Epinephrine
FDA Label NDC 70385-2009

Epinephrine injection, USP auto-injector is indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which includes 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-injector is intended for immediate administration in patients who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions.

Anaphylactic reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria, or angioedema.

Epinephrine injection, USP auto-injector is intended for immediate administration as emergency supportive therapy only and is not a replacement or substitute for immediate medical care.

Selection of the appropriate epinephrine injection, USP auto-injector dosage strength is determined 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 to 30 kg (33 pounds to 66 pounds): epinephrine injection, USP auto-injector 0.15 mg

Inject epinephrine injection, USP auto-injector intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary.

Each epinephrine injection, USP auto-injector contains a single dose of epinephrine for single use injection. 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.

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 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 viewing window of epinephrine injection, USP auto-injector should be inspected visually for particulate matter and discoloration. Epinephrine is light sensitive and should be stored in the outer case provided to protect it from light [ see How Supplied/Storage and Handling ( 16.2) ].

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

None.

Epinephrine injection, USP auto-injector is intended for immediate administration as emergency supportive therapy and is 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 and Usage ( 1), Dosage and Administration ( 2) and Patient Counseling Information ( 17) ].

Epinephrine injection, USP auto-injector should ONLY be injected into the anterolateral aspect of the thigh [ see Dosage and 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 a 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 the development of gas gangrene. Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower the 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) ].

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 bisulfite, 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.

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 epinephrine injection, USP auto-injector 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.

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 ( 5.4) ].

Arrhythmias, including fatal ventricular fibrillation, have been reported, particularly in patients with underlying cardiac disease or those receiving certain drugs [ see Warnings and Precautions ( 5.4) and Drug Interactions ( 7) ].

Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease [ see Warnings and Precautions ( 5.4) ].

Angina may occur in patients with coronary artery disease [ see Warnings and Precautions ( 5.4) ].

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.

Injection into the buttock has resulted in cases of gas gangrene [ see Warnings and Precautions ( 5.2) ].

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 ( 5.4) ].

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.

Teratogenic Effects: Pregnancy Category C.

There are no adequate and well controlled studies of the acute effect of epinephrine in pregnant women.

Epinephrine was teratogenic in rabbits, mice and hamsters. Epinephrine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (fetal anoxia, spontaneous abortion, or both).

Epinephrine has been shown to have teratogenic effects when administered subcutaneously in rabbits at approximately 30 times the maximum recommended daily subcutaneous or intramuscular dose (on a mg/m ² basis at a maternal dose of 1.2 mg/kg/day for two to three days), in mice at approximately 7 times the maximum daily subcutaneous or intramuscular dose (on a mg/m ² basis at a maternal subcutaneous dose of 1 mg/kg/day for 10 days), and in hamsters at approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose (on a mg/m ² basis at a maternal subcutaneous dose of 0.5 mg/kg/day for 4 days).

These effects were not seen in mice at approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose (on a mg/m ² basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days).

It is not known whether epinephrine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when epinephrine injection, USP auto-injector is administered to a nursing woman.

Epinephrine injection, USP auto-injector may be administered to pediatric patients at a dosage appropriate to body weight [ see Dosage and 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 dose of epinephrine delivered from epinephrine injection, USP auto-injector is fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary.

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, epinephrine injection, USP auto-injector 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 ( 5.4) and Overdosage ( 10) ].

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.

Epinephrine injection, USP auto-injector 0.3 mg and 0.15 mg is an auto-injector and a combination product containing drug and device components.

Each epinephrine injection, USP auto-injector 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 auto-injector 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 auto-injector 0.3 mg and epinephrine injection, USP auto-injector 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 auto-injector 0.3 mg and epinephrine injection, USP auto-injector 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 auto-injector 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 auto-injector 0.15 mg contains 0.15 mg epinephrine, 1.3 mg sodium chloride, not more than 0.75 mg chlorobutanol, 0.225 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:

Formula (Formula)

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 auto-injector 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 auto-injector with patients and caregivers prior to use [ see Patient Counseling Information ( 17) ].

Epinephrine acts on both alpha- and beta-adrenergic receptors.

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 intramuscularly or subcutaneously, epinephrine has a rapid onset and short duration of action.

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 and to be an oxidative mutagen in a WP2 bacterial reverse mutation assay.

Epinephrine was positive in the DNA Repair test with B. subtilis (REC) assay, but was not mutagenic in the Salmonella bacterial reverse mutation assay.

The potential for epinephrine to impair fertility has not been evaluated.

This should not prevent the use of epinephrine under the conditions noted under Indications and Usage ( 1) .

Package containing one epinephrine injection, USP auto-injector 0.3 mg: NDC 70385-2009-1

Rx only

Protect from light. Epinephrine is light sensitive and should be stored in the carrying-case provided to protect it from light. Store at room temperature (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.

[ see FDA-Approved Patient Labeling ( Patient Information and Instructions for Use) ]

A healthcare provider should review the patient instructions and operation of epinephrine injection, USP auto-injector, 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

Patients and/or caregivers should be instructed in the appropriate use of epinephrine injection, USP auto-injector. Epinephrine injection, USP auto-injector should be injected into the middle of the outer thigh (through clothing if necessary). Each epinephrine injection, USP auto-injector is a single-use injection. Advise patients to seek immediate medical care in conjunction with administration of epinephrine injection, USP auto-injector.

Complete patient information, including dosage, directions for proper administration and precautions can be found inside each epinephrine injection, USP auto-injector carton. A printed label on the surface of epinephrine injection, USP auto-injector shows instructions for use and a diagram depicting the injection process.

Patients and/or caregivers should be instructed to use the Trainer to familiarize themselves with the use of epinephrine injection, USP auto-injector in an allergic emergency. The Trainer may be used multiple times.

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 ( 5.4)] .

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 vasodilation if there is such an accidental injection to these areas [see Warnings and Precautions ( 5.2)] .

Storage and Handling

Instruct patients to inspect the epinephrine solution visually through the viewing window periodically. Epinephrine injection, USP auto-injector should be replaced if the epinephrine solution appears discolored (pinkish or brown), cloudy, or contains particles. Epinephrine is light sensitive and should be stored in the outer case provided to protect it from light. Patients should be instructed that epinephrine injection, USP auto-injector must be properly disposed of once the blue caps have been removed or after use [see How Supplied/Storage and Handling ( 16.2)] .

Complete patient information, including dosage, directions for proper administration and precautions are provided inside each epinephrine injection, USP auto-injector carton.

Manufactured for and Distributed by: Lineage Therapeutics Inc., Horsham, PA 19044

© 2014 Lineage Therapeutics Inc., Horsham, PA. All rights reserved. This product and the use thereof is proprietary and protected under one or more of United States Patents 5,358,489; 5,540,664; 5,833,669; 5,665,071; 5,695,472; 7,297,136; 7,905,352; 7,621,891; 7,927,303; 7,931,618; 8,187,224; and/or related patents in countries other than the U.S.

For inquiries call 1-888-894-6528

71006-07

Instructions for Use

EPINEPHRINE INJECTION, USP AUTO-INJECTOR (ep-in-eph-rine)

For allergic emergencies (anaphylaxis)

Read these Instructions for Use carefully before you use epinephrine injection, USP auto-injector. Before you need to use your epinephrine injection, USP auto-injector, 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 epinephrine injection, USP auto-injector should also understand how to use it well. If you have any questions, ask your healthcare provider.

Your epinephrine injection, USP auto-injector

Injectors (Injectors)

STEP 1. Prepare epinephrine injection, USP auto-injector for injection

• Remove epinephrine injection, USP auto-injector from its protective carrying case.
• Pull off blue end caps; you will now see a red tip. Grasp the auto-injector in your fist with the red tip pointing downward. See Figure A.

Note:

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

  Figurea (Figurea)

• STEP 2. Administer epinephrine injection, USP auto-injector
• Put the red tip against the middle of the outer thigh (upper leg) at a 90° angle (perpendicular) to the thigh.
• Press down hard and hold firmly against the thigh for approximately 10 seconds to deliver the medicine. See Figure B.


Figureb (Figureb)

• Only inject into the middle of the outer thigh. Do not inject into any other part of the body.
• Remove epinephrine injection, USP auto-injector from the thigh.
• Massage the area for 10 seconds.
• Check the red tip. The injection is complete and you have received the correct dose of the medicine if you see the needle sticking out of the red tip. If you do not see the needle repeat Step 2.

STEP 3. Get emergency medical help right away. You may need further medical attention. You may need to use a second epinephrine injection, USP auto-injector if symptoms continue or recur.

STEP 4. After use / Disposal

Carefully cover the needle with the carrying case.

• Lay the labeled half of the carrying case cover down on a flat surface. Use one hand to carefully slide the end of the auto-injector, needle first, into the labeled carrying case cover. See Figure C.


Figurec (Figurec)

• After the needle is inside the labeled cover, push the unlabeled half of the carrying case cover firmly over the non-needle end of the auto-injector. See Figure D.


Figured (Figured)

• Take your used epinephrine injection, USP 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 epinephrine injection, USP auto-injector to the healthcare provider for inspection and proper disposal.
• Ask for a refill, if needed.

Note:

• Epinephrine injection, USP auto-injector is a single-use injectable device that delivers a fixed dose of epinephrine. The auto-injector cannot be reused. 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 you see the needle sticking out of the red tip.
• A separate epinephrine injection, USP auto-injector Trainer is available. The epinephrine injection, USP auto-injector Trainer has a beige color. The beige epinephrine injection, USP auto-injector Trainer contains no medicine and no needle. Practice with your epinephrine injection, USP auto-injector Trainer, but always carry your real epinephrine injection, USP auto-injector in case of an allergic emergency.
• Do not try to take the epinephrine injection, USP auto-injector apart.

For more information and video instructions on the use of epinephrine injection, USP auto-injector, go to www.epinephrineautoinject.com or call 1-888-894-6528.

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

10/2014

© 2014 Lineage Therapeutics Inc., Horsham, PA. All rights reserved.

Manufactured for and Distributed by:

Lineage Therapeutics Inc.

Horsham, PA 19044

71007-07

PRINCIPAL DISPLAY PANEL - 0.3 mg WRAP LABEL

Lineage Therapeutics

epinephrine injection, USP

auto-injector

0.3 mg

Wraplabel (Wraplabel)

PRINCIPAL DISPLAY PANEL - 0.3 mg PACKAGE LABEL

Pdp (2009)