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.[45416] [49567] [54140] [56575] [60589]

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.[45416] [49567] [54140] [60589]

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.[45416] [49567] [54140] [60589]

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.[45416] [57081] 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.[52618] [54685] [60589] Skin laceration and bent or embedded needles have been reported when epinephrine has been injected into the thigh of young children who are uncooperative; caregivers should be instructed 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). Patients should seek medical care if they develop signs and symptoms of infection at the injection site (e.g., persistent redness, warmth, swelling, tenderness). Injection site ecchymosis, bleeding, skin discoloration, erythema, and skeletal injury have also been associated with intramuscular and subcutaneous use.[57081] Piloerection, a common sympathetic reflex, has been associated with intravenous administration.[60589]

Transient increases in blood sugar or hyperglycemia may occur in diabetic patients administered inhaled or systemic epinephrine. Hypoglycemia and insulin resistance also has been reported with the intravenous use of epinephrine. Hypokalemia has been reported. Metabolic acidosis secondary to lactic acidosis has been associated with long-term administration or overdose of epinephrine.[56575] [60589]

Intravenously administered epinephrine may initially produce constriction of renal blood vessels, resulting in oliguria. Renal insufficiency has been associated with intravenous infusion.[60589]

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).[60589]

Epinephrine may induce cardiac arrhythmias, myocardial ischemia, and angina pectoris in patients, especially patients with coronary artery disease, cardiomyopathy, organic cardiac disease, high blood pressure, or patients receiving drugs that sensitize the myocardium.[56575] [60589] Certain epinephrine formulations that are intended only for hypersensitivity reactions, cardiac resuscitation, ophthalmological use, or regional anesthesia are contraindicated in nonanaphylactic shock.[45416] [49567] However, other epinephrine formulations are indicated for hypotension associated with septic shock. Correct hypovolemia 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.[60589]

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.[45416] [49567] [54140] [56575]

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.[45416] [49567]

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).[45416] [49567] [53965] [54140] [54685] [54686] [54687] [60589]

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.[49567] [54140] [60589]

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.[45416] [49567] [54140] [60589]

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.[45416] [49567] [54140] [60589]

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.[49567] [54140] [60589]

Prolonged experience with epinephrine use during human pregnancy 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 and obstetric delivery. In animal studies, subcutaneous epinephrine resulted in adverse developmental effects (e.g., gastroschisis, embryonic lethality, delayed skeletal ossification) when given during organogenesis at doses approximately 2 times the maximum recommended parenteral daily dose. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of epinephrine on the fetus. Delaying treatment in pregnant women with hypotension associated with septic shock may increase the risk of maternal and fetal morbidity and mortality.[56575] Epinephrine is the first-line medication of choice for the treatment of anaphylaxis and should be used during pregnancy in the same manner as it is used in non-pregnant patients.[54140] [56575] Although epinephrine can improve maternal hypotension associated with septic shock and anaphylaxis, it may result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia. Avoid use during the second stage of labor; epinephrine may cause a prolonged period of uterine atony with hemorrhage at dosages sufficient to reduce uterine contractions. Avoid use if the maternal blood pressure exceeds 130/80 mmHg.[56575] [60589]

There is no information regarding the presence of epinephrine in human milk or its effects on the breastfed infant or milk production. Epinephrine exposure is expected to be very low in the breastfed infant due to poor bioavailability and short half-life.[56575] Albuterol may be an alternative to inhaled epinephrine in a breast-feeding woman. According to the 2004 recommendations of the National Asthma Education and Prevention Program for managing asthma during pregnancy, there is no contraindication for the use of short-acting inhaled beta₂-agonists, including albuterol, during lactation.[31822]

Epinephrine injection must be diluted 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 and corneal edema when used in the eye at undiluted concentrations (1 mg/mL).[60589]

Use epinephrine with caution in patients with Parkinson's disease. Patients with Parkinson's disease may experience psychomotor agitation or a temporary worsening of symptoms.[56575] [60589]

Use epinephrine cautiously in patients with renal disease. When administered intravenously, epinephrine may initially constrict the renal blood vessels resulting in a decrease in urine production. Renal insufficiency has been associated with intravenous infusion.[45416] [60589]

Lacerations, bent needles, and embedded needles have been reported when epinephrine has been injected into the thigh of infants or young children who are uncooperative and kick or move during an injection. To minimize the risk of injury, caregivers should be instructed to hold the leg of young children firmly in place and limit movement prior to and during injection.[57081] Safety and efficacy of non-prescription epinephrine for oral inhalation (e.g., Primatene Mist) has not been established in neonates, infants, or children less than 12 years of age.[63740]