Epinephrine 0.3 Adults

1 INDICATIONS AND USAGE Epinephrine injection, USP auto-injectors are 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. Epinephrine injection, USP auto-injectors are 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. Epinephrine injection, USP auto-injectors are intended for immediate administration as emergency supportive therapy only and are not a substitute for immediate medical care. Epinephrine injection, USP auto-injector is a non-selective alpha and beta-adrenergic receptor agonist indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis. ( 1 )

2 DOSAGE AND ADMINISTRATION Patients greater than or equal to 30 kg (66 lbs): epinephrine injection, USP auto-injector , 0.3 mg ( 2 ) Patients 15 to 30 kg (33 lbs to 66 lbs): epinephrine injection, USP auto-injector, 0.15 mg ( 2 ) Inject intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Each device is a single-dose injection. ( 2 ) 2.1 Recommended Dosage According to Patient Body Weight Patients greater than or equal to 30 kg (approximately 66 pounds or more): epinephrine injection, USP auto-injector, 0.3 mg Patients 15 kg to 30 kg (33 pounds to 66 pounds): epinephrine injection, USP auto-injector, 0.15 mg 2.2 Administration Instructions Inject the single-dose epinephrine injection, USP auto-injector 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 [see Warnings and Precautions (5.2) ]. Instruct caregivers of young children who are prescribed an epinephrine injection, USP auto-injector and who may be uncooperative and kick or move during an injection to hold the leg firmly in place and limit movement prior to and during an injection [see Warnings and Precautions (5.2) ] . Each epinephrine injection, USP auto-injector is a single-dose epinephrine injection for single use. Since the doses of epinephrine delivered from epinephrine injection, USP auto-injector are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary. With severe persistent anaphylaxis, repeat injections with an additional epinephrine injection, USP auto-injector may be necessary. More than two sequential doses of epinephrine should only be administered under direct medical supervision [see Warnings and Precautions (5.1) ] . The epinephrine solution in the clear window of the additional epinephrine injection, USP auto-injector should be inspected visually for particulate matter and discoloration. Discarding After Use: The epinephrine injection, USP contains 2 mL epinephrine solution. Approximately 1.7 mL remains in the auto-injector after activation, but is not available for future use, and should be discarded .

3 DOSAGE FORMS AND STRENGTHS Injection: 0.3 mg (0.3 mg/0.3 mL) of clear and colorless solution in single-dose pre-filled auto-injector Injection: 0.15 mg (0.15 mg/0.15 mL) of clear and colorless solution in single-dose pre-filled auto-injector Injection: 0.3 mg (0.3 mg/0.3 mL) single-dose pre-filled auto-injector ( 3 ) Injection: 0.15 mg (0.15 mg/0.15 mL) single-dose pre-filled auto-injector ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS 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. 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) ]. Cardiovascular Reactions 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) ] . Angina may occur in patients with coronary artery disease [see Warnings and Precautions (5.5) ] . Rare cases of stress cardiomyopathy have been reported in patients treated with epinephrine. Reactions from Accidental Injection and/or Improper Technique Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [see Warnings and Precautions (5.2) ] . Adverse reactions 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. Lacerations, bent needles, and embedded needles have been reported when epinephrine injection, USP auto-injector has been injected into the thigh of young children who are uncooperative and kick or move during the injection [see Warning and Precautions (5.2) ] . Injection into the buttock has resulted in cases of gas gangrene [see Warnings and Precautions (5.2) ]. Skin and Soft Tissue Infections Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported following epinephrine injection, including epinephrine injection, USP auto-injector, in the thigh [see Warnings and Precautions (5.3) ] . Adverse reactions to epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and/or respiratory difficulties. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Cardiac Glycosides, Diuretics, and Anti-arrhythmics Patients who receive epinephrine while concomitantly taking cardiac glycosides, diuretics, or anti-arrhythmics should be observed carefully for the development of cardiac arrhythmias [see Warnings and Precautions (5.5)] . Antidepressants, Monoamine Oxidase Inhibitors, Levothyroxine, and Antihistamines The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine. Beta-Adrenergic Blockers The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta- adrenergic blocking drugs, such as propranolol. Alpha-Adrenergic Blockers The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha-adrenergic blocking drugs, such as phentolamine. Ergot Alkaloids Ergot alkaloids may also reverse the pressor effects of epinephrine. Cardiac glycosides or diuretics: observe for development of cardiac arrhythmias. ( 7 ) Tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines: potentiate effects of epinephrine. ( 7 ) Beta-adrenergic blocking drugs: antagonize cardiostimulating and bronchodilating effects of epinephrine. ( 7 ) Alpha-adrenergic blocking drugs: antagonize vasoconstricting and hypertensive effects of epinephrine. ( 7 ) Ergot alkaloids: may reverse the pressor effects of epinephrine. ( 7 )

8 USE IN SPECIFIC POPULATIONS Elderly patients may be at greater risk of developing adverse reactions. ( 5.5 , 8.5 ) 8.1 Pregnancy Risk Summary There are no available human data on the use of epinephrine injection in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, epinephrine administered by the subcutaneous route to rabbits, mice, and hamsters during the period of organogenesis was teratogenic at doses 7 times and higher than the maximum recommended daily subcutaneous or intramuscular dose on a mg/m 2 basis ( see Data ). Epinephrine is the first-line medication of choice for the treatment of anaphylaxis during pregnancy in humans. Epinephrine should be used for treatment of anaphylaxis during pregnancy in the same manner as it is used in non-pregnant patients. 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 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. Data Animal Data In an embryofetal development study with rabbits dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including gastroschisis and embryonic lethality) at doses approximately 40 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 1.2 mg/kg/day for two to three days). In an embryofetal development study with mice dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including embryonic lethality) at doses approximately 8 times the maximum recommended intramuscular or subcutaneous 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 4 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 hamsters dosed during the period of organogenesis from gestation days 7 to 10, epinephrine was shown to be teratogenic at doses approximately 7 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day). 8.2 Lactation Risk Summary There are no data on the presence of epinephrine in human milk, or the effects of epinephrine on the breastfed infant or on milk production. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in breastfeeding and no-breastfeeding patients. 8.4 Pediatric Use Epinephrine injection may be administered to pediatric patients at a dosage appropriate to body weight [see Dosage and Administration (2.1)] . Clinical experience with the use of epinephrine suggests that the adverse reactions seen in children are similar in nature and extent to those both expected and reported in adults. Since the dose of epinephrine delivered from epinephrine injection is fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary. 8.5 Geriatric Use Clinical studies for the treatment of anaphylaxis have not been performed in subjects aged 65 and o …

12.1 Mechanism of Action Epinephrine acts on both alpha- and beta-adrenergic receptors.

11 DESCRIPTION Epinephrine injection, USP 0.3 mg and 0.15 mg is an auto-injector and a combination product containing drug and device components. Each epinephrine injection, USP 0.3 mg delivers a single dose of 0.3 mg epinephrine from epinephrine injection, USP (0.3 mL) in a sterile solution. Each epinephrine injection, USP 0.15 mg delivers a single dose of 0.15 mg epinephrine from epinephrine injection, USP (0.15 mL) in a sterile solution. Epinephrine injection, USP 0.3 mg and epinephrine injection, USP 0.15 mg each contain 1.1 mL of epinephrine solution. 0.3 mL and 0.15 mL epinephrine solution are dispensed for epinephrine injection, USP 0.3 mg and epinephrine injection, USP 0.15 mg, respectively, when activated. The solution remaining after activation is not available for future use and should be discarded. Each 0.3 mL in epinephrine injection, USP 0.3 mg contains 0.3 mg epinephrine, 2.6 mg sodium chloride, not more than 1.5 mg chlorobutanol, 0.45 mg sodium bisulfite, hydrochloric acid and sodium hydroxide to adjust pH, and water for injection. The pH range is 2.2-5.0. Each 0.15 mL in epinephrine injection, USP 0.15 mg contains 0.15 mg epinephrine, 1.3 mg sodium chloride, not more than 0.75 mg chlorobutanol, 0.225 mg sodium bisulfite, hydrochloric acid and sodium hydroxide 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. Replace epinephrine injection, USP if the epinephrine solution appears discolored (pinkish or brown color), cloudy, or contains particles. Thoroughly review the patient instructions and operation of epinephrine injection, USP with patients and caregivers prior to use [see Patient Counseling Information ( 17 ) ]. Chemical 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. Treatment consists of a rapidly acting vasodilators or alpha-adrenergic blocking drugs and/or respiratory support. Epinephrine overdosage can 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. Treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug such as propranolol. Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis, and kidney failure. Suitable corrective measures must be taken in such situations.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Epinephrine Injection, USP Auto-Injectors, 0.3 mg 2-Pak is supplied with 2 single-dose pre-filled auto-injectors and 1 auto-injector trainer device: 0.3 mg/0.3 mL (NDC 49502-102-02) Epinephrine Injection, USP Auto-Injectors, 0.15 mg 2-Pak is supplied with 2 single-dose pre-filled auto-injectors and 1 auto-injector trainer device: 0.15 mg/0.3 mL (NDC 49502-101-02) Epinephrine Injection, USP Auto-Injectors also include an S-clip to clip two carrier tubes together. Storage and Handling Protect from light. Epinephrine is light sensitive and should be stored in the carrier tube provided to protect it from light. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F 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 (pinkish or brown color), cloudy, or contains particle. Properly dispose all used, unwanted or expired epinephrine injection, USP auto-injectors.