EPIPEN

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 EpiPen 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 EpiPen, 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.

4 CONTRAINDICATIONS None None ( 4 )

11 DESCRIPTION EpiPen (epinephrine injection, USP) 0.3 mg and EpiPen Jr (epinephrine injection, USP) 0.15 mg are single-dose auto-injectors and combination products containing drug and device components. Each EpiPen Auto-Injector, 0.3 mg delivers a single dose of 0.3 mg epinephrine from epinephrine injection, USP 0.3 mg/0.3 mL in a sterile solution. Each EpiPen Jr Auto-Injector, 0.15 mg delivers a single dose of 0.15 mg epinephrine from epinephrine injection, USP 0.15 mg/0.3 mL in a sterile solution. Each 0.3 mL in the EpiPen Auto-Injector contains 0.3 mg epinephrine, 1.8 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid to adjust pH, and Water for Injection. The pH range is 2.2-5.0. Each 0.3 mL in the EpiPen Jr Auto-Injector contains 0.15 mg epinephrine, 1.8 mg sodium chloride, 0.5 mg sodium metabisulfite, 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. Replace EpiPen and EpiPen Jr if the epinephrine solution appears discolored (pinkish or brown color), cloudy, or contains particles. Thoroughly review the patient instructions and operation of EpiPen or EpiPen Jr with patients and caregivers prior to use [ see Patient Counseling Information (17) ]. Epinephrine Structural Formula

2 DOSAGE AND ADMINISTRATION Patients greater than or equal to 30 kg (66 lbs): EpiPen 0.3 mg ( 2 ) Patients 15 to 30 kg (33 lbs to 66 lbs): EpiPen Jr 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): EpiPen 0.3 mg Patients 15 kg to 30 kg (33 pounds to 66 pounds): EpiPen Jr 0.15 mg 2.2 Administration Instructions Inject the single-dose EpiPen or EpiPen Jr 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 EpiPen or EpiPen Jr 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 EpiPen or EpiPen Jr is a single-dose epinephrine injection for single use. Since the doses of epinephrine delivered from EpiPen or EpiPen Jr 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 EpiPen or EpiPen Jr 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 EpiPen or EpiPen Jr Auto-Injector should be inspected visually for particulate matter and discoloration. Discarding After Use: The EpiPen and EpiPen Jr each contain 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 .

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

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 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.

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 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Epinephrine acts on both alpha- and beta-adrenergic receptors. 12.2 Pharmacodynamics Through its action on alpha-adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension. Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation and helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis. Epinephrine also alleviates pruritus, urticaria, and angioedema and may relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus and urinary bladder. When given subcutaneously or intramuscularly, epinephrine has a rapid onset and short duration of action.

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

12.2 Pharmacodynamics Through its action on alpha-adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension. Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation and helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis. Epinephrine also alleviates pruritus, urticaria, and angioedema and may relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus and urinary bladder. When given subcutaneously or intramuscularly, epinephrine has a rapid onset and short duration of action.

20230413

6

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

EPIPEN epinephrine SODIUM CHLORIDE SODIUM METABISULFITE HYDROCHLORIC ACID WATER EPINEPHRINE EPINEPHRINE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate the carcinogenic potential of epinephrine have not been conducted. Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro . Epinephrine was positive in the Salmonella bacterial reverse mutation assay, positive in the mouse lymphoma assay, and negative in the in vivo micronucleus assay. Epinephrine is an oxidative mutagen based on the E. coli WP2 Mutoxitest bacterial reverse mutation assay. This should not prevent the use of epinephrine where indicated [see Indications and Usage (1) ]. The potential for epinephrine to impair reproductive performance has not been evaluated, but epinephrine has been shown to decrease implantation in female rabbits dosed subcutaneously with 1.2 mg/kg/day (40-fold the highest human intramuscular or subcutaneous daily dose) during gestation days 3 to 9.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate the carcinogenic potential of epinephrine have not been conducted. Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro . Epinephrine was positive in the Salmonella bacterial reverse mutation assay, positive in the mouse lymphoma assay, and negative in the in vivo micronucleus assay. Epinephrine is an oxidative mutagen based on the E. coli WP2 Mutoxitest bacterial reverse mutation assay. This should not prevent the use of epinephrine where indicated [see Indications and Usage (1) ]. The potential for epinephrine to impair reproductive performance has not been evaluated, but epinephrine has been shown to decrease implantation in female rabbits dosed subcutaneously with 1.2 mg/kg/day (40-fold the highest human intramuscular or subcutaneous daily dose) during gestation days 3 to 9.

NDA019430

EPIPEN

epinephrine

70518-1224

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR

DRUG: EPIPEN GENERIC: epinephrine DOSAGE: INJECTION ADMINSTRATION: INTRAMUSCULAR NDC: 70518-1224-0 PACKAGING: 0.3 mL in 1 SYRINGE OUTER PACKAGING: 1 in 1 CONTAINER OUTER PACKAGING: 2 in 1 CARTON ACTIVE INGREDIENT(S): EPINEPHRINE 0.3mg in 0.3mL INACTIVE INGREDIENT(S): SODIUM CHLORIDE SODIUM METABISULFITE HYDROCHLORIC ACID WATER Remedy_Label

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling ( Patient Information and Instructions for Use ) A healthcare provider should review the patient instructions and operation of EpiPen and EpiPen Jr in detail, with the patient or caregiver. Epinephrine is essential for the treatment of anaphylaxis. Patients who are at risk of or with a history of severe allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs, and other allergens, as well as idiopathic and exercise-induced anaphylaxis, should be carefully instructed about the circumstances under which epinephrine should be used. Administration Instruct patients and/or caregivers in the appropriate use of EpiPen and EpiPen Jr. EpiPen should be injected into the middle of the outer thigh (through clothing, if necessary). Each device is a single-use injection. Advise patients to seek immediate medical care in conjunction with administration of EpiPen. Instruct caregivers to hold the leg of young children firmly in place and limit movement prior to and during injection. Lacerations, bent needles, and embedded needles have been reported when EpiPen and EpiPen Jr have been injected into the thigh of young children who are uncooperative and kick or move during an injection [ see Warnings and Precautions (5.2) ]. Instruct patients and/or caregivers to throw away the blue safety release immediately after using EpiPen and EpiPen Jr. This small part may pose a choking hazard for children. Complete patient information, including dosage, directions for proper administration and precautions can be found inside each EpiPen or EpiPen Jr carton. A printed label on the surface of EpiPen shows instructions for use and a diagram depicting the injection process. Training Instruct patients and/or caregivers to use and practice with the Trainer to familiarize themselves with the use of EpiPen in an allergic emergency. The Trainer may be used multiple times. A Trainer device is provided in 2-Pak cartons. Instruct patients and/or caregivers to immediately place the blue safety release back on the Trainer and reset it after practicing. This small part may pose a choking hazard for children. Adverse Reactions Epinephrine may produce symptoms and signs that include an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These signs and symptoms usually subside rapidly, especially with rest, quiet and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson’s disease may notice a temporary worsening of symptoms [ see Warnings and Precautions (5.5) ] . Accidental Injection Advise patients to seek immediate medical care in the case of accidental injection. Since epinephrine is a strong vasoconstrictor when injected into the digits, hands, or feet, treatment should be directed at vasodilatation if there is such an accidental injection to these areas [ see Warnings and Precautions (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 [ see Warnings and Precautions (5.3) ]. Storage and Handling Instruct patients to inspect the epinephrine solution visually through the clear window of the auto-injector periodically. Replace EpiPen and EpiPen Jr if the epinephrine solution appears discolored (pinkish or brown color), cloudy, or contains particles. Epinephrine is light sensitive and should be stored in the carrier tube provided to protect it from light. The carrier tube is not waterproof. Instruct patients that EpiPen and EpiPen Jr must be used or properly disposed once the blue safety release is removed or after use [ see Storage and Handling (16.2) ]. Advise patients and caregivers to give used EpiPen and EpiPen Jr auto-injectors to their healthcare provider for inspection and proper disposal. Advise patients and caregivers to promptly dispose of medicines that are no longer needed. Dispose of expired, unwanted, or unused EpiPen and EpiPen Jr auto-injectors in an FDA-cleared sharps container. Instruct patients not to dispose EpiPen or EpiPen Jr in their household trash. Instruct patients that if they do not have a FDA-cleared sharps disposal container, they may use a household container that is made of a heavy-duty plastic, can be closed with a tight-fitting and puncture-resistant lid without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. Inform patients that they can visit the FDA website for additional information on disposal of unused medicines. Complete patient information, including dosage, directions for proper administration and precautions can be found inside each EpiPen Auto-Injector carton. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

8.5 Geriatric Use Clinical studies for the treatment of anaphylaxis have not been performed in subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience with use of epinephrine for the treatment of anaphylaxis has identified that geriatric patients may be particularly sensitive to the effects of epinephrine. Therefore, EpiPen should be administered with caution in elderly individuals, who may be at greater risk for developing adverse reactions after epinephrine administration [ see Warnings and Precautions (5.5) , Overdosage (10) ].

8.4 Pediatric Use EpiPen or EpiPen Jr 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 doses of epinephrine delivered from EpiPen and EpiPen Jr are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary.

8.1 Pregnancy Risk Summary There are no adequate and well controlled studies of the acute effect of epinephrine in pregnant women. In animal reproductive 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 human intramuscular and subcutaneous dose on a mg/m 2 basis. 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 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 adequate and well controlled studies of the acute effect of epinephrine in pregnant women. In animal reproductive 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 human intramuscular and subcutaneous dose on a mg/m 2 basis. 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 is no information on the presence of epinephrine in human milk, the effects on breastfed infants, or the effects 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 non-breastfeeding patients. 8.4 Pediatric Use EpiPen or EpiPen Jr 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 doses of epinephrine delivered from EpiPen and EpiPen Jr are 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 over to determine whether they respond differently from younger subjects. However, other reported clinical experience with use of epinephrine for the treatment of anaphylaxis has identified that geriatric patients may be particularly sensitive to the effects of epinephrine. Therefore, EpiPen should be administered with caution in elderly individuals, who may be at greater risk for developing adverse reactions after epinephrine administration [ see Warnings and Precautions (5.5) , Overdosage (10) ].

16 HOW SUPPLIED/STORAGE AND HANDLING EpiPen 2-Pak (epinephrine) injection is supplied with 2 single-dose pre-filled auto-injectors and 1 auto-injector trainer device: 0.3 mg/0.3 mL NDC: 70518-1224-00 PACKAGING: 2 in 1 CARTON, 1 in 1 CONTAINER, 0.3 mL in 1 SYRINGE GLASS, TYPE 2 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 EpiPen and EpiPen Jr auto-injectors. 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]. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762