Epinephrine

Adrenalin® (epinephrine injection, USP) is a clear, colorless, sterile solution containing 1 mg/mL (1:1000) epinephrine, packaged as 1 mL of solution in a single-use clear glass vial or 30 mL of solution in a multiple-dose amber glass vial. In the 1 mL vial, each 1 mL of Adrenalin® solution contains 1 mg epinephrine, 9.0 mg sodium chloride, 1.0 mg sodium metabisulfite, hydrochloric acid to adjust pH, and water for injection. In the 30 mL vial, each 1 mL of Adrenalin® solution contains 1 mg epinephrine, 6.15 mg sodium chloride, 0.457 mg sodium metabisulfite, 0.920 mg sodium hydroxide, 2.25 mg tartaric acid, 0.20 mg disodium edetate dihydrate, hydrochloric acid to adjust pH, 5.25 mg chlorobutanol as a preservative and water for injection. The pH range is 2.2-5.0.

Epinephrine is a sympathomimetic catecholamine. The chemical name of epinephrine is: 1,2-Benzenediol, 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]-, or (-)-3,4-Dihydroxy-α-[2(methylamino)ethyl]benzyl alcohol.

The chemical structure of epinephrine is:

The molecular weight of epinephrine is 183.2.

Epinephrine solution deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin.

Adrenalin® is available as a single-use 1 mL vial and a multiple-use 30 mL vial. The 1 mL vial is for intramuscular, subcutaneous, and intraocular use. The 30 mL vial is for intramuscular and subcutaneous use only, and is NOT FOR OPHTHALMIC USE.

Anaphylaxis (Adrenalin® 1 mL Single-Use And 30 mL Multiple-Dose Vials)

Emergency treatment of allergic reactions (Type I), including anaphylaxis, which may result from allergic reactions to insect stings, biting insects, foods, drugs, sera, diagnostic testing substances and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. The signs and symptoms associated with anaphylaxis include flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with hypotension, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, airway swelling, laryngospasm, bronchospasm, pruritus, urticaria or angioedema, swelling of the eyelids, lips, and tongue.

Induction And Maintenance Of Mydriasis During Intraocular Surgery (Adrenalin® 1 mL Single-Use Vial Only)

Induction and maintenance of mydriasis during intraocular surgery.

Included as part of the "PRECAUTIONS" Section

Epinephrine is a prescription medications used to treat life-threatening allergic reactions in adults and children. Epinephrine  belongs to a group of drugs called sympathomimetic agents. They relax muscles in the airways and tighten the blood vessels, reversing severely low blood pressure and symptoms of allergic reaction.

This medication comes in an injectable form and is injected in the thigh during a serious allergic reaction.

Common side effects of epinephrine include fast and irregular heartbeat, sweating, and nausea. 

Seek emergency medical attention, even after epinephrine use, to treat severe allergic reactions.

Epinephrine is part of the drug class:

• Adrenergic and dopaminergic agents

Epinephrine is an endogenous catecholamine that is the active principle of the adrenal medulla; epinephrine acts directly on both α- and β-adrenergic receptors.a

Administration

Effective May 1, 2016, USP changed its labeling standard for all single-entity preparations of epinephrine injection, USP to require that dosage strengths be expressed only in terms of strength per mL (e.g., mg/mL).227 Use of ratio expressions (e.g., 1:1000 or 1:10,000) no longer is acceptable.226 227 Labeling change was prompted by numerous reports of serious medication errors caused by confusion with different ratio expressions.200 226

Usually administered parenterally (by IM, sub-Q, or IV injection or by continuous IV infusion).163 169 172 193 195 212

Select appropriate concentration and route of administration carefully; serious adverse effects (e.g., cerebral hemorrhage) have occurred after concentrated solutions of epinephrine intended for IM administration were administered IV.163 197 199 200 201 212 221 Generally administer IV only in extreme situations (e.g., septic or anaphylactic shock, cardiac arrest, or when patient is unresponsive to multiple IM injections).196 197 198 199 200 201 204 228 Always use dilute solutions of epinephrine (e.g., 0.1 mg/mL) when administering IV.101 172 200 212 Commercially available epinephrine solutions for IM or sub-Q injection are more concentrated (1 mg/mL) and should not be administered IV without dilution.172 212

Also has been administered by intraosseous (IO) injection or infusion† in the ACLS setting, generally when IV access not readily available; onset of action and systemic concentrations are comparable to those achieved with venous administration.401 403

May be administered endotracheally if vascular access (IV or IO) cannot be established during cardiac arrest.175 193 401 403

Also has been administered by intracardiac injection (into the left ventricular chamber) during cardiac arrest;161 172 193 212 however, this route of administration not recommended in current ACLS guidelines.400 401 403

Solutions of epinephrine have been applied topically to the skin, mucous membranes, or other tissues for local hemostasis.a

Also has been administered by oral inhalation in the treatment of asthma; however, an oral inhalation preparation no longer commercially available in the US.166 223 236

IM or Sub-Q Injection

Injections containing 1 mg/mL may be administered IM or sub-Q; avoid IM injections in the buttock.169 195 197 219 221 When epinephrine is used for the treatment of anaphylaxis, inject into anterolateral aspect of thigh; injection into or near smaller muscles (i.e., deltoid muscle) not recommended because of possible differences in absorption.169 195 197 219 221 When administered sub-Q, absorption and subsequent achievement of peak plasma concentrations is slower and may be substantially delayed if shock is present.196

Commercially available as a prefilled auto-injector for emergency treatment of allergic reactions.163 219 221 When using the auto-injector, administer appropriate weight-based dose by IM or sub-Q injection into anterolateral aspect of thigh; may administer through clothing if necessary.163 164 219 221 Do not reuse auto-injectors.164 220 222 Consult manufacturer's prescribing information for additional instructions.163 164 219 220 221 222

For self-medication, instruct patients and caregivers about proper administration techniques using the auto-injector provided by the manufacturer.163 164 219 221 First aid providers should be familiar with the auto-injector in order to assist patients experiencing an anaphylactic reaction, and they should be able to administer the auto-injector in the event that patient is unable to self-administer, provided that state law permits and valid prescription exists.217

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

May administer by slow, direct IV injection or continuous IV infusion.193 195 197 Commercially available as a 0.1-mg/mL solution for IV administration.193 212 Must further dilute the commercially available 1-mg/mL solution prior to IV administration.101 195 238

Extreme caution recommended when epinephrine is administered by direct IV injection since risk of overdosage and adverse cardiovascular effects is substantially higher; administer slowly and with close hemodynamic monitoring.193 196 198 228

During cardiac resuscitation, may administer IV into a central or peripheral line.212 401 CPR should not be interrupted for placement of a central line.401 After administration through a peripheral line, flush with 20 mL of IV fluid and elevate extremity to ensure drug delivery into central compartment.401

To minimize risk of necrosis, administer continuous IV infusions into a large vein.195 Avoid catheter tie-in technique to avoid stasis and increased local concentrations of the drug.195 Take care to avoid extravasation because local necrosis may result.195

Must dilute the commercially available 1-mg/mL solution prior to IV administration.101 195 238

Various methods have been described for diluting epinephrine solutions for IV administration; consult manufacturers' information for specific instructions.101 195 238

Administer slowly (after appropriate dilution) by IV injection or continuous IV infusion.193 195 196 197 228

Recommended rates of infusion vary based on indicated use.196 228 401 403 404 While low rates (e.g., <0.3 mcg/kg per minute) generally produce predominantly β-adrenergic effects and higher rates (e.g., >0.3 mcg/kg per minute) produce α-adrenergic vasoconstriction,403 there is substantial interindividual variability; titrate infusion rate based on clinical response.196 228 401 403 404 (See Dosage under Dosage and Administration.)

Topical Administration

Apply solutions topically as a spray or on cotton or gauze to the skin, mucous membranes, or other tissues.a

Dosage

Dosage of epinephrine salts is expressed in terms of epinephrine.a

Pediatric Patients

0.01 mg/kg (0.01 mL/kg of a 1-mg/mL solution) (up to 0.3–0.5 mg per dose depending on patient weight); repeat every 5–15 minutes as needed.169 195 197 212 218 Some clinicians state that doses may be repeated at 20-minute to 4-hour intervals depending on severity of the condition and patient response.211

For self-administration using a prefilled auto-injector, inject 0.15 or 0.3 mg, depending on body weight; 0.3 mg recommended for patients weighing ≥30 kg and 0.15 mg recommended for patients weighing 15–30 kg.163 219 221 Use alternative injectable forms if dose <0.15 mg considered more appropriate.163 219 221 For severe persistent anaphylaxis, repeat doses may be needed; if >2 sequential doses are required, administer subsequent doses only under direct medical supervision.163 219 221

If necessary, initial dose of 0.01 mg/kg (0.1 mL/kg of a 0.1-mg/mL solution) may be administered.101 If repeat doses are required, initiate a continuous IV infusion at a rate of 0.1 mcg/kg per minute; increase gradually to 1.5 mcg/kg per minute to maintain BP.101

Neonates: Usual IV dose is 0.01–0.03 mg/kg (0.1–0.3 mL/kg of a 0.1-mg/mL solution).213 214 Higher doses not recommended because of risk of exaggerated hypertension, decreased myocardial function, and worsening neurologic function.213

Pediatric patients: Usual IV/IO dose is 0.01 mg/kg (0.1 mL/kg of a 0.1-mg/mL solution), up to a maximum single dose of 1 mg, repeated every 3–5 minutes as needed.402 403 Lack of survival benefit and potential harm from routine use of higher doses, particularly in cases of asphyxia.181 403 However, may consider high-dose epinephrine in exceptional circumstances (e.g., β-adrenergic blocking agent overdose).403

For postresuscitation stabilization in pediatric patients, usual dosage is 0.1–1 mcg/kg per minute by IV/IO infusion; adjust based on patient response.403 Low-dose infusions (<0.3 mcg/kg per minute) generally produce predominantly β-adrenergic effects, while higher-dose infusions (>0.3 mcg/kg per minute) result in α-adrenergic vasoconstriction.403

For emergency treatment of infants and children with bradycardia and cardiopulmonary compromise (with a palpable pulse), may give 0.01 mg/kg (0.1 mL/kg of a 0.1-mg/mL solution) by IV/IO injection, repeated every 3–5 minutes as needed.403

Optimum dose not established.403

Neonates: If endotracheal route is used, doses of 0.01 or 0.03 mg/kg will likely be ineffective.213 Although safety and efficacy not established, consider endotracheal administration of a higher dose (0.05–0.1 mg/kg) while IV access is being obtained.213 214

Pediatric patients: Usual dose is 0.1 mg/kg (0.1 mL/kg of a 1-mg/mL solution), up to a maximum single dose of 2.5 mg, for cardiac resuscitation; repeat every 3–5 minutes as needed.402 403 Flush with at least 5 mL of 0.9% sodium chloride injection after each dose.403

For emergency treatment of infants and children with bradycardia and cardiopulmonary compromise (with a palpable pulse), may administer endotracheally at a dose of 0.1 mg/kg (0.1 mL/kg of a 1-mg/mL solution) if IV/IO access not available.403

If epinephrine is used in pediatric patients, some clinicians have recommended an infusion rate of 0.05–0.3 mcg/kg per minute, titrated to effect.204 237

When therapy is discontinued, decrease infusion rate gradually (e.g., by reducing every 30 minutes over a 12- to 24- hour period).195

Pediatric patients ≤12 years of age: For severe asthma, inject 0.01 mg/kg (0.01 mL/kg of a 1-mg/mL solution) every 20 minutes as needed for 3 doses; do not exceed 0.3–0.5 mg per dose.160

Adolescents >12 years of age: 0.3–0.5 mg every 20 minutes as needed for 3 consecutive doses.160 162

Neonates: 0.01 mg/kg by slow IV injection has been recommended.193 211

Infants: Initially, 0.05 mg by slow IV injection; may repeat every 20–30 minutes as needed.193 211

Adults

Usual dose is 0.2–0.5 mg (0.2–0.5 mL of a 1-mg/mL solution); repeat every 5–15 minutes as needed.163 169 195 196 197 200 212 228

For self-administration using a prefilled auto-injector, inject 0.3 mg.163 219 221 For severe persistent anaphylaxis, repeat doses may be needed; if >2 sequential doses are needed, administer subsequent doses only under direct medical supervision.163 219 221

In extreme circumstances (e.g., anaphylactic shock, cardiac arrest, or no response to initial IM injections), IV administration may be necessary.175 196 198 200 201 228

Usual IV dose is 0.1–0.25 mg (1–2.5 mL of a 0.1-mg/mL solution); repeat every 5–15 minutes as necessary.193 212

Alternatively, may administer as a continuous infusion at a rate of 2–15 mcg/minute; titrate based on severity of the reaction and clinical response.196 228

ACLS guidelines recommend 1 mg every 3–5 minutes by IV/IO injection.400 401

Higher doses (e.g., 0.1–0.2 mg/kg) do not provide any benefits in terms of survival or neurologic outcomes compared with the standard dose (1 mg) and may be harmful.115 118 175 400

Optimal timing of administration, particularly in relation to defibrillation, not known and may vary based on patient-specific factors and resuscitation conditions.400 In adults with asystole or PEA, may administer as soon as feasible after onset of cardiac arrest based on studies demonstrating improved survival to hospital discharge and increased ROSC when the drug is administered early during course of treatment for a nonshockable rhythm.400 401

For postresuscitation stabilization, usual IV dosage is 0.1–0.5 mcg/kg per minute; adjust based on patient response.404

Optimal dose not established, but typical doses are 2–2.5 times those administered IV.401

For symptomatic bradycardia, initial IV infusion rate of 2–10 mcg/minute has been recommended; adjust according to patient response.401

In conjunction with local anesthetics, has been used in concentrations of 0.002–0.02 mg/mL; most frequently used concentration is 0.005 mg/mL.a

As a topical hemostatic, solution concentrations of 0.002–0.1% have been sprayed or applied with cotton or gauze to the skin, mucous membranes, or other tissues.a

Manufacturer suggests IV infusion of 0.05–2 mcg/kg per minute.195 May increase infusion rate by 0.05–0.2 mcg/kg per minute every 10–15 minutes to achieve desired BP goal.195 Duration of therapy or total dose required not known; treatment may be necessary for several hours or days until the patient's hemodynamic status improves.195

When therapy is discontinued, decrease infusion rate gradually (e.g., by reducing every 30 minutes over a 12- to 24-hour period).195

For severe asthma, 0.3–0.5 mg (0.3–0.5 mL of a 1-mg/mL solution) may be administered every 20 minutes for 3 doses.160

Alternatively, may administer 0.01 mg/kg (using a 1-mg/mL solution) divided into 3 doses of approximately 0.3 mg each, given at 20-minute intervals.196

0.1–0.25 mg (1–2.5 mL of a 0.1-mg/mL solution) injected slowly.193

Prescribing Limits

Pediatric Patients

Maximum for pediatric patients: 0.3–0.5 mg of epinephrine per dose depending on weight.169 195 197 211 212 218

Maximum single dose of 1 mg.402 403

Maximum single dose of 2.5 mg.403

Maximum for pediatric patients ≤12 years of age: 0.3–0.5 mg per dose.a 160 162

Adults

Single doses should not exceed 0.5 mg.169 195 197

Contraindications

• No absolute contraindications to use in life-threatening conditions.200

• Relative contraindications include shock (other than anaphylactic and septic shock), known hypersensitivity to sympathomimetic amines, coronary insufficiency, or cardiac dilatation, as well as use in most patients with angle-closure glaucoma, or organic brain damage.193 195 212 Contraindicated for use during general anesthesia with agents such as cyclopropane and halogenated hydrocarbon anesthetics (e.g., halothane).193 212

• Contraindicated in conjunction with local anesthetics for use in certain areas (e.g.,fingers, toes, ears).172 212

Warnings/Precautions

Warnings

Inadvertent induction of high arterial BP with epinephrine can cause angina pectoris, aortic rupture, or cerebral hemorrhage.172 193

Vasopressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes.212 Correct blood volume depletion as fully as possible before epinephrine administration.195

Avoid extravasation; severe local adverse effects (e.g., tissue necrosis) may occur as a result of local vasoconstriction.195

Check site of infusion frequently for free flow and observe infused vein for blanching.195

Avoid injection into leg veins, especially in geriatric patients or those with occlusive vascular diseases (e.g., arteriosclerosis, atherosclerosis, Buerger’s disease, diabetic endarteritis).195

If blanching is observed in the infused vein, changing the injection site periodically may be advisable.195

If extravasation occurs, infiltrate affected area liberally with 10–15 mL of sodium chloride solution containing 5–10 mg of phentolamine mesylate.195 Immediate and conspicuous local hyperemic changes occur if area is infiltrated within 12 hours; therefore, administer phentolamine as soon as possible after extravasation noted.195

Adverse reactions most likely to occur in hypertensive or hyperthyroid patients; use with extreme caution, if at all.a

Use with caution in patients with Parkinson's disease, diabetes mellitus, pheochromocytoma, cardiovascular disease, or psychoneurotic disorders.195 212

Can induce serious cardiac arrhythmias in patients without heart disease, in those with organic heart disease, and in those with drug-induced myocardial sensitization.172 193

Can convert asystole to VF in anesthetic cardiac accidents since many anesthetics sensitize the myocardium to epinephrine.212

Cyclopropane or halogenated hydrocarbon general anesthetics that increase cardiac irritability and seem to sensitize the myocardium to epinephrine may cause arrhythmias including VPC, VT, or VF.a 172 193 (See Contraindications under Cautions.)

Sensitivity Reactions

Some formulations contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.102

Presence of sulfites in a parenteral epinephrine preparation and the possibility of allergic-type reactions should not deter use of the drug when indicated for the treatment of serious allergic reactions or for other emergency situations.102 Epinephrine is the preferred treatment for such conditions, and currently available alternatives to epinephrine may not be optimally effective.102

Consider that sulfites may be responsible for paradoxical worsening of respiratory function in asthmatics or for worsening symptoms or decreased bronchodilatory response with increasing use of the drug.a

Caution in those with a history of sensitivity to sympathomimetic amines.a

General Precautions

Can cause VF, but beneficial effects in restoring electrical activity and enhancing defibrillation are well documented.172 193

May cause tachycardia, ventricular ectopy, tachyarrhythmias, hypertension, and vasoconstriction in patients with a perfusing rhythm.175

Caution in patients with underlying cardiovascular disease (e.g., cardiac arrhythmias, coronary artery disease, organic heart disease).163

Extreme caution in patients with prefibrillatory rhythm because of excitatory cardiac activity.193

Overdosage or inadvertent IV administration may cause cerebrovascular hemorrhage secondary to a marked increase in BP.212

Caution in patients with long-standing bronchial asthma and substantial emphysema who may also have degenerative heart disease.a

Can cause pulmonary edema secondary to peripheral vasoconstriction and cardiac stimulation.195

May decrease vascular vasopressor response.172 193

Use vasopressors cautiously with MAO inhibitors.172 193

Specific Populations

Category C.163 172 193

Use during pregnancy only if clearly indicated.195 212

Some manufacturers state that epinephrine injection should be avoided during the second stage of labor or when maternal BP is >130/80 mm Hg.195 212

When administered in ACLS, may decrease blood flow to the uterus; however, the woman must be resuscitated for survival of the fetus.195 196

Risk unknown.171

Used in pediatric patients of all ages, dosing according to body weight.101 160 162 163 172 193 403

Use with caution.a 195

Common Adverse Effects

Fear, anxiety, tenseness, restlessness, headache, tremor, dizziness, lightheadedness, nervousness, sleeplessness, excitability, and weakness.a Increased rigidity and tremor in patients with parkinsonian syndrome. May aggravate or induce psychomotor agitation, disorientation, impaired memory, assaultive behavior, panic, hallucinations, suicidal or homicidal tendencies, and psychosis characterized by clear consciousness with schizophrenic-like thought disorder and paranoid delusions.a Nausea, vomiting, sweating, pallor, respiratory difficulty, or respiratory weakness and apnea.a

ECG changes including a decrease in T-wave amplitude in all leads in normal individuals.a Disturbances of cardiac rhythm and rate may result in palpitation and tachycardia.a Aggravation or precipitation of angina pectoris by increasing cardiac work and accentuating the insufficiency of the coronary circulation.a Potentially fatal ventricular arrhythmias including fibrillation, especially in patients with organic heart disease or those receiving other drugs that sensitize the heart to arrhythmias.a

Hypertension secondary to overdosage or inadvertent IV injection of usual sub-Q doses.a Subarachnoid hemorrhage and hemiplegia have resulted from hypertension, even following usual sub-Q doses.a

Necrosis from repeated injections because of vascular constriction at the injection site.a Tissue necrosis in the extremities, kidneys, and liver.a

Severe metabolic acidosis from prolonged use or overdosage because of elevated blood concentrations of lactic acid.a

Absorption from the respiratory tract following large orally inhaled doses may result in adverse effects similar to those occurring after parenteral administration.a Rebound bronchospasm may occur when the effects of epinephrine end.a Further reductions in arterial oxygen tension.a Dryness of pharyngeal membranes may follow oral inhalation.a

Specific Drugs

Absorption

Bioavailability

Rapidly metabolized in the GI tract and liver after oral ingestion; pharmacologically active concentrations are not reached when given orally.a

Well absorbed after sub-Q or IM injection; absorption can be hastened by massaging the injection site.a

Absorbed rapidly through the lung capillary bed following endotracheal administration;193 serum concentrations achieved only 10% of those with an equivalent IV dose.161

Absorption is slight and the effects are restricted mainly to the respiratory tract after usual orally inhaled doses; absorption somewhat increased when larger doses are inhaled, and systemic effects may occur.a

Onset

Rapid onset of action when solutions are administered parenterally or by oral inhalation.a 163

Sub-Q injection in asthmatic attacks may produce bronchodilation within 5–10 minutes and maximal effects in about 20 minutes.a

After oral inhalation, bronchodilation usually occurs within 1 minute.a

Duration

Short duration of action when solutions are administered parenterally or by oral inhalation.a 163

Distribution

Extent

Epinephrine crosses the placenta but not the blood-brain barrier.a

Distributed into milk.a

Elimination

Metabolism

Pharmacologic actions are terminated mainly by uptake and metabolism in sympathetic nerve endings.a

Circulating drug is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and MAO.a

Elimination Route

40% excreted in urine, mainly as inactive metabolites.a