Auvi-Q

6 ADVERSE REACTIONS Due to lack of randomized, controlled clinical trials of epinephrine for the treatment of anaphylaxis, the true incidence of adverse reactions associated with the systemic use of epinephrine is difficult to determine. Adverse reactions reported in observational trials, case reports, and studies are listed below. Common adverse reactions to systemically administered epinephrine include anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism [ see WARNINGS AND PRECAUTIONS ( 5.5 ) ]. 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. Injection of epinephrine 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 at the injection site following epinephrine injection in the thigh [ see WARNINGS AND PRECAUTIONS ( 5.2 ) ]. 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 kaleo, Inc. at 1-877-302-8847 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

4 CONTRAINDICATIONS None. None. ( 4 )

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

2 DOSAGE AND ADMINISTRATION Selection of the appropriate dosage strength (AUVI-Q 0.3 mg, AUVI-Q 0.15 mg or AUVI-Q 0.1 mg) is determined according to patient body weight. Patients greater than or equal to 30 kg (approximately 66 pounds or more): AUVI-Q 0.3 mg Patients 15 to 30 kg (33 to 66 pounds): AUVI-Q 0.15 mg Patients 7.5 to 15 kg (16.5 to 33 pounds): AUVI-Q 0.1 mg Inject AUVI-Q intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Instruct caregivers of young children and infants who are prescribed AUVI-Q and who may be uncooperative and kick or move during an injection to hold the child’s leg firmly in place and limit movement prior to and during an injection [ see WARNINGS AND PRECAUTIONS ( 5.2 ) ]. Each AUVI-Q contains a single dose of epinephrine for single-use injection. Since the doses of epinephrine delivered from AUVI-Q are fixed, consider using other forms of injectable epinephrine if doses lower than 0.1 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 AUVI-Q 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 AUVI-Q 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 STORAGE AND HANDLING ( 16.2 ) ]. Patients greater than or equal to 30 kg (66 lbs): AUVI-Q 0.3 mg ( 2 ) Patients 15 to 30 kg (33 to 66 lbs): AUVI-Q 0.15 mg ( 2 ) Patients 7.5 to 15 kg (16.5 to 33 lbs): AUVI-Q 0.1 mg ( 2 ) Inject AUVI-Q intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Each device is a single-use injection. ( 2 )

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

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3 DOSAGE FORMS AND STRENGTHS 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 Injection, 0.1 mg/0.1 mL epinephrine injection, USP, pre-filled auto-injector Injection, 0.3 mg: 0.3 mg/0.3 mL epinephrine injection, USP, pre-filled auto-injector ( 3 ) Injection, 0.15 mg: 0.15 mg/0.15 mL epinephrine injection, USP, pre-filled auto-injector ( 3 ) Injection, 0.1 mg: 0.1 mg/0.1 mL epinephrine injection, USP, pre-filled auto-injector ( 3 )

Auvi-Q epinephrine EPINEPHRINE EPINEPHRINE SODIUM CHLORIDE SODIUM BISULFITE WATER HYDROCHLORIC ACID Auvi-Q epinephrine EPINEPHRINE EPINEPHRINE SODIUM CHLORIDE SODIUM BISULFITE WATER HYDROCHLORIC ACID Auvi-Q epinephrine EPINEPHRINE EPINEPHRINE SODIUM CHLORIDE SODIUM BISULFITE WATER HYDROCHLORIC ACID

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 the 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 under the conditions noted under the 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.

NDA201739

Auvi-Q

epinephrine

60842-021

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR

PRINCIPAL DISPLAY PANEL - NDC: 60842-023-01 - 0.3 mg 2-plus-1 Carton Label 0.3 mg 2-plus-1 Carton Label

TRAINER FOR AUVI-Q® Trainer Instructions for Use Important: The TRAINER for AUVI-Q Does Not contain a needle or medicine. In case of an allergic emergency, use the real AUVI-Q and not the gray Trainer. Always carry your real Auvi-Q with you in case of an allergic emergency. Important Information about the TRAINER for AUVI-Q: Inside your TRAINER for AUVI-Q are: batteries a speaker that will make a beeping sound and that produces electronic voice instructions red and green blinking lights The TRAINER for AUVI-Q batteries are made to last long enough for you to practice 1 time each day for 2 years. If your TRAINER for AUVI-Q does not work properly call your healthcare provider for a new Trainer. What is the TRAINER for AUVI-Q? The TRAINER for AUVI-Q does not contain a needle or medicine and can be reused to practice your injection. Practice with the TRAINER for AUVI-Q before an allergic emergency happens to make sure you are able to safely use the real AUVI-Q in an emergency. Your TRAINER for AUVI-Q Figure A TRAINER for AUVI-Q Top view AUVI-Q AUVI-Q 0.3 mg is orange AUVI-Q 0.15 mg is blue AUVI-Q 0.1 mg is white and lavender TRAINER for AUVI-Q: is inside a gray outer case does not have a needle or medicine inside can be reused (the red safety guard can be placed back on the base of the Trainer after use) has no expiration date has embossed “TRAINER” on top of the device AUVI-Q: is inside an orange (0.3 mg) or blue (0.15 mg) or white and lavender (0.1 mg) outer case contains a needle and epinephrine medicine cannot be reused (the red safety guard cannot be placed back on the base of AUVI-Q after use) has a medicine expiration date listed on the device In case of an allergic emergency, use the real AUVI-Q and not the gray Trainer. Who should practice using the TRAINER for AUVI-Q? Anyone who may need to help you with AUVI-Q in case of an allergic emergency: You Caregivers Family Friends Co-workers Teachers Child Care or Day Care Workers Have them practice using the Trainer and review the Patient Information Leaflet included in the packaging with each prescription of AUVI-Q. For more information and video instructions on the use of AUVI -Q, go to www.AUVI-Q.com or call 1-877-302-8847. Practicing with the TRAINER for AUVI-Q Practice with the TRAINER for AUVI-Q before an allergic emergency happens to make sure you are able to safely use the real AUVI-Q in an emergency. You should practice daily for the first week after you receive your TRAINER for AUVI-Q to help you feel comfortable using AUVI-Q quickly and safely. Even when you are comfortable using the Trainer, continue to practice using it often. How to Use the Trainer How the TRAINER for AUVI-Q works Although the Trainer does not have a needle and contains no medicine, it works the same way as the real AUVI-Q. As with the real AUVI-Q, the TRAINER for AUVI-Q contains an electronic voice instruction system to help guide you through each step of your injection. If the voice instructions do not work for the TRAINER for AUVI-Q for any reason, you can still use the TRAINER for AUVI-Q as instructed in this leaflet to practice. The TRAINER for AUVI-Q has the same blinking red and green lights as the real AUVI-Q. As with the real AUVI-Q, if practicing with a young child or infant, hold the leg firmly in place while using the TRAINER for AUVI-Q. Ask your healthcare provider to show you how to properly hold the leg to practice so that you will be prepared before an allergic emergency happens. Follow These Steps 1.Pull the TRAINER for AUVI-Q from the outer case. See Figure B 2. Pull Red safety guard down and off of the Trainer. See Figure C . Figure B Figure C Note: The red safety guard is made to fit tight similar to the safety guard on the real AUVI-Q. Pull firmly to remove. 3. Place black end against the middle of the outer thigh (through clothing, if needed), then push firmly until you hear a click and hiss sound, and hold in place for 2 seconds. See Figure D . As with the real AUVI-Q, if practicing with a young child or infant, hold the leg firmly in place while using the TRAINER for AUVI-Q. (See Figure E ). Figure D Figure E Note: In an actual emergency, after the injection you would need to seek medical help right away. Only practice using the middle of your outer thigh. The outer thigh is where you would inject with the real AUVI-Q. Note: The TRAINER for AUVI-Q makes a distinct sound (click and hiss) when you push it firmly against your outer thigh. This is the same sound that is made with the real AUVI-Q. This is normal, and indicates AUVI-Q is working correctly. Do not pull AUVI-Q away from your leg when you hear the click and hiss sound. 4. After practicing, reset the TRAINER for AUVI-Q: a. Replace the Red safety guard. Do not hold the black base while inserting the Red safety guard. The Black base will drop down into its original location during Red safety guard insertion. See Figure F . b. Slide the TRAINER for AUVI-Q all the way back into the gray outer case to reset the electronic voice system. See Figure G . Figure F Figure G Note: Leave the TRAINER for AUVI-Q in its outer case for at least 5 seconds between each time you practice to allow the electronic voice system to reset. Storage: Store the TRAINER for AUVI-Q at room temperature; the TRAINER for AUVI-Q should not be used at temperatures less than 50°F (10°C) or greater than 104°F (40°C). Store the TRAINER for AUVI-Q in its outer case. Keep the TRAINER for AUVI-Q away from dirt, chemicals, and water. Disposal: The TRAINER for AUVI-Q contains electronics and lithium coin cell batteries, and should be disposed of in the correct manner. Follow your State and local environmental regulations for disposal. For California Only: This product uses batteries containing Perchlorate Material - special handling may apply. See www.dtsc.ca.gov/hazardouswaste/perchlorate Manufactured for: Kaleo, Inc. Richmond, VA 23219 USA This product may be covered by one or more U.S. patents or pending patent applications. See www.kaleopharma.com/pat for details. Rev Nov 2017 Figure A1 Figure A2 Figure A3 Figure A4 Figure A5 Figure B Figure C Figure D Figure E Figure F Figure G

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 AUVI-Q, 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 AUVI-Q. AUVI-Q 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 AUVI-Q. Young children or infants may be uncooperative and kick or move during an injection. Instruct caregivers to hold the leg of young children or infants firmly in place and limit movement prior to and during injection. [ see WARNINGS AND PRECAUTIONS ( 5.2 ) ] Complete patient information, including dosage, directions for proper administration and precautions can be found inside each AUVI-Q carton. Review AUVI-Q’s instructional and safety systems with patients and/or caregivers. These systems include the printed label on the surface of AUVI-Q showing instructions for use and a diagram depicting the injection process, an automatic needle retraction system, visual prompts, electronic beeps, and voice instructions for use. Instruct patients and/or caregivers that the needle will not be visible after the injection and they may not feel the injection when it occurs. Instruct patients that AUVI-Q includes a 2-second countdown after it is activated and then the voice instructions will indicate the injection is complete and to seek emergency medical attention. Instruct patients that AUVI-Q’s black base will lock up onto the device housing and the lights will blink red after the injection is complete. These post-use indicators help patients and/or caregivers know that AUVI-Q has been activated and an epinephrine injection administered. Instruct patients and/or caregivers to use and practice with the Trainer to familiarize themselves with the use of AUVI-Q 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 symptoms and signs 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 Patients should be advised 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 Patients should be instructed to inspect the epinephrine solution visually through the viewing window periodically. AUVI-Q should be replaced if the epinephrine solution appears discolored (pinkish color or darker than slightly yellow), cloudy, or contains particles. Epinephrine is light sensitive and should be stored in the outer case provided to protect it from light. Instruct patients that AUVI-Q must be used or properly disposed once the red safety guard is removed [ see STORAGE AND HANDLING ( 16.2 ) ]. Complete patient information, including dosage, directions for proper administration and precautions can be found inside each AUVI-Q carton. Manufactured for: Kaleo, Inc. Richmond, VA 23219 USA This product may be covered by one or more U.S. patents or pending patent applications. See www.kaleopharma.com/pat for details. *For California Only: This product uses batteries containing Perchlorate Material – special handling may apply. See www.dtsc.ca.gov/hazardouswaste/perchlorate

Instructions for Use Read these Instructions for Use carefully before you need to use your AUVI-Q. Before you use AUVI-Q, make sure your healthcare provider shows you the right way to use it. If you have any questions, ask your healthcare provider. If you are administering AUVI-Q to a young child or infant, hold the leg firmly in place and limit movement prior to and while administering an injection. Automated Voice Instructions AUVI-Q contains an electronic voice instruction system to help guide you through each step of your injection. If the voice instructions do not work for any reason, use AUVI-Q as instructed in these Instructions for Use. It will still work during an allergic reaction emergency. How to use your AUVI-Q Figure A. 1. Pull AUVI-Q up from the outer case. See Figure B . Do not go to step 2 until you are ready to use AUVI-Q. If you are not ready to use AUVI-Q, put it back in the outer case. Figure B. 2. Pull Red safety guard down and off of AUVI-Q. See Figure C . To reduce the chance of an accidental injection, do not touch the black base of the auto-injector, which is where the needle comes out. If an accidental injection happens, get medical help right away. Note: The red safety guard is made to fit tight. Pull firmly to remove. Figure C. 3. Place black end of AUVI-Q against the middle of the outer thigh (through clothing, if needed), then push firmly until you hear a click and hiss sound, and hold in place for 2 seconds. See Figure D . Only inject into the middle of the outer thigh. Do not inject into any other part of the body. If you are administering AUVI-Q to a young child or infant, hold the leg firmly in place while administering an injection See Figure E . Figure D. (For AUVI-Q 0.3 mg and AUVI-Q 0.15 mg) Figure E. (For AUVI-Q 0.1 mg) Note: AUVI-Q makes a distinct sound (click and hiss) when you push it against your outer thigh. This is normal and indicates AUVI-Q is working correctly. Do not pull AUVI-Q away from your leg when you hear the click and hiss sound. The needle automatically retracts after the injection is complete, so the needle will not be visible after the injection. AUVI-Q includes a 2-second countdown after it is activated, then the voice instruction will indicate the injection is complete, and to seek emergency medical attention, AUVI-Q will beep, and the lights will blink red. 4. Get emergency medical help right away. Replace the outer case and talk to your healthcare provider about the right way to throw away your AUVI-Q. Ask your healthcare provider for an AUVI-Q prescription refill. After the use of AUVI-Q: The black base will lock into place. The voice instruction system will say “seek emergency medical attention”, say “this AUVI-Q has been used…”, and the lights will blink red. The red safety guard cannot be replaced. The viewing window will no longer be clear. It is normal for some medicine to remain in your AUVI-Q after you have received your dose of medicine. Talk to your healthcare provider about the right way to throw away your AUVI-Q. AUVI-Q is a single-use auto-injector and cannot be reused. Until you throw away your used AUVI-Q, the electronic voice instruction system will remind you that it has been used when the outer case is removed. If you will be administering AUVI-Q to a young child or infant, ask your healthcare provider to show you how to properly hold the leg in place while administering a dose. This Patient Information has been approved by the U.S. Food and Drug Administration. Rev Nov 2017 Manufactured for: Kaleo, Inc. Richmond, VA 23219 USA This product may be covered by one or more U.S. patents or pending patent applications. See www.kaleopharma.com/pat for details. *For California Only: This product uses batteries containing Perchlorate Material – special handling may apply. See www.dtsc.ca.gov/hazardouswaste/perchlorate

8.5 GERIATRIC USE Clinical studies of AUVI-Q did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Epinephrine 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 AUVI-Q 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 doses of epinephrine delivered from AUVI-Q are fixed, consider using other forms of injectable epinephrine if doses lower than 0.1 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 a 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 daily intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day for 4 days).

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 a 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 daily intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day for 4 days). 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 AUVI-Q 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 doses of epinephrine delivered from AUVI-Q are fixed, consider using other forms of injectable epinephrine if doses lower than 0.1 mg are deemed necessary. 8.5 GERIATRIC USE Clinical studies of AUVI-Q did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Epinephrine 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 16.1 HOW SUPPLIED Carton containing two AUVI-Q (epinephrine injection, USP) 0.3 mg auto-injectors and a single AUVI-Q Trainer - NDC 60842-023-01 Carton containing two AUVI-Q (epinephrine injection, USP) 0.15 mg auto-injectors and a single AUVI-Q Trainer - NDC 60842-022-01 Carton containing two AUVI-Q (epinephrine injection, USP) 0.1 mg auto-injectors and a single AUVI-Q Trainer - NDC 60842-021-01 Rx only 16.2 STORAGE AND HANDLING Epinephrine is light sensitive and should be stored in the outer case provided to protect it from light. Store at 20°to 25°C (68°to 77°F); excursions permitted to 15°to 30°C (59°to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate. Before using, check to make sure the solution in the auto-injector is clear and colorless. Replace the auto-injector if the solution is discolored, cloudy, or contains particles.

16.1 HOW SUPPLIED Carton containing two AUVI-Q (epinephrine injection, USP) 0.3 mg auto-injectors and a single AUVI-Q Trainer - NDC 60842-023-01 Carton containing two AUVI-Q (epinephrine injection, USP) 0.15 mg auto-injectors and a single AUVI-Q Trainer - NDC 60842-022-01 Carton containing two AUVI-Q (epinephrine injection, USP) 0.1 mg auto-injectors and a single AUVI-Q Trainer - NDC 60842-021-01 Rx only