EPINEPHRINE INJECTION, USP AUTO INJECTOR

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use EPIPEN ® and EPIPEN Jr ® safely and effectively. See full prescribing information for EPIPEN and EPIPEN Jr. EPIPEN ® (epinephrine injection, USP), Auto-Injector 0.3 mg, EPIPEN Jr ® (epinephrine injection, USP) Auto-Injector 0.15 mg, for intramuscular or subcutaneous use Initial U.S. Approval: 1939

INDICATIONS AND USAGE

EpiPen and EpiPen Jr contain epinephrine, a non-selective alpha and beta-adrenergic receptor agonist, indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis. ( 1)

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 EpiPen and EpiPen Jr intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Each device is a single-use injection. ( 2)

DOSAGE FORMS AND STRENGTHS

• EpiPen: Injection, 0.3 mg: 0.3 mg/0.3 mL epinephrine, USP, pre-filled auto-injector ( 3) • EpiPen Jr: Injection, 0.15 mg: 0.15 mg/0.3 mL epinephrine, USP, pre-filled auto-injector ( 3)

CONTRAINDICATIONS

None ( 4)

WARNINGS AND PRECAUTIONS

• In conjunction with use, seek immediate medical or hospital care. 5 ( 5.1) • Do not inject intravenously, into buttock, or into digits, hands, or feet. 5 ( 5.2) • To minimize the risk of injection related injury, instruct caregivers to hold the child’s leg firmly in place and limit movement prior to and during injection when administering to young children. 5 ( 5.2) • Rare cases of serious skin and soft tissue infections have been reported following epinephrine injection. Advise patients to seek medical care if they develop signs or symptoms of infection. 5 ( 5.3) • The presence of a sulfite in this product should not deter use. 5 ( 5.4) • Administer with caution in patients with heart disease; may aggravate angina pectoris or produce ventricular arrhythmias. 5 ( 5.5)

ADVERSE REACTIONS

Adverse reactions to epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and/or respiratory difficulties. 6 (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.

DRUG INTERACTIONS

• Cardiac glycosides or diuretics: observe for development of cardiac arrhythmias. 7 ( 7) • Tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines: potentiate effects of epinephrine. 7 ( 7) • Beta-adrenergic blocking drugs: antagonize cardiostimulating and bronchodilating effects of epinephrine. 7 ( 7) • Alpha-adrenergic blocking drugs: antagonize vasoconstricting and hypertensive effects of epinephrine. 7 ( 7) • Ergot alkaloids: may reverse the pressor effects of epinephrine. 7 ( 7)

USE IN SPECIFIC POPULATIONS

• Elderly patients may be at greater risk of developing adverse reactions. 5 ( 5.5), 8 (8.5)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 8/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Emergency Treatment 5.2 Injection-Related Complications 5.3 Serious Infections at the Injection Site 5.4 Allergic Reactions Associated with Sulfite 5.5 Disease Interactions 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS & 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.

2 DOSAGE & ADMINISTRATION

Selection of the appropriate dosage strength (EpiPen 0.3 mg or EpiPen Jr 0.15 mg) is determined according to patient body weight.

• Patients greater than or equal to 30 kg (approximately 66 pounds or more): EpiPen 0.3 mg • Patients 15 to 30 kg (33 pounds to 66 pounds): EpiPen Jr 0.15 mg

Inject EpiPen or EpiPen Jr intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. 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 contains a single dose of epinephrine for single-use injection. 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.

The prescriber should carefully assess each patient to determine the most appropriate dose of epinephrine, recognizing the life-threatening nature of the reactions for which this drug is indicated. 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 Auto-Injector should be inspected visually for particulate matter and discoloration. Epinephrine is light sensitive and should be stored in the carrier tube provided to protect it from light [see HOW SUPPLIED/STORAGE AND HANDLING (16.2)].

3 DOSAGE FORMS & STRENGTHS

• EpiPen: Injection, 0.3 mg/0.3 mL epinephrine injection, USP, pre-filled auto-injector • EpiPen Jr: Injection, 0.15 mg/0.3 mL, epinephrine injection, USP, pre-filled auto-injector

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Emergency Treatment

EpiPen and EpiPen Jr are intended for immediate administration as emergency supportive therapy and are not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision [see INDICATIONS & USAGE (1), DOSAGE & ADMINISTRATION (2) and PATIENT COUNSELING INFORMATION (17)].

5.2 Injection-Related Complications

EpiPen and EpiPen Jr should only be injected into the anterolateral aspect of the thigh [see DOSAGE & ADMINISTRATION (2) and PATIENT COUNSELING INFORMATION (17)].

• Do not inject intravenously. Large doses or accidental intravenous injection of 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. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis. Additionally, injection into the buttock has been associated with Clostridial infections (gas gangrene). Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower this risk. • Do not inject into digits, hands or feet. Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. Advise the patient to go immediately to the nearest emergency room and to inform the healthcare provider in the emergency room of the location of the accidental injection. Treatment of such inadvertent administration should consist of vasodilation, in addition to further appropriate treatment of anaphylaxis [ see ADVERSE REACTIONS (6)]. • Hold leg firmly 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. To minimize the risk of injection related injury when administering EpiPen to young children, instruct caregivers to hold the child’s leg firmly in place and limit movement prior to and during injection.

5.3 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. Clostridium spores can be present on the skin and introduced into the deep tissue with subcutaneous or intramuscular injection. While cleansing with alcohol may reduce presence of bacteria on the skin, alcohol cleansing does not kill Clostridium spores. To decrease the risk of Clostridium infection, do not inject EpiPen into the buttock [see WARNINGS AND PRECAUTIONS (5.2)]. 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.

5.4 Allergic Reactions Associated with Sulfite

The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive.

Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium metabisulfite, a sulfite that may, in other products, cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons.

The alternatives to using epinephrine in a life-threatening situation may not be satisfactory.

5.5 Disease Interactions

Some patients may be at greater risk for developing adverse reactions after epinephrine administration. Despite these concerns, it should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation. Therefore, patients with these conditions, and/or any other person who might be in a position to administer EpiPen or EpiPen Jr to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used.

• Patients with Heart Disease

Epinephrine should be administered with caution to patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In such patients, or in patients who are on drugs that may sensitize the heart to arrhythmias, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias [see DRUG INTERACTIONS (7) and ADVERSE REACTIONS (6)].

• Other Patients and Diseases

Epinephrine should be administered with caution to patients with hyperthyroidism, diabetes, elderly individuals, and pregnant women. Patients with Parkinson’s disease may notice a temporary worsening of symptoms.

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)].

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.

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 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.

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 WARNINGS AND PRECAUTIONS (5.2)].

Injection into the buttock has resulted in cases of gas gangrene [see WARNINGS AND PRECAUTIONS (5.2)].

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)].

7 DRUG INTERACTIONS

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)].

The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine.

The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta- adrenergic blocking drugs, such as propranolol.

The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha- adrenergic blocking drugs, such as phentolamine.

Ergot alkaloids may also reverse the pressor effects of epinephrine.

8 USE IN SPECIFIC POPULATIONS

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/m2 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/m2 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/m2 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/m2 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/m2 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 & ADMINISTRATION (2)]. 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)].

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.

11 DESCRIPTION

EpiPen (epinephrine injection, USP) 0.3 mg and EpiPen Jr (epinephrine injection, USP) 0.15 mg are 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.

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.

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)].

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.

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 under the conditions noted under INDICATIONS & 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.

16 HOW SUPPLIED/STORAGE & HANDLING

EPIPEN® (EPINEPHRINE INJECTION, USP) is supplied in the following dosage forms. NDC 51662-1224-1 EPIPEN® (EPINEPHRINE INJECTION, USP) AUTO INJECTOR 0.30mg

NDC 51662-1225-1 EPIPEN JR® (EPINEPHRINE INJECTION, USP) AUTO INJECTOR 0.15mg

HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275

Also supplied in the following manufacture supplied dosage forms

16.1 How Supplied

EpiPen Auto-Injectors (epinephrine injections, USP 0.3 mg/0.3 mL) are available as EpiPen 2-Pak®, NDC 49502-500-02, a pack that contains two EpiPen Auto-Injectors (epinephrine injections, USP 0.3 mg/0.3 mL) and one EpiPen Auto-Injector trainer device.

EpiPen Jr Auto-Injectors (epinephrine injections, USP 0.15 mg/0.3 mL) are available as EpiPen Jr 2-Pak®, NDC 49502-501-02, a pack that contains two EpiPen Jr Auto-Injectors (epinephrine injections, USP 0.15 mg/0.3 mL) and one EpiPen Auto-Injector trainer device.

EpiPen 2-Pak® and EpiPen Jr 2-Pak® also include an S-clip to clip two carrier tubes together.

Rx only

16.2 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° 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 (pinkish or brown color), cloudy, or contains particles.

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 and Training

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)].

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.

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.

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)].

Complete patient information, including dosage, directions for proper administration and precautions can be found inside each EpiPen Auto-Injector carton.

Manufactured for Mylan Specialty L.P., Morgantown, WV 26505, U.S.A. by Meridian Medical Technologies, Inc., Columbia, MD 21046, U.S.A., a Pfizer company

EpiPen® and EpiPen Jr® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned affiliate, Mylan Specialty L. P. of Morgantown, WV 26505, U.S.A.

Revised: 8/2018 MS:EPI:R4

0002029

PATIENT INFORMATION/INSTRUCTIONS FOR USE

EPIPEN® (epinephrine injection, USP) Auto-Injector 0.3 mg EpiPen® = one dose of 0.3 mg epinephrine, USP 0.3 mg/0.3 mL

EPIPEN JR® (epinephrine injection, USP) Auto-Injector 0.15 mg EpiPen Jr® = one dose of 0.15 mg epinephrine, USP 0.15 mg/0.3 mL

For allergic emergencies (anaphylaxis)

Patient Information

Read this Patient Information Leaflet carefully before using the EpiPen® or EpiPen Jr® Auto-Injector and each time you get a refill. There may be new information. You, your parent, caregiver, or others who may be in a position to administer EpiPen or EpiPen Jr Auto-Injector, should know how to use it before you have an allergic emergency.

This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about the EpiPen and EpiPen Jr?

1. EpiPen and EpiPen Jr contain epinephrine, a medicine used to treat allergic emergencies (anaphylaxis). Anaphylaxis can be life threatening, can happen within minutes, and can be caused by stinging and biting insects, allergy injections, foods, medicines, exercise, or unknown causes. Symptoms of anaphylaxis may include:

• trouble breathing • wheezing • hoarseness (changes in the way your voice sounds) • hives (raised reddened rash that may itch) • severe itching • swelling of your face, lips, mouth, or tongue • skin rash, redness, or swelling • fast heartbeat • weak pulse • feeling very anxious • confusion • stomach pain • losing control of urine or bowel movements (incontinence) • diarrhea or stomach cramps • dizziness, fainting, or “passing out” (unconsciousness)

2. Always carry your EpiPen or EpiPen Jr with you because you may not know when anaphylaxis may happen. Talk to your healthcare provider if you need additional units to keep at work, school, or other locations. Tell your family members, caregivers, and others where you keep your EpiPen or EpiPen Jr and how to use it before you need it. You may be unable to speak in an allergic emergency. 3. When you have an allergic emergency (anaphylaxis)

• Use the EpiPen or EpiPen Jr right away. • Get emergency medical help right away. You may need further medical attention. You may need to use a second EpiPen or EpiPen Jr if symptoms continue or recur. Only a healthcare provider should give additional doses of epinephrine if you need more than 2 injections for a single anaphylaxis episode.

What are EpiPen and EpiPen Jr?

• EpiPen and EpiPen Jr are disposable, prefilled automatic injection devices (auto-injectors) used to treat life-threatening, allergic emergencies including anaphylaxis in people who are at risk for or have a history of serious allergic emergencies. Each device contains a single dose of epinephrine. • EpiPen and EpiPen Jr are for immediate self (or caregiver) administration and do not take the place of emergency medical care. You should get emergency help right away after using EpiPen and EpiPen Jr. • EpiPen and EpiPen Jr are for people who have been prescribed this medicine by their healthcare provider. • The EpiPen Auto-Injector (0.3 mg) is for patients who weigh 66 pounds or more (30 kilograms or more). • The EpiPen Jr Auto-Injector (0.15 mg) is for patients who weigh about 33 to 66 pounds (15 to 30 kilograms). • It is not known if EpiPen and EpiPen Jr are safe and effective in children who weigh less than 33 pounds (15 kilograms).

What should I tell my healthcare provider before using the EpiPen or EpiPen Jr?

Before you use EpiPen or EpiPen Jr, tell your healthcare provider about all your medical conditions, but especially if you:

• have heart problems or high blood pressure • have diabetes • have thyroid problems • have asthma • have a history of depression • have Parkinson’s disease • have any other medical conditions • are pregnant or plan to become pregnant. It is not known if epinephrine will harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if epinephrine passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tell your healthcare provider of all known allergies.

Especially tell your healthcare provider if you take certain asthma medicines.

EpiPen or EpiPen Jr and other medicines may affect each other, causing side effects. EpiPen or EpiPen Jr may affect the way other medicines work, and other medicines may affect how EpiPen or EpiPen Jr works.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

Use your EpiPen or EpiPen Jr for treatment of anaphylaxis as prescribed by your healthcare provider, regardless of your medical conditions or the medicines you take.

How should I use EpiPen and EpiPen Jr?

• Each EpiPen or EpiPen Jr Auto-Injector contains only 1 dose of medicine. • EpiPen or EpiPen Jr should be injected into the middle of your outer thigh (upper leg). It can be injected through your clothing if needed. • Read the Instructions for Use at the end of this Patient Information Leaflet about the right way to use EpiPen and EpiPen Jr. • Your healthcare provider will show you how to safely use the EpiPen or EpiPen Jr Auto-Injector. • Use your EpiPen or EpiPen Jr exactly as your healthcare provider tells you to use it. You may need to use a second EpiPen or EpiPen Jr if symptoms continue or recur. Only a healthcare provider should give additional doses of epinephrine if you need more than 2 injections for a single anaphylaxis episode. • Caution: Never put your thumb, fingers, or hand over the orange tip. Never press or push the orange tip with your thumb, fingers, or hand. The needle comes out of the orange tip. Accidental injection into finger, hands or feet may cause a loss of blood flow to these areas. If this happens, go immediately to the nearest emergency room. Tell the healthcare provider where on your body you received the accidental injection. • Your EpiPen and EpiPen Jr Auto-Injector may come packaged with an EpiPen Trainer and separate Trainer Instructions for Use. The EpiPen Trainer has a grey color. The grey EpiPen Trainer contains no medicine and no needle. Periodically practice with your EpiPen Trainer before an allergic emergency happens to make sure you are able to safely use the real EpiPen and EpiPen Jr Auto-Injector in an emergency. Always carry your real EpiPen or EpiPen Jr Auto-Injector with you in case of an allergic emergency. Additional training resources are available at www.epipen.com. • Do not drop the carrier tube or auto-injector. If the carrier tube or auto-injector is dropped, check for damage and leakage. Dispose of the auto-injector and carrier tube, and replace if damage or leakage is noticed or suspected.

What are the possible side effects of the EpiPen and EpiPen Jr?

EpiPen and EpiPen Jr may cause serious side effects.

• The EpiPen or EpiPen Jr should only be injected into the middle of your outer thigh (upper leg).Do not inject the EpiPen or EpiPen Jr into your:

• veins • buttocks • fingers, toes, hands, or feet

If you accidentally inject EpiPen or EpiPen Jr into any other part of your body, go to the nearest emergency room right away. Tell the healthcare provider where on your body you received the accidental injection. • Rarely, patients who have used EpiPen or EpiPen Jr may develop infections at the injection site within a few days of an injection. Some of these infections can be serious. Call your healthcare provider right away if you have any of the following at an injection site:

• redness that does not go away • swelling • tenderness • the area feels warm to the touch

• Cuts on the skin, bent needles, and needles that remain in the skin after the injection, have happened in young children who do not cooperate and kick or move during an injection. If you inject a young child with EpiPen or EpiPen Jr, hold their leg firmly in place before and during the injection to prevent injuries. Ask your healthcare provider to show you how to properly hold the leg of a young child during injection. • If you have certain medical conditions, or take certain medicines, your condition may get worse or you may have longer lasting side effects when you use your EpiPen or EpiPen Jr. Talk to your healthcare provider about all your medical conditions.

Common side effects of EpiPen and EpiPen Jr include:

• fast, irregular or “pounding” heartbeat • sweating • headache • weakness • shakiness • paleness • feelings of over excitement, nervousness or anxiety • dizziness • nausea or vomiting • breathing problems

These side effects may go away with rest. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of the EpiPen or EpiPen Jr. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store EpiPen and EpiPen Jr?

• Store EpiPen and EpiPen Jr at room temperature between 68° to 77° F (20° to 25° C). • Protect from light. • Do not expose to extreme cold or heat. For example, do not store in your vehicle’s glove box and do not store in the refrigerator or freezer. • Examine the contents in the clear window of your auto-injector periodically. The solution should be clear. If the solution is discolored (pinkish or brown color) or contains solid particles, replace the unit. • Always keep your EpiPen or EpiPen Jr Auto-Injector in the carrier tube to protect it from damage; however, the carrier tube is not waterproof. • The blue safety release helps to prevent accidental injection. Keep the blue safety release on until you need to use EpiPen or EpiPen Jr. • Your EpiPen or EpiPen Jr has an expiration date. Replace it before the expiration date.

Keep EpiPen and EpiPen Jr and all medicines out of the reach of children.

General information about the safe and effective use of EpiPen and EpiPen Jr

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use the EpiPen or EpiPen Jr for a condition for which it was not prescribed. Do not give your EpiPen or EpiPen Jr to other people.

This Patient Information Leaflet summarizes the most important information about EpiPen and EpiPen Jr. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about EpiPen and EpiPen Jr that is written for health professionals.

For more information and video instructions on the use of EpiPen and EpiPen Jr, go to www.epipen.com or call 1-800-395-3376.

What are the ingredients in EpiPen and EpiPen Jr?

Active Ingredients: Epinephrine Inactive Ingredients: sodium chloride, sodium metabisulfite, hydrochloric acid, and water.

Important Information

• The EpiPen Auto-Injector has a yellow colored label. • The EpiPen Jr Auto-Injector has a green colored label. • The EpiPen Trainer has a grey color and contains no medicine and no needle. • Your auto-injector is designed to work through clothing. • The blue safety release on the EpiPen and EpiPen Jr Auto-Injector helps to prevent accidental injection of the device. Do not remove the blue safety release until you are ready to use it. • Only inject into the middle of the outer thigh (upper leg). Never inject into any other part of the body. • Never put your thumb, fingers, or your hand over the orange tip. The needle comes out of the orange tip. • If an accidental injection happens, get medical help right away. • Do not place patient information or any other foreign objects in the carrier tube with the Auto-Injector, as this may prevent you from removing the Auto-Injector for use.

Instructions for Use

EPIPEN® (epinephrine injection, USP) Auto-Injector 0.3 mg EpiPen® = one dose of 0.3 mg epinephrine, USP 0.3 mg/0.3 mL

EPIPEN JR® (epinephrine injection, USP) Auto-Injector 0.15 mg EpiPen Jr® = one dose of 0.15 mg epinephrine, USP 0.15 mg/0.3 mL

For allergic emergencies (anaphylaxis)

Read these Instructions for Use carefully before you use EpiPen or EpiPen Jr. Before you need to use your EpiPen or EpiPen Jr, make sure your healthcare provider shows you the right way to use it. Parents, caregivers, and others who may be in a position to administer EpiPen or EpiPen Jr Auto-Injector should also understand how to use it as well. If you have any questions, ask your healthcare provider.

Your EpiPen and EpiPen Jr Auto-Injector

A dose of EpiPen or EpiPen Jr® requires 3 simple steps: Prepare, Administer and Get emergency medical help

Step 1. Prepare EpiPen or EpiPen Jr for injection

Note:

• The needle comes out of the orange tip. • To avoid an accidental injection, never put your thumb, fingers or hand over the orange tip. If an accidental injection happens, get medical help right away.

Step 2. Administer EpiPen or EpiPen Jr

Step 3. Get emergency medical help now. You may need further medical attention. You may need to use a second EpiPen or EpiPen Jr Auto-Injector if symptoms continue or recur.

• Take your used auto-injector with you when you go to see a healthcare provider. • Tell the healthcare provider that you have received an injection of epinephrine. Show the healthcare provider where you received the injection. • Give your used EpiPen or EpiPen Jr Auto-Injector to the healthcare provider for inspection and proper disposal. • Ask for a refill, if needed.

Note:

• The used auto-injector with extended needle cover will not fit in the carrier tube. • EpiPen and EpiPen Jr are single-use injectable devices that deliver a fixed dose of epinephrine. The auto-injector cannot be reused. Do not attempt to reuse EpiPen after the device has been activated. It is normal for most of the medicine to remain in the auto-injector after the dose is injected. The correct dose has been administered if the orange needle tip is extended and the window is blocked. • Your EpiPen and EpiPen Jr Auto-Injector may come packaged with an EpiPen Trainer and separate Trainer Instructions for Use. The EpiPen Trainer has a grey color. The grey EpiPen Trainer contains no medicine and no needle. Practice with your EpiPen Trainer, but always carry your real EpiPen or EpiPen Jr Auto-Injector in case of an allergic emergency. • If you are administering EpiPen or EpiPen Jr to a young child, ask your healthcare provider to show you how to properly hold the leg in place while administering a dose. • Do not try to take the EpiPen or EpiPen Jr Auto-Injector apart.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured for:

Mylan Specialty L.P., Morgantown, WV 26505, U.S.A. by Meridian Medical Technologies, Inc., Columbia, MD 21046, U.S.A., a Pfizer company

EpiPen® and EpiPen Jr® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned affiliate, Mylan Specialty L.P. of, Morgantown, WV 26505, U.S.A.

Revised: 2/2017 MS:PIL:EPI:R3 0001984

EPIPEN® (epinephrine injection, USP) Auto-Injector 0.3 mg EpiPen® = one dose of 0.3 mg epinephrine, USP 0.3 mg/0.3 mL

EPIPEN JR® (epinephrine injection, USP) Auto-Injector 0.15 mg EpiPen Jr® = one dose of 0.15 mg epinephrine, USP 0.15 mg/0.3 mL

MyEpiPen.com

• Free EpiPen Auto-Injector Refill Reminder Program. It is important to keep your auto-injector up-to-date.

• Receive periodic information related to allergies and allergens. • Instructional Video

For more information about EpiPen or EpiPen Jr Auto-Injectors and proper use of the product, call Mylan at 1-877-446-3679 or visit www.epipen.com.

EpiPen Trainer Instructions for Use

In an emergency: Do not use the grey Trainer. Use your real yellow EpiPen® or green EpiPen Jr® Auto-Injector.

Important Information

• The Trainer label has a grey color. • The Trainer contains no medicine and no needle. • Periodically practice with the grey colored Trainer before an allergic emergency (anaphylaxis) happens to make sure you are able to safely use the real yellow EpiPen or green EpiPen Jr Auto-Injector in case of an emergency. • Always carry your real yellow EpiPen or green EpiPen Jr Auto-Injector in case of an allergic emergency.

The EpiPen Trainer

Familiarize yourself with this grey Trainer. Practice until you are comfortable using it.

Your grey colored Trainer:

• Never put your thumb, other fingers, or hand over the Orange Tip. • The Orange Tip is where the needle comes out of your EpiPen or EpiPen Jr Auto-Injector.

Note: With the real yellow EpiPen or green EpiPen Jr Auto-Injector, the orange tip covers the needle after self-injection to help protect you from accidentally sticking yourself or others.

Practice Session Information

In case of an allergic emergency, use the real yellow EpiPen or green EpiPen Jr Auto-Injector and not the grey Trainer.

Follow instructions above. Repeat as often as needed until you are able to self-inject quickly and correctly.

Reread:

• These Trainer Instructions for Use • The “Patient Information” that comes with your EpiPen or EpiPen Jr Auto-Injector

Train others who could help you in an emergency:

• Your parents, caregivers, and others who may be in a position to administer EpiPen or EpiPen Jr should know how to help you during an allergic emergency (anaphylaxis). Before an emergency occurs, have them:

• Practice activating the Trainer • Read these Trainer Instructions and the “Patient Information”

For more information about the EpiPen and EpiPen Jr Auto-Injector and the proper use of the products, go to www.epipen.com.

Caution:

Important differences between the Trainer and your real yellow EpiPen or green EpiPen Jr Auto-Injector

This Trainer Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured for Mylan Specialty L.P., Morgantown, WV 26505, U.S.A. by Meridian Medical Technologies, Inc., Columbia, MD 21046, U.S.A., a Pfizer company

EpiPen® and EpiPen Jr® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned affiliate, Mylan Specialty L. P. of Morgantown, WV 26505, U.S.A.

Revised: 2/2017 MS:EPIT:R4 0001994

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