Epinephrine

Epinephrine is a non-selective alpha and beta adrenergic agonist indicated:

• For emergency treatment of allergic reactions (Type 1), including anaphylaxis, in adults and pediatric patients. ( 1.1 )
• To increase mean arterial blood pressure in adult patients with hypotension associated with septic shock. ( 1.2 )

1.1 Anaphylaxis Epinephrine Injection is indicated for emergency treatment of type I allergic reactions, including anaphylaxis, in adults and pediatric patients.

1.2 Hypotension associated with Septic Shock Epinephrine Injection is indicated to increase mean arterial blood pressure in adult patients with hypotension associated with septic shock.

Injection: Epinephrine injection USP is a sterile, nonpyrogenic, clear and colorless solution supplied as 30 mg/30 mL(1 mg/mL) in a multiple dose amber glass vial. Injection solution: 30 mg/30 mL (1 mg/mL) Multiple Dose Vial ( 3 )

None. None. ( 4 )

• Do not inject into buttocks, digits, hands, or feet. ( 5.1 )
• Avoid extravasation into tissues, which can cause local necrosis. ( 5.3 )
• Monitor patient for acute severe hypertension. ( 5.4 )
• Potential for pulmonary edema, which may be fatal. ( 5.5 )
• May constrict renal blood vessels and decrease urine formation. ( 5.6 )
• May induce potentially serious cardiac arrhythmias or aggravate angina
• pectoris, particularly in patients with underlying heart disease. ( 5.7 )
• Presence of sulfite in this product should not deter use. ( 5.8 )

5.1 Injection-Related Complications for Anaphylaxis Injection into the anterolateral aspect of the thigh (vastus lateralis muscle) is the most appropriate location for administration because of its location, size, and available blood flow. Injection into (or near) smaller muscles, such as in the deltoid, is not recommended. Do not administer repeated injections of epinephrine at the same site, as the resulting vasoconstriction may cause tissue necrosis. Do Not Inject Intravenously Large doses or accidental intravenous injection of undiluted 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 and has been associated with the development of Clostridial infections (gas gangrene). Do not inject into digits, hands, or feet. 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 tissue necrosis.

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.

5.3 Extravasation and Tissue Necrosis with Intravenous Infusion Avoid extravasation of epinephrine into the tissues, to prevent local necrosis. When Epinephrine Injection is administered intravenously, the infusion site should be checked frequently for free flow. Blanching along the course of the infused vein, sometimes without obvious extravasation, may be attributed to vasa vasorum constriction with increased permeability of the vein wall, permitting some leakage. This also may progress on rare occasions to superficial slough. Hence, if blanching occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside. There is a potential for gangrene in a lower extremity when infusions of catecholamine are given in an ankle vein. Antidote for Extravasation Ischemia: To prevent sloughing and necrosis in areas in which extravasation has taken place, infiltrate the area with 10 mL to 15 mL of saline solution containing from 5 mg to 10 mg of phentolamine, an adrenergic blocking agent. Use a syringe with a fine hypodermic needle, with the solution being infiltrated liberally throughout the area, which is easily identified by its cold, hard, and pallid appearance. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours.

5.4 Hypertension Because individual response to epinephrine may vary significantly, monitor blood pressure frequently and titrate to avoid excessive increases in blood pressure. Patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types may experience severe, prolonged hypertension when given epinephrine.

5.5 Pulmonary Edema Epinephrine increases cardiac output and causes peripheral vasoconstriction, which may result in pulmonary edema.

5.6 Renal Impairment Epinephrine constricts renal blood vessels, which may result in oliguria or renal impairment.

5.7 Cardiac Arrhythmias and Ischemia Epinephrine may induce cardiac arrhythmias and myocardial ischemia in patients, especially patients suffering from coronary artery disease, or cardiomyopathy.

5.8 Allergic Reactions Associated with Sulfite Epinephrine is the preferred treatment for serious allergic 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. The presence of sulfite(s) in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations.

The following adverse reactions associated with the use of epinephrine were identified in clinical use, observational trials, case reports, 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. Adverse reactions are listed below by body system: Cardiovascular : angina, arrhythmias, cerebral hemorrhage (particularly in elderly patients with cardiovascular disease), hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, ventricular ectopy and stress cardiomyopathy. Gastrointestinal: nausea, vomiting Metabolism and Nutrition Disorders: transient hyperglycemia, sweating Neurological : disorientation, dizziness, headache, impaired memory, panic, psychomotor agitation (particularly in patients with Parkinson's disease), sleepiness, tingling, tremor, weakness. Psychiatric : anxiety, apprehensiveness, restlessness. Respiratory: respiratory difficulties Skin and subcutaneous tissue disorders: skin and soft tissue infections, necrotizing fasciitis, myonecrosis (gas gangrene) Most common adverse reactions to systemically administered epinephrine are headache; anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; peripheral coldness; nausea/vomiting; and/or respiratory difficulties. Arrhythmias, including fatal ventricular fibrillation, rapid rises in blood pressure producing cerebral hemorrhage, and angina have occurred. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

• Drugs that counter the pressor effects of epinephrine include alpha blockers, vasodilators such as nitrates, diuretics, antihypertensives, and ergot alkaloids, phenothiazine antipsychotics. ( 7.1 )
• Drugs that potentiate the effects of epinephrine include sympathomimetics, beta blockers, tricyclic antidepressants, MAO inhibitors, COMT inhibitors, clonidine, doxapram, oxytocin. ( 7.2 )
• Drugs that increase the arrhythmogenic potential of epinephrine include beta blockers, cyclopropane and halogenated hydrocarbon anesthetics, quinidine, antihistamines, exogenous thyroid hormones, diuretics, and cardiac glycosides. Observe for development of cardiac arrhythmias. ( 7.3 )
• Potassium-depleting drugs, including corticosteroids, diuretics, and theophylline, potentiate the hypokalemic effects of epinephrine. ( 7.4 )

7.1 Drugs Antagonizing Pressor Effects of Epinephrine

• α-blockers, such as phentolamine
• Vasodilators, such as nitrates
• Diuretics
• Antihypertensives
• Ergot alkaloids
• Phenothiazine antipsychotics

7.2 Drugs Potentiating Pressor Effects of Epinephrine

• Sympathomimetics
• β-blockers, such as propranolol
• Tricyclic anti-depressants
• Monoamine oxidase (MAO) inhibitors
• Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone
• Clonidine
• Doxapram
• Oxytocin

7.3 Drugs Potentiating Arrhythmogenic Effects of Epinephrine Cardiac arrhythmias are more common among patients receiving any of the following drugs [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6 )]

• β-blockers, such as propranolol
• Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane
• Antihistamines
• Thyroid hormones
• Diuretics
• Cardiac glycosides, such as digitalis glycosides
• Quinidine

7.4 Drugs Potentiating Hypokalemic Effects of Epinephrine

• Potassium depleting diuretics
• Corticosteroids
• Theophylline

• Pregnancy: May cause fetal harm. ( 8.1 )
• Elderly patients and pregnant women may be at greater risk of developing adverse reactions when epinephrine is administered parenterally. ( 8.1 , 8.5 )

8.1 Pregnancy Risk Summary Prolonged experience with epinephrine use in pregnant women over several decades, based on published literature, does not identify 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 hypotension associated with shock, 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, resulted in adverse developmental effects (including gastroschisis, embryonic lethality, and delayed skeletal ossification) at doses approximately 2 times the maximum recommended daily intramuscular, subcutaneous, or intravenous dose (see Data ). The estimated 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 United States 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/or 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. Hypotension associated with septic shock is a medical emergency in pregnancy which can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic shock may increase the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of epinephrine on the fetus. Labor or Delivery Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner for patients in labor or delivery. Hypotension Associated with Septic Shock Epinephrine usually inhibits spontaneous or oxytocin induced contractions of the pregnant human uterus and may delay the second stage of labor. Avoid epinephrine during the second stage of labor. In dosage sufficient to reduce uterine contractions, the drug may cause a prolonged period of uterine atony with hemorrhage. Avoid epinephrine in obstetrics when maternal blood pressure exceeds 130/80 mmHg. Although epinephrine may improve maternal hypotension associated with septic shock, it may result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia. Data Animal Data In an embryofetal development study with pregnant rabbits dosed during the period of organogenesis (on days 3 to 5, 6 to 7, or 7 to 9 of gestation), epinephrine caused teratogenic effects (including gastroschisis) at doses approximately 15 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 1.2 mg/kg/day for 2 to 3 days). Animals treated on days 6 to 7 had decreased number of implantations. In an embryofetal development study, pregnant mice were administered epinephrine (0.1 to 10 mg/kg/day) on Gestation Days 6 to 15. Teratogenic effects, embryonic lethality, and delays in skeletal ossification were observed at approximately 3 times the maximum recommended intramuscular, subcutaneous, or intravenous 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 2 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 pregnant hamsters dosed during the period of organogenesis from gestation days 7 to 10, epinephrine produced reductions in litter size and delayed skeletal ossification at doses approximately 2 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day).

8.2 Lactation Risk Summary There is no information regarding the presence of epinephrine in human milk or the effects of epinephrine on the breastfed infant or on milk production. However, due to its poor oral bioavailability and short half-life, epinephrine exposure is expected to be very low in the breastfed infant. Treatment for anaphylaxis or hypotension associated with septic shock in breastfeeding patients should not be delayed.

8.4 Pediatric Use Anaphylaxis The safety and effectiveness of Epinephrine Injection for the emergency treatment of type I allergic reactions, including anaphylaxis, have been established in pediatric patients. The use of Epinephrine Injection for this indication is supported by clinical use data, which support weight-based dosing for treatment of anaphylaxis in pediatric patients, and other reported clinical experience with the use of epinephrine suggests that the adverse reactions seen in pediatric patients are similar in nature and extent to those both expected and reported in adults. Hypotension Associated with Septic Shock Safety and effectiveness of epinephrine in pediatric patients with septic shock have not been established.

8.5 Geriatric Use Anaphylaxis Clinical studies for the emergency treatment of type I allergic reactions, including 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 emergency treatment of type I allergic reactions, including anaphylaxis, has identified that geriatric patients may be particularly sensitive to the effects of epinephrine. Therefore, for the emergency treatment of type I allergic reactions, including anaphylaxis, consider monitoring geriatric patients for adverse reactions to take into account potential concomitant disease or other drug therapy. Hypotension Associated with Septic Shock Clinical studies of epinephrine for the treatment of hypotension associated with septic shock 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. In general, due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy, consider monitoring geriatric patients for adverse reactions. Avoid the veins in the leg in geriatric patients.

Anaphylaxis 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. It may also 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. Hypotension Epinephrine acts on both alpha and beta-adrenergic receptors. The mechanism of the rise in blood pressure is 3-fold: a direct myocardial stimulation that increases the strength of ventricular contraction (positive inotropic action), an increased heart rate (positive chronotropic action), and peripheral vasoconstriction.