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, and 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 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, subcutan …

12.1 Mechanism of Action Epinephrine acts on both alpha (α)- and beta (β)-adrenergic receptors. The mechanism of the rise in blood pressure is 3-fold: a direct myocardial stimulation that increases the strength of ventricular contraction (positive inotropic action), an increased heart rate (positive chronotropic action), and peripheral vasoconstriction.

11 DESCRIPTION AUVI-Q (epinephrine injection, USP) 0.3 mg, 0.15 mg and 0.1 mg is an auto-injector and a combination product containing drug and device components. AUVI-Q includes audible (electronic voice instructions, beeps) and visible (LED lights) cues for use. The needle automatically retracts after the injection is complete. Each AUVI-Q 0.3 mg delivers a single dose of 0.3 mg epinephrine from epinephrine injection, USP (0.3 mL) in a sterile solution. Each AUVI-Q 0.15 mg delivers a single dose of 0.15 mg epinephrine from epinephrine injection, USP (0.15 mL) in a sterile solution. Each AUVI-Q 0.1 mg delivers a single dose of 0.1 mg epinephrine from epinephrine injection, USP (0.1 mL) in a sterile solution . AUVI-Q 0.3 mg, AUVI-Q 0.15 mg and AUVI-Q 0.1 mg each contain 0.76 mL epinephrine solution. 0.3 mL, 0.15 mL and 0.1 mL epinephrine solution is dispensed for AUVI-Q 0.3 mg, AUVI-Q 0.15 mg and AUVI-Q 0.1 mg, respectively, when activated. The remaining solution is not available for future use and should be discarded. Each 0.3 mL in AUVI-Q 0.3 mg contains 0.3 mg epinephrine, 2.3 mg sodium chloride, 0.5 mg sodium bisulfite, hydrochloric acid to adjust pH, and water for injection. The pH range is 2.2–5.0. Each 0.15 mL in AUVI-Q 0.15 mg contains 0.15 mg epinephrine, 1.2 mg sodium chloride, 0.2 mg sodium bisulfite, hydrochloric acid to adjust pH, and water for injection. The pH range is 2.2–5.0. Each 0.1 mL in AUVI-Q 0.1 mg contains 0.1 mg epinephrine, 0.78 mg sodium chloride, 0.15 mg sodium bisulfite, hydrochloric acid to adjust pH, and water for injection. The pH range is 2.2–5.0. Epinephrine is a sympathomimetic catecholamine. Chemically, epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl]benzyl alcohol with the following structure: Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin. AUVI-Q is not made with natural rubber latex. AUVI-Q instructional and safety systems should be thoroughly reviewed with patients and caregivers prior to use [see PATIENT COUNSELING INFORMATION 17 (17.1)]. STRUCTURE

10. OVERDOSAGE Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients. Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Epinephrine overdosage may also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Myocardial ischemia and infarction, cardiomyopathy, extreme pallor and coldness of the skin, metabolic acidosis due to elevated blood lactic acid levels, and renal insufficiency and failure have also been reported. Epinephrine is rapidly inactivated in the body and treatment following overdose is primarily supportive. Treatment of pulmonary edema consists of a rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support. Treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug (such as propranolol). If necessary, pressor effects may be counteracted by rapidly acting vasodilators (such as nitrites) or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measures, it may be necessary to administer another pressor drug.

16 HOW SUPPLIED/STORAGE AND HANDLING AUVI-Q(R) EPINEPHRINE INJECTION, USP is supplied in the following dosage forms. NDC 51662-1320-1 AUVI-Q(R) EPINEPHRINE INJECTION, USP 0.3mg AUTO INJECTOR NDC 51662-1320-2 AUVI-Q(R) EPINEPHRINE INJECTION, USP 0.3mg 2PK AUTO INJECTOR NDC 51662-1321-1 AUVI-Q(R) EPINEPHRINE INJECTION, USP 0.15mg AUTO INJECTOR NDC 51662-1321-2 AUVI-Q(R) EPINEPHRINE INJECTION, USP 0.15mg 2PK AUTO INJECTOR HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms 16.1 HOW SUPPLIED Carton containing two AUVI-Q (epinephrine injection, USP) 0.3 mg auto-injectors and a single AUVI-Q Trainer - NDC 60842-023-01 Carton containing two AUVI-Q (epinephrine injection, USP) 0.15 mg auto-injectors and a single AUVI-Q Trainer - NDC 60842-022-01 Carton containing two AUVI-Q (epinephrine injection, USP) 0.1 mg auto-injectors and a single AUVI-Q Trainer - NDC 60842-021-01 Rx only 16.2 STORAGE AND HANDLING Epinephrine is light sensitive and should be stored in the outer case provided to protect it from light. Store at 20°to 25°C (68°to 77°F); excursions permitted to 15°to 30°C (59°to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate. Before using, check to make sure the solution in the auto-injector is clear and colorless. Replace the auto-injector if the solution is discolored, cloudy, or contains particles.