EPINEPHRINE (Generic for ADRENALIN)

Administration


General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use solutions that are pinkish to brownish in color, cloudy, or contain a precipitate or particulate matter.
-Avoid extravasation and inadvertent digital or intraarterial injection.
-Never inject epinephrine or epinephrine-containing products into extremities such as fingers, toes, hands, or feet.
-Do not administer repeated injections at the same site.
-If extravasation or accidental injection occurs, infiltrate the ischemic area as soon as possible with phentolamine.
-Updates for coronavirus disease 2019 (COVID-19): The FDA is allowing epinephrine 1 mg/mL and 30 mg/30 mL to be used beyond the labeled in-use time to help ensure access during COVID-related drug shortages. This period should be as short as possible, and for a maximum of 2 hours at room temperature or 4 hours when refrigerated. In-use time is defined as the maximum amount of time allowed to elapse between penetration of a closed-container system or after reconstitution of a lyophilized drug before patient administration.
Intravenous Administration
-Use a central vein whenever possible. If peripheral administration is necessary, use a 20-gauge or larger catheter. Administration via a low-lying umbilical venous catheter provides the most rapid and reliable medication delivery in neonates. Avoid administration in an ankle vein.
-Check the infusion site frequently for free flow. If blanching along the course of the infused vein occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside.
-Epinephrine is inactivated in alkaline solutions; it is incompatible with sodium bicarbonate.

IV Push
-May administer at a concentration of 0.1 mg/mL directly into the vein.
-Do not interrupt CPR to administer epinephrine. Administer epinephrine during chest compressions; the timing of drug administration is less important than the need to minimize chest compression interruption.
-Follow administration with a saline flush to promote entry into central circulation.

Continuous IV Infusion
Dilution
-Dilute with a compatible IV solution prior to administration. Although FDA-approved labeling recommends dilution in dextrose-containing solutions to protect against significant loss of potency by oxidation, dilution in 0.9% Sodium Chloride Injection is physically compatible.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 20 mcg/mL or 40 mcg/mL.
-Neonates: Maximum concentration should not exceed 60 mcg/mL.
-Infants, children, and adolescents: Concentrations of 16 mcg/mL, 32 mcg/mL, and 64 mcg/mL have been commonly used; maximum concentration should not exceed 64 mcg/mL.
Administration
-Administer via a large vein, whenever possible. Avoid using a catheter tie-in technique.
-Adjust the rate of infusion as needed to maintain desired response. In general, low-dose infusions (less than 0.3 mcg/kg/minute) produce beta-adrenergic effects (e.g., tachycardia, inotropy, decreased systemic vascular resistance), while higher dose infusions (more than 0.3 mcg/kg/minute) cause alpha-adrenergic vasoconstriction.

Extravasation Management
-Stop the infusion or injection immediately.
-Before removing the catheter or needle, attempt to aspirate fluid from the extravasated area.
-Elevate the affected limb to minimize swelling and encourage lymphatic resorption of the drug.
-Apply warm compresses to modify viscosity, increase local blood flow, and enhance drug removal.
-Neonates: Infiltrate the area with 1 mL (in 5 divided doses of 0.2 mL) of a solution containing preservative free saline and phentolamine at a concentration of 0.25 to 0.5 mg/mL.
-Infants, children, and adolescents: Infiltrate the area with 1 to 5 mL (in 5 divided doses) of a solution containing preservative free saline and phentolamine at a concentration of 0.5 to 1 mg/mL. FDA-approved labeling recommends infiltrating the area with 10 to 15 mL of a saline solution containing 5 to 10 mg of phentolamine.
-Use a syringe with a fine hypodermic needle and liberally infiltrate throughout the ischemic area which is easily identified by its cold, hard, and pallid appearance. The solution can also be administered through the infiltrated cannula, if still in place.
-Sympathetic blockade with phentolamine causes immediate and noticeable local hyperemic changes if the area is infiltrated within 12 hours of extravasation.
-May redose phentolamine if the patient remains symptomatic.
-Alternatives to phentolamine include topical nitroglycerin 2% (apply 1-inch strip to area, may redose every 8 hours) and terbutaline (1 mg in 10 mL saline, injected locally).
-Digital ischemia may require smaller administration volumes.

Intramuscular Administration
-Inject epinephrine into the anterolateral aspect of the thigh, through clothing if necessary. Do NOT inject into the buttock, digits, hands, or feet. Avoid injection into or near smaller muscles, such as the deltoid, due to possible differences in absorption.
-Instruct caregivers to hold the leg of young children firmly in place and limit movement prior to and during the injection.
-Device failure has been reported with epinephrine auto-injectors. Device failure may result from spontaneous activation caused by using a sideways force to remove the blue safety release, inadvertent or spontaneous activation due to a raised blue safety release, or difficulty removing the device from the carrier tube. Review appropriate use instructions with patients and their caregivers. Prior to dispensing or using, ensure that the auto-injector slides out of the carrier tube and that the blue safety release is not raised. If the blue safety release is raised, the auto-injector should not be used because the device could activate by accident. Do not try to push the blue safety release back down. A device that has been activated by accident cannot be used for a patient in an emergency.
-Consult product-specific labeling for device use instructions. Recommended "hold times" may vary among devices.
-Most auto-injectors and prefilled syringes are for single-use only. Instruct patients to carry 2 auto-injectors in case 2 doses are needed or if the first auto-injector is activated before the dose can be given.
-Instruct patients to seek medical attention immediately after administration of the first injection.

Subcutaneous Administration
-Subcutaneous epinephrine is not routinely recommended in the treatment of anaphylaxis due to delayed absorption.
-Inject epinephrine into the anterolateral aspect of the thigh, through clothing if necessary. Do NOT inject into the buttock, digits, hands, or feet. Avoid injection into or near smaller muscles, such as the deltoid, due to possible differences in absorption.
-Instruct caregivers to hold the leg of young children firmly in place and limit movement prior to and during the injection.
-Device failure has been reported with epinephrine auto-injectors. Device failure may result from spontaneous activation caused by using a sideways force to remove the blue safety release, inadvertent or spontaneous activation due to a raised blue safety release, or difficulty removing the device from the carrier tube. Review appropriate use instructions with patients and their caregivers. Prior to dispensing or using, ensure that the auto-injector slides out of the carrier tube and that the blue safety release is not raised. If the blue safety release is raised, the auto-injector should not be used because the device could activate by accident. Do not try to push the blue safety release back down. A device that has been activated by accident cannot be used for a patient in an emergency.
-Consult product-specific labeling for device use instructions. Recommended "hold times" may vary among devices.
-Most auto-injectors and prefilled syringes are for single-use only. Instruct patients to carry 2 auto-injectors in case 2 doses are needed or if the first auto-injector is activated before the dose can be given.
-Instruct patients to seek medical attention immediately after administration of the first injection.

Other Injectable Administration
Intraosseous Administration
NOTE: Epinephrine is not FDA-approved for intraosseous administration.
-During cardiopulmonary resuscitation, the same dosage may be given via the intraosseous route if IV access is unsuccessful or not feasible.
-Follow administration with a saline flush to promote entry into central circulation.



Topical Administration
Other Topical Formulations
Topical Nasal Administration
-Do not use solutions that are pinkish to brownish in color.
-Dilute the 1 mg/mL epinephrine solution with isotonic salt solution to a final concentration of 0.1, 0.2, or 0.5 mg/mL prior to administration.
-Apply locally as drops, spray, or with a sterile swab.



Inhalation Administration
Oral Inhalation Administration
Inhalation Solution (Primatene Mist Aerosol Spray, nonprescription product)
-Before first use, activate the inhaler by shaking well and then prime into the air with 4 pumps.
-Shake well and then prime into the air with 1 pump before each subsequent use.
-Exhale completely and place mouthpiece into mouth. Inhale deeply while pressing down on the top of inhaler, then continue the deep breath.
-Hold breath as long as possible before exhaling.
-Wait at least 1 minute. If symptoms are not relieved, take a second inhalation.
-Do not exceed recommended daily dosage. Wait at least 4 hours between doses.
-Wash inhaler after each day of use by running water through the mouthpiece for 30 seconds.



Ophthalmic Administration
-Epinephrine injection MUST be diluted prior to intraocular use.
-Only use the 1 mg/mL single-use vial or ampule intended for ophthalmic administration.
-Visually inspect the product for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use solutions that are pinkish to brownish in color, cloudy, or contain a precipitate or particulate matter.

Irrigation for intraocular use
-Dilute 1 mL of epinephrine 1 mg/mL solution in 100 to 1,000 mL of an ophthalmic irrigation fluid to a final concentration of 1 to 10 mcg/mL.
-Use as an irrigating solution as needed for surgical procedure.

Intracameral injection for intraocular use
-Dilute 1 mL of epinephrine 1 mg/mL solution in an ophthalmic irrigation fluid to a final concentration of 2.5 to 10 mcg/mL.
-Inject a bolus dose of 0.1 mL of diluted solution intracamerally.


Other Administration Route(s)
Endotracheal Administration
NOTE: Epinephrine is not FDA-approved for endotracheal (ET) administration.
-Consider ET administration only when other access is not available. ET administration is the least-preferred route of administration due to its association with unpredictable (but generally low) drug concentrations and lower rates of ROSC and survival.
-If CPR is in progress, stop chest compressions briefly and administer the medication.
-Neonates: Use the 0.1 mg/mL parenteral solution. Dilute the dose in 1 to 5 mL of saline or follow drug administration with a saline flush and 5 consecutive positive-pressure ventilations. If response is inadequate, it may be reasonable to administer an epinephrine dose as soon as IV or IO access is obtained, regardless of the interval.
-Infants, children, and adolescents: Use the 1 mg/mL parenteral solution. Dilute the dose in 1 to 5 mL of saline or follow drug administration with a saline flush (5 mL or more) and 5 consecutive positive-pressure ventilations.

Transient and moderate anxiety, disorientation, hyperactivity, restlessness, apprehension, excitability, memory impairment, nervousness, panic, psychomotor agitation, weakness, dizziness, drowsiness, lightheadedness, headache, tingling, and tremor may occur with therapeutic doses of systemic epinephrine and are more likely in patients with hypertension or hyperthyroidism. Paresthesias, stroke, and central nervous system bleeding have been reported with intravenous epinephrine infusion.

Adrenergically modulated vasoactive and smooth muscle responses to epinephrine can result in nausea, vomiting, diaphoresis, pallor, respiratory distress, respiratory weakness, dyspnea, or apnea. These reactions can occur with therapeutic doses of epinephrine and are more likely to occur in patients with heart disease, hypertension, or hyperthyroidism.

Cardiac arrhythmias (or arrhythmia exacerbation), including palpitations, premature ventricular contractions (PVCs), sinus tachycardia, supraventricular tachycardia (SVT), and severe ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), are well described potential adverse effects of epinephrine due to beta-stimulation of the myocardium and conduction system. Myocardial ischemia and myocardial infarction have also been associated with epinephrine infusion. Chest pain (unspecified) and angina may occur, the latter occurring more frequently in adult patients with coronary artery disease. Stress cardiomyopathy has been reported rarely in patients treated with systemic epinephrine. Patients at risk for epinephrine-induced arrhythmias and ischemia include those with organic heart disease, coronary artery disease, cerebrovascular disease, high blood pressure, and those receiving drugs that sensitize the myocardium. Severe hypertension may occur in patients receiving intravenous epinephrine. Hypertension occurring quickly has resulted in cerebral hemorrhage, especially in patients with cardiovascular disease. When epinephrine is administered as a continuous intravenous infusion, vital signs should be monitored during titration; invasive arterial blood pressure monitoring and central venous pressure monitoring are recommended. Peripheral constriction and cardiac stimulation produced by intravenous administration of epinephrine may result in pulmonary edema. If pulmonary edema occurs, administer a rapid acting alpha-adrenergic blocking drug (e.g., phentolamine) and provide respiratory support. Rales have also been reported. The potential for these serious cardiovascular risks should not outweigh the beneficial effects of the use of epinephrine for acute, life-threatening conditions.

Epinephrine administration may lead to local and/or peripheral vasoconstriction depending on the route of administration. Accidental injection into the fingers, hands, or feet may result in loss of blood flow to those areas which may present as site pallor, coldness, or hypoesthesia. Extravasation of epinephrine, especially with repeated injections or high infusion rates, can result in an injection site reaction leading to severe tissue damage and tissue necrosis. When epinephrine is administered intravenously, the infusion site should be checked frequently for free flow. If skin blanching along the course of the infused vein occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside. If extravasation of intravenous drug or accidental digital injection occurs, infiltrate a diluted phentolamine solution into the area as soon as possible to antagonize vasoconstriction and reduce and/or prevent devastating sloughing and tissue necrosis. Phentolamine causes sympathetic blockage resulting in immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours. Skin laceration and bent or embedded needles have been reported when epinephrine has been injected into the thigh of young children who are uncooperative; instruct caregivers to hold the child's leg firmly to limit movement prior to and during injection. Rare cases of serious skin and soft tissue infection, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene) have been reported at the epinephrine injection site when used for anaphylaxis. Cleansing with alcohol does not kill bacterial spores and does not lower the risk; intramuscular and subcutaneous epinephrine for anaphylaxis should only be administered into the anterolateral aspect of the thigh (not the buttock). Injection site ecchymosis, bleeding, skin discoloration, erythema, and skeletal injury have also been associated with intramuscular and subcutaneous use. Piloerection, a common sympathetic reflex, has been associated with intravenous administration.

Hypoglycemia, hyperglycemia, insulin resistance, hypokalemia, and lactic acidosis have been associated with intravenous epinephrine infusion. Transient increases in blood sugar or hyperglycemia may occur in diabetic patients administered epinephrine. Metabolic acidosis secondary to accumulation of lactic acid has been associated with long-term administration or overdose of epinephrine.

Intravenously administered epinephrine may initially produce constriction of renal blood vessels, resulting in oliguria. Renal insufficiency has been associated with intravenous infusion.

Appropriate product selection and proper dilution with the intraocular use of epinephrine are imperative. Certain excipients may be harmful to the eye when used ophthalmically. For example, epinephrine products containing sodium bisulfite have been associated with corneal endothelial damage and corneal edema when used in the eye at undiluted concentrations (1 mg/mL).

Although there are no absolute contraindications to the use of parenteral epinephrine when used in acute, life-threatening situations, some product labeling describe epinephrine as contraindicated in persons with known hypersensitivity to sympathomimetic amines, such as epinephrine.

Epinephrine may induce cardiac arrhythmias, myocardial ischemia, and angina pectoris in patients, especially those with coronary artery disease (e.g., angina, acute myocardial infarction), cardiomyopathy, organic cardiac disease, high blood pressure, or those receiving drugs that sensitize the myocardium. Due to cardiac stimulation and peripheral constriction, pulmonary edema may also occur. If pulmonary edema occurs, administer a rapid acting alpha-adrenergic blocking drug (e.g., phentolamine) and provide respiratory support. Although there are no absolute contraindications to the use of parenteral epinephrine when used in acute, life-threatening situations, some product labeling states epinephrine is contraindicated in nonanaphylactic shock. However, some FDA-approved labels include an indication for hypotension associated with septic shock. Use epinephrine with caution in hypovolemia, including in cases of hemorrhagic shock. If possible, correct volume depletion prior to vasopressor initiation. When, as an emergency measure, intraaortic pressures must be maintained to prevent cerebral or coronary artery ischemia, epinephrine can be administered before and concurrently with blood volume replacement.

Although there are no absolute contraindications to the use of parenteral epinephrine when used in acute, life-threatening situations, some product labeling states epinephrine is contraindicated in closed-angle glaucoma because it can exacerbate this condition.

Avoid the use of epinephrine, if possible, in patients with organic brain syndrome or cerebrovascular disease due to the risk of cerebral hemorrhage caused by a sharp rise in blood pressure associated with the intravenous administration of epinephrine. Patients with cerebrovascular disease are at risk for epinephrine-induced cardiac arrhythmias and angina.

Some epinephrine preparations contain sodium metabisulfite and should not be used in patients with sulfite hypersensitivity unless the patient is being treated for an emergent condition such as anaphylaxis or cardiac arrest. Epinephrine is the preferred treatment for anaphylaxis, and the alternatives to using epinephrine in anaphylaxis may not be satisfactory. The presence of sulfite in epinephrine emergency kits or syringes should not deter administration of the drug for emergent treatment of anaphylaxis, even if the patient is sulfite-sensitive.

Epinephrine is a potent vasoconstrictor; inadvertent digital or intraarterial administration can lead to vasoconstriction, vasospasm, thrombosis, and subsequent tissue necrosis. Epinephrine and epinephrine-containing products (e.g., local anesthetics with epinephrine) should never be injected into extremities such as fingers, toes, ears, nose, and genitalia. Do not administer repeated injections at the same site. In addition, caution should be observed to avoid extravasation during intravenous administration as peripheral ischemia, tissue necrosis, and/or gangrene in the surrounding area can occur. Infusion sites should be checked frequently for free flow. If blanching along the course of the infused vein occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside. If inadvertent digital injection or extravasation occurs, the affected area should be infiltrated as soon as possible with a 0.9% Sodium Chloride Injection solution containing phentolamine; inject liberally throughout the ischemic area using a fine hypodermic needle. The ischemic area may be identified by a cool, hard, and pallid appearance. Sympathetic blockade with phentolamine causes immediate and noticeable local hyperemic changes if the area is infiltrated within 12 hours of extravasation. When used for anaphylaxis, epinephrine should be administered into the anterolateral aspect of the thigh (vastus lateralis muscle) because of its location, size, and available blood flow. Injection into the buttock may not be effective for anaphylaxis and has been associated with the development of gas gangrene; cleansing with alcohol does not kill bacterial spores and does not lower the risk. Advise patients to seek medical care if they develop signs or symptoms of infection at the injection site (e.g., persistent redness, warmth, swelling, tenderness).

Use epinephrine with great caution in patients with hypertension, as dangerously high blood pressure may occur. Increases in blood pressure can put patients with hypertension at risk for cardiac arrhythmias. When administered intravenously, monitor vital signs during infusion titration; invasive arterial blood pressure and central venous pressure monitoring are recommended. Patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types may experience severe, prolonged hypertension when given epinephrine.

Epinephrine should be used with caution in patients with thyroid disease such as hyperthyroidism or thyrotoxicosis as well as those with pheochromocytoma; these patients may experience a greater sensitivity to the adverse effects of epinephrine. This is typically not of concern in acute, life-threatening situations.

Epinephrine should be administered with caution to patients with diabetes mellitus. Diabetic patients may experience transient increases in blood glucose. Epinephrine can cause hyperglycemia due to increased glycogenolysis in the liver, decreased tissue uptake of glucose, and decreased insulin release from the pancreas. This is typically not of concern when diluted for admixture with local anesthetics to reduce absorption and prolong the action of the anesthetic or in acute, life-threatening situations.

Use systemic epinephrine cautiously in persons with renal impairment. When administered intravenously, epinephrine may produce constriction of renal blood vessels and a decrease in urine formation.

Dilute epinephrine injection prior to intraocular use. Use only the 1 mg/mL single use vial or ampule specifically intended for ophthalmic administration; concentration and formulation affect the safety of ophthalmic administration. Epinephrine products containing sodium bisulfite have been associated with corneal endothelial damage when used in the eye at undiluted concentrations (1 mg/mL).

Lacerations, bent needles, and embedded needles have been reported when epinephrine has been injected into the thigh of infants and young children who are uncooperative and kick or move during an injection. To minimize the risk of injury, instruct caregivers to hold the leg of young children firmly in place and limit movement prior to and during injection.

Description: Epinephrine is an endogenous sympathomimetic catecholamine produced primarily from norepinephrine in the adrenal medulla. Epinephrine is a nonselective adrenergic agonist; it has a high affinity for beta1-, beta2-, and alpha1-receptors. Exogenous epinephrine is a sympathomimetic drug with dose-dependent effects; beta-adrenergic effects (e.g., inotropy, vasodilation) are more pronounced at low doses and alpha-adrenergic effects (e.g., vasoconstriction) at high doses. Epinephrine has many therapeutic applications. Epinephrine is the drug of choice for anaphylaxis; prompt administration at the onset of symptoms is essential, and the use of intramuscular auto-injector devices in patients with a history of severe allergic reactions is widely accepted. Intravenous epinephrine use is recommended during cardiopulmonary resuscitation (CPR), specifically for the treatment of symptomatic bradycardia, cardiac arrest (asystole, pulseless electrical activity), and as an adjunct to electrical defibrillation in ventricular fibrillation/pulseless ventricular tachycardia. Additionally, epinephrine is used for hypotension, fluid-resistant shock, and inotropic support in a variety of settings (e.g., post-resuscitation and postoperative). Epinephrine and norepinephrine are considered first-line vasopressors for pediatric patients with fluid-refractory septic shock. Although no studies directly compare epinephrine to norepinephrine, epinephrine is generally chosen in the setting of myocardial dysfunction and low cardiac output. Compared to dopamine, epinephrine is associated with a lower risk of mortality and more organ failure-free days in pediatric patients with septic shock. Inhaled racemic epinephrine is used for the treatment of severe croup symptoms and as a bronchodilator; routine use of inhaled epinephrine in young children with bronchiolitis is not recommended. In the U.S., epinephrine administered by a pressurized inhaler is available without a prescription (OTC) for treatment of mild, intermittent asthma and is approved only for pediatric patients 12 years and older who have been diagnosed with asthma by a healthcare provider; it is not a replacement for prescription treatments. While this OTC inhaler is marketed, asthma guidelines do not recommend the use of inhaled epinephrine for the routine management of asthma or as reliever therapy; selective short-acting inhaled beta-2 agonists (SABAs) should be used instead. Injectable epinephrine is generally not recommended for use during asthma exacerbations unless it is needed in addition to standard therapy for acute asthma exacerbation associated with anaphylaxis and angioedema or for exacerbations unresponsive to standard therapy. Parenteral epinephrine is FDA-approved in pediatric patients with no defined age range (auto-injector devices are approved for use in patients weighing 15 kg or more); inhaled racemic epinephrine is approved in patients 4 years of age and older.

For use in cardiopulmonary resuscitation (CPR)*, specifically for the emergency treatment of symptomatic bradycardia*, cardiac arrest* (pulseless electrical activity* or ventricular asystole*), or as an adjunct to electrical defibrillation in the treatment of ventricular fibrillation*/pulseless ventricular tachycardia*:
Intermittent Intravenous or Intraosseous dosage:
Neonates: 0.01 to 0.03 mg/kg/dose (0.1 to 0.3 mL/kg/dose of a 0.1 mg/mL solution) IV or IO; may repeat every 3 to 5 minutes. Do not interrupt CPR to administer drug therapy. After administration, flush the IV line with 0.5 to 1 mL of normal saline to ensure drug delivery. Higher doses of epinephrine are not recommended.
Infants, Children, and Adolescents: 0.01 mg/kg/dose (0.1 mL/kg/dose of a 0.1 mg/mL solution) IV or IO; may repeat every 3 to 5 minutes. Max: 1 mg/dose (10 mL/dose of a 0.1 mg/mL solution). Do not interrupt CPR to administer drug therapy. Higher doses of epinephrine are not recommended except when indicated for exceptional circumstances (e.g., beta-blocker overdosage).
Endotracheal dosage:
NOTE: Vascular access (IV or IO) is the preferred route of epinephrine administration during CPR; endotracheal (ET) administration should only be used if vascular access is delayed or cannot be obtained. Effectiveness of endotracheal epinephrine is controversial; drug absorption is unpredictable, and optimal doses are unknown. Animal studies suggest that the lower epinephrine blood concentrations attained after ET drug administration may result in transient beta2-vasodilation, resulting in decreased blood pressure, lower coronary artery perfusion pressure and flow, and a reduced potential for return of spontaneous circulation.
Neonates: 0.05 to 0.1 mg/kg/dose (0.5 to 1 mL/kg/dose of a 0.1 mg/mL solution) ET; may repeat every 3 to 5 minutes until vascular access is obtained. Follow ET administration with saline flush or dilute the drug in isotonic saline (0.5 to 1 mL) and deliver several consecutive positive-pressure ventilations.
Infants, Children, and Adolescents: 0.1 mg/kg/dose (0.1 mL/kg/dose of a 1 mg/mL solution) ET; may repeat every 3 to 5 minutes until vascular access obtained. Max: 2.5 mg/dose (2.5 mL/dose of a 1 mg/mL solution). If CPR is in progress, stop chest compressions briefly to administer medication. Follow ET administration with saline flush or dilute the drug in isotonic saline (5 mL or more) and deliver several consecutive positive-pressure ventilations.
Continuous Intravenous or Intraosseous dosage for postresuscitation stabilization:
Neonates: 0.1 to 1 mcg/kg/minute continuous IV or IO infusion may be used to maintain cardiac output and/or stabilize the patient after resuscitation. Titrate to desired effect. There is great interpatient variability in response. In general, low-dose infusions (less than 0.3 mcg/kg/minute) generally produce beta-adrenergic effects (tachycardia, inotropy, decreased systemic vascular resistance), while higher-dose infusions (more than 0.3 mcg/kg/minute) cause alpha-adrenergic vasoconstriction.
Infants, Children, and Adolescents: 0.1 to 1 mcg/kg/minute continuous IV or IO infusion may be used to maintain cardiac output and/or stabilize the patient after resuscitation. Titrate to desired effect. There is great interpatient variability in response. In general, low-dose infusions (less than 0.3 mcg/kg/minute) generally produce beta-adrenergic effects (tachycardia, inotropy, decreased systemic vascular resistance), while higher-dose infusions (more than 0.3 mcg/kg/minute) cause alpha-adrenergic vasoconstriction.
-for the treatment of low blood pressure or persistent bradycardia with a pulse in a patient with an at-risk myocardium to prevent cardiac arrest and allow time to treat an acute reversible problem*:
Intravenous or Intraosseous dosage:
Infants, Children, and Adolescents: 0.001 mg/kg/dose IV or IO (one-tenth the standard resuscitation dose); titrate to desired hemodynamic effect. A continuous infusion of 0.01 to 0.2 mcg/kg/minute IV or IO has also been recommended.

For the treatment of hypotension, including during shock* (e.g., anaphylactic shock*, cardiogenic shock*, septic shock*):
Continuous Intravenous Infusion dosage:
Neonates: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate to clinical response. Doses up to 5 mcg/kg/minute may be necessary for shock.
Infants, Children, and Adolescents: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate to clinical response. Doses up to 5 mcg/kg/minute may be necessary for shock.

For the treatment of anaphylaxis:
Intramuscular dosage (general dosing):
Infants and Children weighing 30 kg or less: 0.01 mg/kg/dose (Max: 0.3 mg/dose) IM; may repeat the dose every 5 to 15 minutes as needed for up to 3 injections. If there is no response after 3 to 4 injections, consider an intravenous infusion.
Children and Adolescents weighing more than 30 kg: 0.01 mg/kg/dose (Max: 0.5 mg/dose) IM; may repeat the dose every 5 to 15 minutes as needed for up to 3 injections. If there is no response after 3 to 4 injections, consider an intravenous infusion.
Subcutaneous dosage (general dosing):
Infants and Children weighing 30 kg or less: 0.01 mg/kg/dose (Max: 0.3 mg/dose) subcutaneously; may repeat the dose every 5 to 15 minutes as needed for up to 3 injections. If there is no response after 3 to 4 injections, consider an intravenous infusion. Subcutaneous epinephrine is not routinely recommended in the treatment of anaphylaxis due to delayed absorption.
Children and Adolescents weighing more than 30 kg: 0.01 mg/kg/dose (Max: 0.5 mg/dose) subcutaneously; may repeat the dose every 5 to 15 minutes as needed for up to 3 injections. If there is no response after 3 to 4 injections, consider an intravenous infusion. Subcutaneous epinephrine is not routinely recommended in the treatment of anaphylaxis due to delayed absorption.
Intramuscular dosage (Adrenaclick, Auvi-Q, EpiPen, Symjepi auto-injector/prefilled syringe):
Infants and Children weighing 7.5 to 9 kg: 0.1 mg/dose IM; may repeat the dose for severe persistent anaphylaxis. The patient should not administer more than 2 sequential doses unless under direct medical supervision.
Infants and Children weighing 10 to 14 kg: 0.1 mg/dose IM; may repeat the dose for severe persistent anaphylaxis. Some experts recommend 0.15 mg/dose. The patient should not administer more than 2 sequential doses unless under direct medical supervision.
Infants and Children weighing 15 to 24 kg: 0.15 mg/dose IM; may repeat the dose for severe persistent anaphylaxis. The patient should not administer more than 2 sequential doses unless under direct medical supervision.
Children weighing 25 to 29 kg: 0.15 mg/dose IM; may repeat the dose for severe persistent anaphylaxis. Some experts recommend 0.3 mg/dose. The patient should not administer more than 2 sequential doses unless under direct medical supervision.
Children and Adolescents weighing 30 kg or more: 0.3 mg/dose IM; may repeat the dose for severe persistent anaphylaxis. The patient should not administer more than 2 sequential doses unless under direct medical supervision.
Subcutaneous dosage (Adrenaclick, Auvi-Q, EpiPen, Symjepi auto-injector/prefilled syringe):
Infants and Children weighing 7.5 to 9 kg: 0.1 mg/dose subcutaneously; may repeat the dose for severe persistent anaphylaxis. The patient should not administer more than 2 sequential doses unless under direct medical supervision. Subcutaneous epinephrine is not routinely recommended in the treatment of anaphylaxis due to delayed absorption.
Infants and Children weighing 10 to 14 kg: 0.1 mg/dose subcutaneously; may repeat the dose for severe persistent anaphylaxis. Some experts recommend 0.15 mg/dose. The patient should not administer more than 2 sequential doses unless under direct medical supervision. Subcutaneous epinephrine is not routinely recommended in the treatment of anaphylaxis due to delayed absorption.
Infants and Children weighing 15 to 24 kg: 0.15 mg/dose subcutaneously; may repeat the dose for severe persistent anaphylaxis. The patient should not administer more than 2 sequential doses unless under direct medical supervision. Subcutaneous epinephrine is not routinely recommended in the treatment of anaphylaxis due to delayed absorption.
Children weighing 25 to 29 kg: 0.15 mg/dose subcutaneously; may repeat the dose for severe persistent anaphylaxis. Some experts recommend 0.3 mg/dose. The patient should not administer more than 2 sequential doses unless under direct medical supervision. Subcutaneous epinephrine is not routinely recommended in the treatment of anaphylaxis due to delayed absorption.
Children and Adolescents weighing 30 kg or more: 0.3 mg/dose subcutaneously; may repeat the dose for severe persistent anaphylaxis. The patient should not administer more than 2 sequential doses unless under direct medical supervision. Subcutaneous epinephrine is not routinely recommended in the treatment of anaphylaxis due to delayed absorption.
Intravenous dosage:
Infants, Children, and Adolescents: 0.01 mg/kg/dose (0.1 mL/kg/dose of a 0.1 mg/mL solution) IV every 3 to 5 minutes as needed. Max: 1 mg/dose (10 mL/dose of a 0.1 mg/mL solution).
Continuous Intravenous Infusion dosage:
Infants, Children, and Adolescents: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate dose according to blood pressure, cardiac rate, and oxygenation. Intravenous epinephrine given by continuous infusion may be considered if inadequate response to IM epinephrine and intravenous saline.

For the temporary relief of mild symptoms of intermittent asthma (i.e., transient mild bronchospasm or episodic wheezing):
Oral Inhalation dosage (non-prescription oral inhaler; e.g., Primatene Mist):
Children and Adolescents 12 to 17 years: 1 oral inhalation (0.125 mg); may repeat once after 1 minute if needed. Wait at least 4 hours between doses. Max: 2 inhalations (0.25 mg)/dose and 8 inhalations (1 mg)/day. Guidelines for asthma treatment do not recommend use; prescribe a selective short-acting beta-agonist (SABA).

For asthma exacerbation (e.g., acute care management):
Subcutaneous dosage:
Children 1 to 12 years: 0.01 mg/kg/dose (Max: 0.5 mg/dose) subcutaneously every 20 minutes as needed for up to 3 doses may be given if an inhaled short-acting beta-agonist (e.g., albuterol) is not available. Guidelines state there is no proven advantage of systemic therapy over the use of inhaled short-acting beta-agonists.
Adolescents: 0.3 to 0.5 mg subcutaneously every 20 minutes as needed for up to 3 doses. Guidelines state there is no proven advantage of systemic therapy over the use of inhaled short-acting beta-agonists.
Intramuscular dosage:
Infants and Children weighing less than 30 kg: 0.01 mg/kg/dose (Max: 0.3 mg/dose) IM every 5 to 15 minutes as needed for up to 3 doses. Reserved for patients with poor inspiratory flow, those who cannot cooperate with inhaled therapy, or those with severe asthma with suboptimal response to initial aerosolized therapy. Also, typically reserved for use in addition to standard therapy for asthma complicated by anaphylaxis or angioedema. Guidelines state there is no proven advantage of systemic therapy over inhaled short-acting beta-agonists.
Children and Adolescents weighing 30 kg or more: 0.01 mg/kg/dose (Max: 0.5 mg/dose) IM every 5 to 15 minutes as needed for up to 3 doses. Reserved for patients with poor inspiratory flow, those who cannot cooperate with inhaled therapy, or those with severe asthma with suboptimal response to initial aerosolized therapy. Also, typically reserved for use in addition to standard therapy for asthma complicated by anaphylaxis or angioedema. Guidelines state there is no proven advantage of systemic therapy over inhaled short-acting beta-agonists.

For the treatment of laryngotracheobronchitis (croup)*:
Respiratory (Inhalation) dosage (solution for injection):
Infants and Children 6 months to 12 years: 0.5 mL/kg/dose (Max: 5 mL/dose) of 1 mg/mL solution diluted in 2 to 2.5 mL of saline inhaled by nebulizer every 20 minutes as needed as an alternative if racemic epinephrine is not available; 5 mL of L-epinephrine 1 mg/mL is equivalent to 0.5 mL of racemic epinephrine 2.25%. In general, improvement is seen within 10 to 30 minutes and lasts 2 hours after administration.

For the treatment of nasal congestion:
Nasal topical dosage:
Infants and Children younger than 6 years: Apply 1% solution topically to the nasal area as drops, spray, or with a sterile swab. See manufacturer's directions for use. Use with caution and only under advice of a physician due to greater sensitivity to sympathomimetic effects in this population.
Children and Adolescents 6 to 17 years: Apply 1% solution topically to nasal area as drops, spray, or with a sterile swab. See manufacturer's directions for use.

For mydriasis induction and maintenance during intraocular surgery:
Ophthalmic dosage:
Infants, Children, and Adolescents: Must dilute prior to intraocular use. Dilute 1 mL of epinephrine 1 mg/mL in 100 to 1,000 mL of an ophthalmic irrigation fluid to create an epinephrine concentration of 10 mcg/mL to 1 mcg/mL. Use the irrigating solution as needed for the surgical procedure. After dilution in an ophthalmic irrigating fluid, the solution may also be injected intracamerally as a bolus dose of 0.1 mL at a dilution of 10 mcg/mL to 2.5 mcg/mL. Check product specific labels; only use 1 mg/mL single-use products intended for ophthalmic administration.

Maximum Dosage Limits:
-Neonates
Dependent on route of administration and indication for therapy. For CPR, 0.03 mg/kg/dose IV and 0.1 mg/kg/dose ET.
-Infants
Dependent on route of administration and indication for therapy. For CPR, 0.01 mg/kg/dose (Max: 1 mg/dose) IV/IO and 0.1 mg/kg/dose (Max: 2.5 mg/dose) ET. For anaphylaxis, 0.01 mg/kg/dose (Max: 0.3 mg/dose IM/subcutaneously and 1 mg/dose IV). For croup, 0.5 mL/dose of a 2.25% racemic epinephrine solution. For bronchospasm, 0.01 mg/kg/dose (Max: 0.5 mg/dose subcutaneously and 0.3 mg/dose IM).
-Children
1 to 3 years: Dependent on route of administration and indication for therapy. For CPR, 0.01 mg/kg/dose (Max: 1 mg/dose) IV/IO and 0.1 mg/kg/dose (Max: 2.5 mg/dose) ET. For anaphylaxis, 0.01 mg/kg/dose (Max: 0.3 mg/dose IM/subcutaneously and 1 mg/dose IV). For croup, 0.5 mL/dose of a 2.25% racemic epinephrine solution. For bronchospasm, 0.01 mg/kg/dose (Max: 0.5 mg/dose subcutaneously and 0.3 mg/dose IM).
4 to 11 years weighing 30 kg or less: Dependent on route of administration and indication for therapy. For CPR, 0.01 mg/kg/dose (Max: 1 mg/dose) IV/IO and 0.1 mg/kg/dose (Max: 2.5 mg/dose) ET. For anaphylaxis, 0.01 mg/kg/dose (Max: 0.3 mg/dose IM/subcutaneously and 1 mg/dose IV). For croup, 0.5 mL/dose of a 2.25% racemic epinephrine solution. For bronchospasm, 0.01 mg/kg/dose (Max: 0.5 mg/dose subcutaneously and 0.3 mg/dose IM).
4 to 11 years weighing more than 30 kg: Dependent on route of administration and indication for therapy. For CPR, 0.01 mg/kg/dose (Max: 1 mg/dose) IV/IO and 0.1 mg/kg/dose (Max: 2.5 mg/dose) ET. For anaphylaxis, 0.01 mg/kg/dose (Max: 0.5 mg/dose IM/subcutaneously and 1 mg/dose IV). For croup, 0.5 mL/dose of a 2.25% racemic epinephrine solution. For bronchospasm, 0.01 mg/kg/dose (Max: 0.5 mg/dose) IM/subcutaneously.
12 years: Dependent on route of administration and indication for therapy. For CPR, 0.01 mg/kg/dose (Max: 1 mg/dose) IV/IO and 0.1 mg/kg/dose (Max: 2.5 mg/dose) ET. For anaphylaxis, 0.01 mg/kg/dose (Max: 0.5 mg/dose IM/subcutaneously and 1 mg/dose IV). For croup, 0.5 mL/dose of a 2.25% racemic epinephrine solution. For bronchospasm, 0.01 mg/kg/dose (Max: 0.5 mg/dose) IM/subcutaneously or 8 oral inhalations/24 hours of epinephrine 0.125 mg oral inhalation (e.g., Primatene Mist inhaler, non-prescription).
-Adolescents
Dependent on route of administration and indication for therapy. For CPR, 0.01 mg/kg/dose (Max: 1 mg/dose) IV/IO and 0.1 mg/kg/dose (Max: 2.5 mg/dose) ET. For anaphylaxis, 0.01 mg/kg/dose (Max: 0.5 mg/dose IM/subcutaneously and 1 mg/dose IV). For bronchospasm, 0.01 mg/kg/dose (Max: 0.5 mg/dose) IM/subcutaneously or 8 oral inhalations/24 hours of epinephrine 0.125 mg oral inhalation (e.g., Primatene Mist inhaler, non-prescription).

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Epinephrine is an endogenous catecholamine that has complex target organ effects. It is a potent agonist at both alpha- and beta- receptors throughout the body except for the sweat glands and facial arteries. Epinephrine is a nonselective adrenergic agonist; it stimulates alpha1-, alpha2-, beta1-, and beta2-adrenergic receptors, although the degree of stimulation at these receptors may vary depending on the dose administered (i.e., the circulating concentration of epinephrine at the receptor). Stimulation of alpha1-receptors by epinephrine leads to arteriolar vasoconstriction, increased peripheral vascular resistance, and decreased mucosal edema. Stimulation of alpha2-receptors inhibits norepinephrine release via negative feedback and decreases insulin resistance. Stimulation of beta1-receptors induces a positive chronotropic and inotropic response. Stimulation of beta2-receptors leads to arteriolar vasodilation, bronchial smooth muscle relaxation, increased glycogenolysis, and decreased mediator release from mast cells and basophils.

Cardiovascular Effects
The potent cardiac effects of epinephrine are primarily mediated via stimulation of beta1-receptors on the myocardium and conducting system of the heart. The stimulation of these receptors results in both increased inotropic and chronotropic effects. Systolic blood pressure is usually elevated as a result of increased inotropy, although diastolic blood pressure is decreased secondary to epinephrine-induced vasodilation. As a result, pulse pressure is increased. Epinephrine indirectly causes coronary artery vasodilation, particularly during cardiac arrest. Epinephrine can simultaneously increase myocardial oxygen supply (secondary to coronary vasodilation) and increase oxygen demand (secondary to a positive inotropic and chronotropic effect on the heart). Increased myocardial excitability and automaticity markedly increase the potential for developing dysrhythmias. Nonspecific beta-stimulation by epinephrine, combined with moderate alpha agonism, results in inotropic effects equal to those of dopamine and dobutamine but greater chronotropic effects than either agent.

Blood flow to skeletal muscles is augmented by epinephrine via beta2-stimulation, resulting in vasodilation. Stimulation of alpha1-receptors by epinephrine leads to arteriolar vasoconstriction while stimulation of beta2-receptors by epinephrine leads to arteriolar vasodilation. At normal therapeutic doses, this effect is only mildly countered by the vasoconstriction caused by alpha-stimulation. At higher doses, however, vasoconstriction and elevation of both peripheral vascular resistance and blood pressure can occur. In anaphylaxis, the alpha-adrenergic vasoconstriction induced by epinephrine reverses peripheral vasodilation and alleviates hypotension, erythema, urticaria, and angioedema.

Respiratory Effects
Epinephrine primarily exerts its relaxant effect on bronchial smooth muscle via stimulation of beta2-receptors. Beta2-stimulation also prevents mast cell secretion of histamine and other autocoids, thus antagonizing its effect on end organs and reversing bronchoconstriction and edema. Furthermore, alpha-stimulation may decrease secretions from the bronchial mucosa, attenuating the development of edema.

Metabolic Effects
The metabolic effects of epinephrine relate primarily to the regulatory processes that control glucose concentration in the plasma. Beta2-stimulation of the skeletal muscle and liver increases glycogenolysis. Alpha-stimulation of the liver increases gluconeogenesis and inhibits insulin release by the pancreatic islet cells. Furthermore, in adipose cells, beta-stimulation will induce the catabolism of triglycerides, therefore increasing plasma free fatty acids. Serum potassium concentrations fluctuate after administration of epinephrine. Initially, hyperkalemia occurs secondary to release of potassium ions from hepatocytes. Hypokalemia quickly follows as potassium ions are taken up by the skeletal muscle.

Local Effects
When used topically on the skin or mucosal surfaces, epinephrine constricts arterioles, thus producing local vasoconstriction and hemostasis in small blood vessels. It has been purposed that local injection of epinephrine may minimize the absorption of antigen from an insect sting. In the case of accidental injection into digits, as seen with epinephrine auto-injector devices, potent alpha-adrenergic vasoconstriction may result in significant pain, discomfort, and tissue ischemia. In this scenario, local infiltration of the alpha-adrenergic antagonist phentolamine may reverse the effects of epinephrine.

Pharmacokinetics: Epinephrine is administered by intravenous, intramuscular, and subcutaneous injection, by inhalation, or topically to the eye. Epinephrine does not penetrate the blood-brain barrier to a great extent. The pharmacologic activity of epinephrine is rapidly inactivated in the liver. Circulating drug is metabolized by the enzymes catechol-O-methyltransferase and monamine oxidase in the liver, kidney, and in other extraneuronal tissues. These inactive metabolites are then conjugated to either sulfates or glucuronides and renally excreted. Minimal amounts of the drug are excreted unchanged in the urine.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
Following intravenous injection, epinephrine produces an immediate response and is rapidly cleared from the plasma with an effective half-life of less than 5 minutes. Steady state is achieved within 10 to 15 minutes after initiating a continuous infusion. In patients with septic shock, epinephrine displays dose-proportional pharmacokinetics in the infusion range of 0.03 to 1.7 mcg/kg/minute.

Intramuscular Route
Absorption is complete and rapid after intramuscular (IM) administration of epinephrine into the anterolateral thigh (vastus lateralis muscle). In an adult study of epinephrine absorption, peak plasma concentrations were significantly higher in those who received epinephrine 0.3 mg administered as an IM injection into the thigh (EpiPen Cmax = 12,222 pg/mL; epinephrine 1 mg/mL Cmax = 9,722 pg/mL), compared to those who received either IM or subcutaneous administration into the deltoid (IM Cmax = 1,821 pg/mL; subcutaneous Cmax = 2,877 pg/mL), most likely due to greater blood flow in the thigh. Absorption of an IM dose may be increased by massaging the area of injection, which increases local blood flow. In a study comparing IM and subcutaneous absorption in children (4 to 12 years of age weighing 15 to 40 kg), those receiving epinephrine 0.3 mg IM (in the vastus lateralis) as a single dose reached a mean Cmax of 2,136 +/- 351 pg/mL within 8 +/- 2 minutes; 75% of children achieved Tmax within 5 minutes. AUC was 108 +/- 18 ng/mL/minute, clearance was 147 +/- 38 mL/kg/minute, and elimination half-life was 4 +/- 15 minutes.

Subcutaneous Route
When compared to intramuscular (IM) administration, the absorption of subcutaneously administered epinephrine is variable and delayed with lower peak plasma concentrations. In an adult study of epinephrine absorption, Cmax was 2,877 pg/mL after subcutaneous administration of epinephrine 0.3 mg into the deltoid. While IM administration of the same dose into the deltoid produced a Cmax of 1,821 pg/mL, IM administration into the thigh produced significantly higher concentrations (EpiPen Cmax = 12,222 pg/mL; epinephrine 1 mg/mL Cmax = 9,722 pg/mL), most likely due to greater blood flow in the thigh. In a study comparing subcutaneous and IM absorption in children (4 to 12 years of age weighing 15 to 40 kg), those receiving epinephrine 0.3 mg subcutaneously as a single dose reached a mean Cmax of 1,802 +/- 214 pg/mL within 34 +/- 14 minutes (range: 5 to 120 minutes); only 22% of children achieved Tmax within 5 minutes. This was significantly slower compared to the IM group (Tmax: 8 +/- 2 minutes). AUC was 67 +/- 13 ng/mL/minute; absorption was too variable to calculate other pharmacokinetic parameters.

Inhalation Route
Bronchodilation occurs within 1 minute after administration of orally inhaled epinephrine.

Other Route(s)
Endotracheal Route
Epinephrine given via the endotracheal (ET) tube is absorbed by the lungs and enters the blood that drains directly into the heart. Medication absorption from the lungs is slower and more unpredictable than if given directly into the bloodstream.

Intraocular Route
The extent of epinephrine systemic exposure at the FDA-approved intraocular dose in humans has not been evaluated; however, significant systemic concentrations or plasma exposure are not expected with intraocular use.


-Special Populations
Pediatrics
Neonates
Endotracheal (ET) administration of epinephrine is slower and more unpredictable than if given directly into the bloodstream in patients of all ages. In neonates, multiple factors make it particularly difficult for a patient to achieve adequate absorption of ET epinephrine during cardiopulmonary resuscitation, including fluid-filled alveoli that may dilute ET epinephrine. In addition, shunting of blood through fetal pathways, particularly during acidemia and hypoxia, may cause circulation to bypass the lung and prevent absorption and distribution of ET epinephrine.

Obesity
The pharmacokinetics of epinephrine are influenced by body weight; higher body weight is associated with a lower concentration plateau and higher plasma clearance.