Epinephrine, Albuterol Sulfate, Nitroglycerin, Diphenhydramine Hydrochloride, Aspirin

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

2 DOSAGE AND ADMINISTRATION Patients greater than or equal to 30 kg (66 lbs): 0.3 mg ( 2 ) Patients 15 to 30 kg (33 lbs-66 lbs): 0.15 mg ( 2 ) Inject intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Each device is a single-dose injection. 2.1 Recommended Dosage According to Patient Body Weight Patients greater than or equal to 30 kg (approximately 66 pounds or more): 0.3 mg Patients 15 kg to 30 kg (33 pounds to 66 pounds): 0.15 mg 2.2 Administration Instructions Inject the single-dose epinephrine injection intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. Do not inject intravenously, and do not inject into buttocks, into digits, hands or feet [see Warnings and Precautions (5.2)]. Instruct caregivers of young children who are prescribed an epinephrine injection and who may be uncooperative and kick or move during an injection to hold the leg firmly in place and limit movement prior to and during an injection [see Warnings and Precautions (5.2)]. Each epinephrine injection is a single-dose of epinephrine injection for single use. Since the doses of epinephrine delivered from epinephrine injection are fixed, consider using other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary. With severe persistent anaphylaxis, repeat injections with an additional epinephrine injection 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 should be inspected visually for particulate matter and discoloration.

6 ADVERSE REACTIONS Due to the lack of randomized, controlled clinical trials of epinephrine for the treatment of anaphylaxis, the true incidence of adverse reactions associated with the systemic use of epinephrine is difficult to determine. Adverse reactions reported in observational trials, case reports, and studies are listed below. Common adverse reactions to systemically administered epinephrine include anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism [see Warnings and Precautions (5.5)] . Cardiovascular Reactions Arrhythmias, including fatal ventricular fibrillation, have been reported, particularly in patients with underlying cardiac disease or those receiving certain drugs [see Warnings and Precautions (5.5) and Drug Interactions (7)] . Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease [see Warnings and Precautions (5.5)] . Angina may occur in patients with coronary artery disease [see Warnings and Precautions (5.5)] . Rare cases of stress cardiomyopathy have been reported in patients treated with epinephrine. Reactions from Accidental Injection and/or Improper Technique Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [see Warnings and Precautions (5.2)] . Adverse reactions experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury. Lacerations, bent needles, and embedded needles have been reported when epinephrine injection has been injected into the thigh of young children who are uncooperative and kick or move during an injection [see Warnings and Precautions (5.2)] . Injection into the buttock has resulted in cases of gas gangrene [see Warnings and Precautions (5.2)] . Skin and Soft Tissue Infections Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported following epinephrine injection in the thigh [see Warnings and Precautions (5.3)] . Adverse reactions to epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and/or respiratory difficulties. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Pharmacokinetics In a single-dose bioavailability study which enrolled six healthy, male volunteers, transient low albuterol levels (close to the lower limit of quantitation) were observed after administration of two puffs from both Albuterol Sulfate Inhalation Aerosol and a CFC 11/12 propelled albuterol inhaler. No formal pharmacokinetic analyses were possible for either treatment, but systemic albuterol levels appeared similar. Clinical Trials In a 12-week, randomized, double-blind, double-dummy, active- and placebo-controlled trial, 565 patients with asthma were evaluated for the bronchodilator efficacy of Albuterol Sulfate Inhalation Aerosol (193 patients) in comparison to a CFC 11/12 propelled albuterol inhaler (186 patients) and an HFA-134a placebo inhaler (186 patients). Serial FEV 1 measurements (shown below as percent change from test-day baseline) demonstrated that two inhalations of Albuterol Sulfate Inhalation Aerosol produced significantly greater improvement in pulmonary function than placebo and produced outcomes which were clinically comparable to a CFC 11/12 propelled albuterol inhaler. The mean time to onset of a 15% increase in FEV 1 was 6 minutes and the mean time to peak effect was 50 to 55 minutes. The mean duration of effect as measured by a 15% increase in FEV 1 was 3 hours. In some patients, duration of effect was as long as 6 hours. In another clinical study in adults, two inhalations of Albuterol Sulfate Inhalation Aerosol taken 30 minutes before exercise prevented exercise-induced bronchospasm as demonstrated by the maintenance of FEV 1 within 80% of baseline values in the majority of patients. In a 4-week, randomized, open-label trial, 63 children, 4 to 11 years of age, with asthma were evaluated for the bronchodilator efficacy of Albuterol Sulfate Inhalation Aerosol (33 pediatric patients) in comparison to a CFC 11/12 propelled albuterol inhaler (30 pediatric patients). Serial FEV 1 measurements as percent change from test-day baseline demonstrated that two inhalations of Albuterol Sulfate Inhalation Aerosol produced outcomes which were clinically comparable to a CFC 11/12 propelled albuterol inhaler. The mean time to onset of a 12% increase in FEV 1 for Albuterol Sulfate Inhalation Aerosol was 7 minutes and the mean time to peak effect was approximately 50 minutes. The mean duration of effect as measured by a 12% increase in FEV 1 was 2.3 hours. In some pediatric patients, duration of effect was as long as 6 hours. In another clinical study in pediatric patients, two inhalations of Albuterol Sulfate Inhalation Aerosol taken 30 minutes before exercise provided comparable protection against exercise-induced bronchospasm as a CFC 11/12 propelled albuterol inhaler. Albut2