EPINEPHRINE INJECTION USP

EPINEPHRINE INJECTION USP

EPINEPHRINE INJECTION USP

Epinephrine Injection USP, 1 mg/mL is supplied as a sterile aqueous solution with a pH range of 2.2-5.0, that is colorless and nonpyrogenic. Each milliliter contains 1 mg epinephrine, sodium chloride 8.6 mg (for isotonicity), hydrochloric acid 6.00 mg as a dissolution agent, hydrochloric acid for pH adjustment, and water for injection, USP, qs. Contains no preservatives or sulfites.

Solution must be diluted prior to intravenous or ocular use.

Epinephrine, USP is a sympathomimetic catecholamine (adrenergic agent) designated chemically as 4-[1-hydroxy-2 (methylamino) ethyl]-1,2 benzenediol, a white, microcrystalline powder.

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.

Mechanism of Action

Epinephrine acts on both alpha (α)- and beta (β)-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.

NDICATIONS AND USAGE

Hypotension associated with Septic Shock: Epinephrine Injection USP, 1 mg/mL is indicated to increase mean arterial blood pressure in adult patients with hypotension associated with septic shock.

Anaphylaxis: 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:

DOSAGE AND ADMINISTRATION

Inspect visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is colored or cloudy, or if it contains particulate matter. Discard any unused portion.

Hypotension associated with Septic Shock

Dilute epinephrine in 5 percent dextrose solution or 5 percent dextrose and sodium chloride solution. These dextrose containing fluids provide protection against significant loss of potency by oxidation. Administration in saline solution alone is not recommended. Whole blood or plasma, if indicated to increase blood volume, should be administered separately.

Add 1 mL (1 mg) of epinephrine from its ampule to 1,000 mL of a 5 percent dextrose containing solution. Each mL of this dilution contains 1 mcg of epinephrine.

Correct blood volume depletion as fully as possible before any vasopressor is administered.

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.

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. Occlusive vascular diseases (for example, atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger’s disease) are more likely to occur in the lower than in the upper extremity; therefore, avoid the veins of the leg in elderly patients or in those suffering from such disorders. There is potential for gangrene in a lower extremity when infusions of catecholamine are given in an ankle vein.

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 to 15 minutes, in increments of 0.05 mcg/kg/min to 0.2 mcg/kg/min, to achieve the desired blood pressure goal.

Continuous epinephrine infusion is generally required over several hours or days until the patient’s hemodynamic status improves. The duration of perfusion or total cumulative dose cannot be predicted.

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

Anaphylaxis

Inject epinephrine intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. When administering to a child, to minimize the risk of injection related injury, hold the leg firmly in place and limit movement prior to and during an injection. The injection may be repeated every 5 to 10 minutes as necessary. 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. Monitor the patient clinically for the severity of the allergic reaction and potential cardiac effects of the drug, with repeat doses titrated to effect. Do not administer repeated injections at the same site, as the resulting vasoconstriction may cause tissue necrosis.

Adults and Children 30 kg (66 lbs) or more: 0.3 to 0.5 mg (0.3 to 0.5 mL) of undiluted epinephrine administered intramuscularly or subcutaneously in the anterolateral aspect of the thigh, up to a maximum of 0.5 mg (0.5 mL) per injection, repeated every 5 to 10 minutes as necessary. Monitor clinically for reaction severity and cardiac effects.

Children less than 30 kg (66 lbs): 0.01 mg/kg (0.01 mL/kg) of undiluted epinephrine administered intramuscularly or subcutaneously in the anterolateral aspect of the thigh repeated every 5 to 10 minutes as necessary. Monitor clinically for reaction severity and cardiac effects.

Induction and Maintenance of Mydriasis during Intraocular Surgery

Epinephrine must be diluted prior to intraocular use. Dilute 1 mL of epinephrine 1 mg/mL (1:1000) in 100 to 1000 mL of an ophthalmic irrigation fluid to create an epinephrine concentration of 1:100,000 to 1:1,000,000 (10 mcg/mL to 1 mcg/mL). Use the irrigating solution as needed for the surgical procedure.

After dilution in an ophthalmic irrigating fluid, epinephrine may also be injected intracamerally as a bolus dose of 0.1 mL at a dilution of 1:100,000 to 1:400,000 (10 mcg/mL to 2.5 mcg/mL).

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Hypertension: When Epinephrine Injection is administered intravenously, titrate the infusion while monitoring vital signs. Invasive arterial blood pressure monitoring and central venous pressure monitoring are recommended. Because of varying response to epinephrine, dangerously high blood pressure may occur

Extravasation and Tissue Necrosis with Intravenous Infusion: When Epinephrine Injection is administered intravenously, the infusion site should be checked frequently for free flow. Avoid extravasation of epinephrine into the tissues, to prevent local necrosis. 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.

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.

Incorrect Locations of Injection for Anaphylaxis: When Epinephrine Injection is used for the treatment of anaphylaxis, the most appropriate location for administration is into the anterolateral aspect of the thigh (vastus lateralis muscle) because of its location, size, and available blood flow. Injection into (or near) smaller muscles, such as in the deltoid, is not recommended due to possible differences in absorption associated with this use.

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). Cleansing with alcohol does not kill bacterial spores, and therefore, does not lower this risk.

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 has been associated with tissue necrosis.

Pulmonary Edema: When Epinephrine Injection is administered intravenously, there is risk of pulmonary edema because of the peripheral constriction and cardiac stimulation produced. Treatment of pulmonary edema consists of a rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support.

Renal Impairment: Intravenously administered epinephrine initially may produce constriction of renal blood vessels and decrease urine formation.

Cardiac Arrhythmias and Ischemia: Epinephrine may induce cardiac arrhythmias and angina pectoris in patients, especially patients suffering from coronary artery disease, organic heart disease, cerebrovascular disease, hypertension, or patients who are receiving drugs that sensitize the myocardium

Injury with Undiluted Intraocular Solution: Epinephrine must be diluted before intraocular use. Other epinephrine products that contain sodium bisulfite have been associated with corneal endothelial damage when used in the eye at undiluted concentrations (1 mg/mL). Although this Epinephrine product contains no sulfites or preservatives, warning is still advised

Serious Infections at the Injection Site: Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site following epinephrine injection for anaphylaxis. Clostridium spores can be present on the skin

and introduced into the deep tissue with subcutaneous or intramuscular injection. While cleansing with alcohol may reduce presence of bacteria on the skin, alcohol cleansing does not kill Clostridium spores. To decrease the risk of Clostridium infection, do not inject Epinephrine Injection into the buttock.

DRUG INTERACTIONS

Drugs antagonizing pressor effects of epinephrine

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

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
  • Drugs potentiating arrhythmogenic effects of epinephrine. Patients who are
  • concomitantly receiving any of the following drugs should be observed carefully for the development of cardiac arrhythmias
  • β-blockers, such as propranolol
  • Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane
  • Antihistamines
  • Thyroid hormones
  • Diuretics
  • Cardiac glycosides, such as digitalis glycosides
  • Quinidine

Drugs potentiating hypokalemic effects of epinephrine

  • Potassium depleting diuretics
  • Corticosteroids
  • Theophylline

Epinephrine should not be used to counteract circulatory collapse or hypotension caused by phenothiazines, as a reversal of the pressor effects of epinephrine may result in further lowering of blood pressure.

Epinephrine may antagonize the neuronal blockade produced by guanethidine resulting in decreased antihypertensive effect and requiring increased dosage of the latter.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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. However, there are risks to the mother and fetus associated with epinephrine use during labor or delivery.

Labor or Delivery: 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.

Lactation: 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.

Epinephrine is the first-line medication of choice for treatment of anaphylaxis; it should be used in the same manner for anaphylaxis in breastfeeding and non-breastfeeding patients.

Pediatric Use

Safety and effectiveness of epinephrine in pediatric patients with septic shock have not been established.

Clinical use data 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 children are similar in nature and extent to those both expected and reported in adults.

The safety and effectiveness of epinephrine (at a dilution of 1:100,000 to 1:400,000) for induction and maintenance of mydriasis during intraocular surgery have been established in pediatric patients. Use of epinephrine for induction and maintenance of mydriasis during intraocular surgery in pediatric patients is supported by adequate and well controlled studies in adults and uncontrolled studies in pediatric patients.

OVERDOSAGE

Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients. Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation.

Epinephrine overdosage may also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Myocardial ischemia and infarction, cardiomyopathy, extreme pallor and coldness of the skin, metabolic acidosis due to elevated blood lactic acid levels, and renal insufficiency and failure have also been reported.

Epinephrine is rapidly inactivated in the body and treatment following overdose is primarily supportive. Treatment of pulmonary edema consists of a rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support. Treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug (such as propranolol). If necessary, pressor effects may be counteracted by rapidly acting vasodilators (such as nitrites) or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measures, it may be necessary to administer another pressor drug.

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