epinephrine

1 INDICATIONS AND USAGE Epinephrine Injection is indicated for the emergency treatment of type I allergic reactions, including anaphylaxis in adult and pediatric patients who weigh 15 kg or greater. Epinephrine Injection is a alpha and beta-adrenergic receptor agonist, indicated for the emergency treatment of type I allergic reactions, including anaphylaxis, in adult and pediatric patients who weigh 15 kg or greater. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of Epinephrine Injection is based on weight. (2.1) Administer Epinephrine Injection intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. (2.2) Recommended Dosage Patient’s Weight Dosage 30 kg or greater 0.3 mg 15 kg to less than 30 kg 0.15 mg In the absence of clinical improvement or if symptoms worsen after the initial treatment, a second dose of Epinephrine Injection may be administered with a second auto-injector starting 5 minutes after the first dose. (2.1) Advise patients when to seek emergency medical assistance for close monitoring of the anaphylactic episode and in the event further treatment is required. (2.1) It is recommended that patients are prescribed and have immediate access to two Epinephrine Injection devices at all times. (2.1) See full prescribing information for administration instructions. (2.2) 2.1 Recommended Dosage Recommended dosage for patients who weigh 15 kg or greater is based on weight and the dosage is provided in Table 1. Administer Epinephrine Injection intramuscularly or subcutaneously into the anterolateral aspect of the thigh. Table 1 Recommended Dosage of Epinephrine Injection Based on Patient’s Weight Patient’s Weight Dosage 30 kg or greater 0.3 mg 15 kg to less than 30 kg 0.15 mg Since the doses of epinephrine delivered from Epinephrine Injection are fixed, use other forms of injectable epinephrine if doses lower than 0.15 mg are deemed necessary. In the absence of clinical improvement or if symptoms worsen after the initial treatment, a second dose of Epinephrine Injection may be administered with a second auto-injector starting 5 minutes after the first dose. Advise patients when to seek emergency medical assistance for close monitoring of the anaphylactic episode and in the event further treatment is required. It is recommended that patients are prescribed and have immediate access to two Epinephrine Injection devices at all times. 2.2 Administration Instructions Injection: 0.3 mg (0.3 mg/0.3 mL) of clear and colorless solution in single-dose pre-filled auto-injector 0.15 mg (0.15 mg/0.15 mL) of clear and colorless solution in single-dose pre-filled auto-injector

5 WARNINGS AND PRECAUTIONS Do not inject intravenously, into buttock, or into digits, hands, or feet. (5.1) Hold the child’s leg firmly in place and limit movement prior to and during injection when administering to young children or infants to minimize the risk of injection-related injury. (5.1) 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. (5.2) Administer with caution in patients with heart disease; may aggravate angina pectoris or produce ventricular arrhythmias. (5.3) May aggravate certain coexisting conditions. (5.3) The presence of a sulfite in this product should not deter use. (5.4) 5.1 Injection-Related Complications Epinephrine Injection should only be injected into the anterolateral aspect of the thigh [see Dosage and Administration (2.2) ] . 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 for this inadvertent administration. Do not inject into buttock Injection into the buttock may not provide effective treatment of anaphylaxis. If Epinephrine Injection is injected into the buttock, advise the patient to administer a second dose of Epinephrine Injection into the anterolateral aspect of the thigh if symptoms worsen or persist, and then go immediately to the nearest emergency room for further treatment of anaphylaxis. Additionally, injection into the buttock has been associated with the development of Clostridial infections (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 and may not provide effective treatment of anaphylaxis. Advise the patient to administer a second dose of Epinephrine Injection into the anterolateral aspect of the thigh if experiencing anaphylaxis, and then go immediately to the nearest emergency room and 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 To minimize the risk of injection related injury when administering Epinephrine Injection to young children or infants, instruct caregivers to hold the child’s leg firmly in place and limit movement prior to and during injection. 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. 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 Epinephrine Injection into the buttock [see Warnings and Precautions (5.1) ] . 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. 5.3 Risks Associated with Use of Epinephrine in Certain Coexisting Conditions 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 si…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Cardiac glycosides, diuretics, or anti-arrhythmics: observe for development of cardiac arrhythmias. (7.1) Tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, certain antihistamines, and catechol-O-methyl transferase inhibitors: may potentiate effects of epinephrine. (7.2) Beta-adrenergic blocking drugs: antagonize cardiostimulating and bronchodilating effects of epinephrine. (7.3) Alpha-adrenergic blocking drugs: antagonize vasoconstricting and hypertensive effects of epinephrine. (7.3) Ergot alkaloids: may reverse the pressor effects of epinephrine. (7.3) 7.1 Drugs Increasing Risk of Cardiac Arrhythmias 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 (5.3) and Adverse Reactions (6) ] . 7.2 Drugs Potentiating Effects of Epinephrine The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine, and catechol-O-methyl transferase (COMT) inhibitors such as entacapone. 7.3 Drugs Antagonizing Effects of Epinephrine 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.

8.1 Pregnancy Risk Summary Prolonged experience with epinephrine use in pregnant women over several decades, based on published literature, have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with anaphylaxis, and treatment with epinephrine should not be delayed (see Clinical Considerations) . In animal reproduction studies, epinephrine administered by the subcutaneous route to pregnant 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 (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Treatment of anaphylaxis during pregnancy should not be delayed. Data Animal Data In an embryofetal development study with rabbits dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including gastroschisis and embryonic lethality) at doses approximately 40 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 1.2 mg/kg/day for two to three days). In an embryofetal development study with mice dosed during the period of organogenesis, epinephrine was shown to be teratogenic (including embryonic lethality) at doses approximately 8 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at maternal subcutaneous dose of 1 mg/kg/day for 10 days). These effects were not seen in mice at approximately 4 times the maximum recommended daily intramuscular or subcutaneous dose (on a mg/m 2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days). In an embryofetal development study with hamsters dosed during the period of organogenesis from gestation days 7 to 10, epinephrine was shown to be teratogenic at doses approximately 7 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Injection-Related Complications [see Warnings and Precautions (5.1) ] Serious Infections at the Injections [see Warnings and Precautions (5.2) ] Risks Associated with Use of Epinephrine in Certain Coexisting Conditions [see Warnings and Precautions (5.3) ] Allergic Reactions Associated with Sulfite [see Warnings and Precautions (5.4) ] The following adverse reactions associated with the use of epinephrine were identified in observational trials, case reports, studies, or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular : angina, arrhythmias (including fatal ventricular fibrillation), cerebral hemorrhage, hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, ventricular ectopy, and stress cardiomyopathy Gastrointestinal Disorders : nausea and vomiting Infections : Clostridial infections (gas gangrene) Metabolism and Nutrition Disorders : transient hyperglycemia, sweating Neurological: disorientation, impaired memory, panic, psychomotor agitation, sleepiness, tingling, weakness, tremor, hypoesthesia, dizziness, headache Psychiatric : anxiety, apprehensiveness, restlessness Respiratory : respiratory difficulties Skin and Subcutaneous Tissue Disorders: bruising, bleeding, discoloration, erythema, necrotizing fasciitis, myonecrosis 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 Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .