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.

2.1 General Considerations

Inspect visually for particulate matter and discoloration prior to administration, solution should be clear and colorless. Do not use if the solution is colored or cloudy, or if it contains particulate matter.

2.2 Recommended Dosage and Administration Instructions for Anaphylaxis

The recommended dosage of Epinephrine Injection is based on weight and is provided in Table 1. Administer undiluted Epinephrine Injection intramuscularly or subcutaneously in the anterolateral aspect of the thigh.

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In the absence of clinical improvement or if symptoms worsen after the initial treatment, additional doses of Epinephrine Injection may be repeated every 5 to 10 minutes as necessary.

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Monitor clinically for cardiac effects.

Administration Instructions

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For intramuscular administration, use a needle long enough (at least 1/2 inch to 5/8 inch) to ensure the injection is administered into the muscle.

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To minimize the risk of injection related injury to a pediatric patient, hold the leg firmly in place and limit movement prior to and during an injection.

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Inject 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.

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Do not administer repeated injections at the same site, as the resulting vasoconstriction may cause tissue necrosis.

2.3 Recommended Dosage and Administration Instructions for Hypotension associated with Septic Shock

Dilute 1 mL (1 mg) of epinephrine from its vial into 1,000 mL of one of the following solutions: 5% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; or 5% Dextrose and 0.2% Sodium Chloride Injection. Each mL of this dilution contains 1 mcg of epinephrine. The diluted solutions can be stored for up to 4 hours at room temperature (20°C to 25°C) or 24 hours under refrigerated conditions (2°C to 8°C). Administration in Sodium Chloride Injection alone is not recommended. If indicated, administer whole blood or plasma separately.

Whenever possible, give infusions of epinephrine into a large vein. Avoid using a catheter tie-in technique, because the obstruction to blood flow around the tubing may cause stasis and increased local concentration of the drug. Avoid the veins of the leg in elderly patients or in those suffering from occlusive vascular disorders.

To provide hemodynamic support in septic shock associated hypotension in adult patients, the suggested dosing infusion rate of intravenously administered epinephrine is 0.05 mcg/kg/min to 2 mcg/kg/min, and is titrated to achieve a desired mean arterial pressure (MAP). The dosage may be adjusted periodically, such as every 10 to15 minutes, in increments of 0.05 mcg/kg/min to 0.2 mcg/kg/min, to achieve the desired blood pressure goal. The ideal body weight (IBW) should be used as the weight parameter for dosing epinephrine in adult patients with septic shock associated hypotension.

After hemodynamic stabilization, wean incrementally over time, such as by decreasing doses of epinephrine every 30 minutes over a 12 to 24 hour period.

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.

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.

7.1 Drugs Antagonizing Pressor Effects of Epinephrine

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α-blockers, such as phentolamine

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Vasodilators, such as nitrates

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Diuretics

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Antihypertensives

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Ergot alkaloids

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Phenothiazine antipsychotics

7.2 Drugs Potentiating Pressor Effects of Epinephrine

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Sympathomimetics

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β-blockers, such as propranolol

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Tricyclic anti-depressants

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Monoamine oxidase (MAO) inhibitors

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Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone

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Clonidine

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Doxapram

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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)]

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β-blockers, such as propranolol

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Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane

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Antihistamines

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Thyroid hormones

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Diuretics

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Cardiac glycosides, such as digitalis glycosides

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Quinidine

7.4 Drugs Potentiating Hypokalemic Effects of Epinephrine

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Potassium depleting diuretics

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Corticosteroids

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Theophylline

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

12.1 Mechanism of Action

12.2 Pharmacodynamics

Epinephrine increases glycogenolysis, reduces glucose up take by tissues, and inhibits insulin release in the pancreas, resulting in hyperglycemia and increased blood lactic acid.

12.3 Pharmacokinetics

Following intravenous injection, epinephrine is rapidly cleared from the plasma with an effective half-life of < 5 min. A pharmacokinetic steady state following continuous intravenous infusion is achieved within 10-15 min. In patients with septic shock, epinephrine displays dose-proportional pharmacokinetics in the infusion dose range of 0.03 to 1.7 mcg/kg/min.

Epinephrine is extensively metabolized with only a small amount excreted unchanged.

Epinephrine is rapidly degraded to vanillylmandelic acid, an inactive metabolite, by monoamine oxidase and catechol-O-methyltransferase that are abundantly expressed in the liver, kidneys and other extraneuronal tissues. The tissues with the highest contribution to removal of circulating exogenous epinephrine are the liver (32%), kidneys (25%), skeletal muscle (20%), and mesenteric organs (12%).

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.

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 (15-fold the highest human intramuscular or subcutaneous daily dose) during gestation days 3 to 9.

13.2 Animal Toxicology and/or Pharmacology

Epinephrine was associated with metabolic effects, decreased mesentery, coronary and renal conductance in a sheep model of septic shock. Data from hemolysis study have shown that epinephrine at 1:1000 dilution is non-hemolytic. Epinephrine infusion significantly increased the MAP (69 vs. 86 mmHg) and cardiac output (6.4 vs. 7.1 L/min) and decreased renal blood flow (330 vs. 247 mL/min).