DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Hypotension associated with septic shock (2.2): Dilute epinephrine in dextrose solution prior to infusion.Infuse epinephrine into large vein.Titrate 0.05 mcg/kg/min to mcg/kg/min to achieve desired blood pressure.Wean gradually. Anaphylaxis (2.3): Administer intramuscularly or subcutaneously into anterolateral thigh every 5-10 minutes as neededAdults and children over 30 kg (66 lbs): 0.3-0.5 mg (0.3-0.5 mL)Children under 30 kg (66 lbs): 0.01 mg/kg (0.01 mL/kg) Hypotension associated with septic shock (2.2): Dilute epinephrine in dextrose solution prior to infusion.Infuse epinephrine into large vein.Titrate 0.05 mcg/kg/min to mcg/kg/min to achieve desired blood pressure.Wean gradually. Anaphylaxis (2.3): Administer intramuscularly or subcutaneously into anterolateral thigh every 5-10 minutes as neededAdults and children over 30 kg (66 lbs): 0.3-0.5 mg (0.3-0.5 mL)Children under 30 kg (66 lbs): 0.01 mg/kg (0.01 mL/kg) Dilute epinephrine in dextrose solution prior to infusion.. Infuse epinephrine into large vein.. Titrate 0.05 mcg/kg/min to mcg/kg/min to achieve desired blood pressure.. Wean gradually. Anaphylaxis (2.3): Administer intramuscularly or subcutaneously into anterolateral thigh every 5-10 minutes as neededAdults and children over 30 kg (66 lbs): 0.3-0.5 mg (0.3-0.5 mL)Children under 30 kg (66 lbs): 0.01 mg/kg (0.01 mL/kg) Anaphylaxis (2.3): Administer intramuscularly or subcutaneously into anterolateral thigh every 5-10 minutes as neededAdults and children over 30 kg (66 lbs): 0.3-0.5 mg (0.3-0.5 mL)Children under 30 kg (66 lbs): 0.01 mg/kg (0.01 mL/kg). Administer intramuscularly or subcutaneously into anterolateral thigh every 5-10 minutes as needed. Adults and children over 30 kg (66 lbs): 0.3-0.5 mg (0.3-0.5 mL). Children under 30 kg (66 lbs): 0.01 mg/kg (0.01 mL/kg). 2.1 General Considerations. Inspect visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy, or if it contains particulate matter. Discard any unused portion.. 2.2 Hypotension associated with Septic Shock. Dilute epinephrine in 5% Dextrose Injection or 5% Dextrose and 0.9% Sodium Chloride Injection. These dextrose containing fluids provide protection against significant loss of potency by oxidation. Administration in 0.9% Sodium Chloride Injection alone is not recommended. Whole blood or plasma, if indicated to increase blood volume, should be administered separately.Add mL (1 mg) of epinephrine from its ampule to 1,000 mL of 5% Dextrose containing solution. Each mL of this dilution contains 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 large vein. Avoid using 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, Buergers 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 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 mcg/kg/min, and is titrated to achieve 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 patients 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 12- to 24-hour period.. 2.3 Anaphylaxis Inject epinephrine intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary. When administering to 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 to 10 minutes as necessary. For intramuscular administration, use 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 mL to 0.5 mL) of undiluted epinephrine administered intramuscularly or subcutaneously in the anterolateral aspect of the thigh, up to maximum of 0.5 mg (0.5 mL) per injection, repeated every 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 to 10 minutes as necessary. Monitor clinically for reaction severity and cardiac effects.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions to systemically administered epinephrine are headache; anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; peripheral coldness; nausea/vomiting; and/or respiratory difficulties. Arrhythmias, including fatal ventricular fibrillation, rapid rises in blood pressure producing cerebral hemorrhage, and angina have occurred. (6.1, 6.2)To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Adverse Reactions associated with Epinephrine Infusion (for Hypotension associated with Septic Shock). The following adverse reactions associated with the infusion of epinephrine were identified in the literature. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to estimate their frequency reliably or to establish causal relationship to drug exposure.Cardiovascular disorders: tachycardia, supraventricular tachycardia, ventricular arrhythmias, myocardial ischemia, myocardial infarction, limb ischemia, pulmonary edema Gastrointestinal disorders: Nausea, vomitingGeneral disorders and administrative site conditions: Chest pain, extravasationMetabolic: hypoglycemia, hyperglycemia, insulin resistance, hypokalemia, lactic acidosisNervous system disorders: Headache, nervousness, paresthesia, tremor, stroke, central nervous system bleedingPsychiatric disorders: Excitability Renal disorders: Renal insufficiency Respiratory: Pulmonary edema, ralesSkin and subcutaneous tissue disorders: Diaphoresis, pallor, piloerection, skin blanching, skin necrosis with extravasation. 6.2 Adverse Reactions associated with Intramuscular or Subcutaneous Use (for Anaphylaxis). Common adverse reactions to systemically administered epinephrine include anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with heart disease, hypertension, or hyperthyroidism [see Warnings and Precautions (5.8)].Due to the lack of randomized, controlled clinical trials of epinephrine for the treatment of anaphylaxis, the true incidence of adverse reactions associated with the systemic use of epinephrine is difficult to determine. Adverse reactions reported in observational trials, case reports, and studies are listed below by body system:Cardiovascular [see Warnings and Precautions (5.6)]: angina, arrhythmias, hypertension, pallor, palpitations, tachyarrhythmia, tachycardia, vasoconstriction, and ventricular ectopy. Angina may occur in patients with coronary artery disease. Arrhythmias, including fatal ventricular fibrillation, have occurred, particularly in patients with underlying organic heart disease or patients receiving drugs that sensitize the heart to arrhythmias. Rapid rises in blood pressure associated with epinephrine use have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease.Respiratory: respiratory difficulties.Neurological: dizziness, disorientation, excitability, headache, impaired memory, lightheadedness, nervousness, panic, psychomotor agitation, sleepiness, tingling, tremor, and weakness.Psychiatric: anxiety, apprehensiveness, restlessness. Gastrointestinal: nausea, vomiting.Skin: sweating.Other: Patients with Parkinsons disease may experience psychomotor agitation or temporary worsening of symptoms [see Warnings and Precautions (5.8)]. Diabetic patients may experience transient increases in blood sugar [see Warnings and Precautions (5.8)].Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area [see Warnings and Precautions (5.3)]. Adverse events experienced as result of an injection into these areas include increased heart rate, local reactions including injection site pallor, coldness, hypoesthesia, and tissue loss, or injury at the injection site resulting in bruising, bleeding, discoloration, erythema, and skeletal injury.Injection into the buttock has resulted in cases of gas gangrene [see Warnings and Precautions (5.3)].Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported following epinephrine injection in the thigh [see Warnings and Precautions (5.7)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Epinephrine acts on both alpha ()- and beta ()-adrenergic receptors. The mechanism of the rise in blood pressure is 3-fold: direct myocardial stimulation that increases the strength of ventricular contraction (positive inotropic action), an increased heart rate (positive chronotropic action), and peripheral vasoconstriction.. 12.2 Pharmacodynamics. Intravenous use for hypotension associated with septic shockFollowing intravenous administration of epinephrine, increases in systolic blood pressure and heart rate are observed. Decreases in systemic vascular resistance and diastolic blood pressure are observed at low doses of epinephrine because of 2-mediated vasodilation, but are overtaken by 1-mediated peripheral vasoconstriction at higher doses leading to increase in diastolic blood pressure. The onset of blood pressure increase following an intravenous dose of epinephrine is 5 minutes and the time to offset blood pressure response occurs within 20 min. Most vascular beds are constricted including renal, splanchnic, mucosal and skin.Intramuscular and subcutaneous use for anaphylaxisThrough its action on alpha-adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension.Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation and helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis.Epinephrine also alleviates pruritus, urticaria, and angioedema and may relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus and urinary bladder.Epinephrine increases glycogenolysis, reduces glucose up take by tissues, and inhibits insulin release in the pancreas, resulting in hyperglycemia and increased blood lactic acid [see Warnings and Precautions (5.8 )].. 12.3 Pharmacokinetics. When administered parenterally, epinephrine has rapid onset and short duration of action.Following intravenous injection, epinephrine is rapidly cleared from the plasma with an effective half-life of 5 min. pharmacokinetic steady state following continuous intravenous infusion is achieved within 10 to 15 min. In patients with septic shock, epinephrine displays dose-proportional pharmacokinetics in the infusion dose range of 0.03 mcg/kg/min to 1.7 mcg/kg/min.Epinephrine is extensively metabolized with only small amount excreted unchanged.Epinephrine is rapidly degraded to vanillylmandelic acid, an inactive metabolite, by monoamine oxidase and catechol-O-methyltransferase that are abundantly expressed in the liver, kidneys and other extraneuronal tissues. The tissues with the highest contribution to removal of circulating exogenous epinephrine are the liver (32%), kidneys (25%), skeletal muscle (20%), and mesenteric organs (12%).Special PopulationsElderlyIn pharmacokinetic study of 45-minute epinephrine infusions given to healthy men aged 20 to 25 years and healthy men aged 60 to 65 years, the mean plasma metabolic clearance rate of epinephrine at steady state was greater among the older men (144.8 versus 78 mL/kg/min for 14.3 ng/kg/min infusion).Body WeightBody weight has been found to influence epinephrine pharmacokinetics. Higher body weight was associated with higher plasma epinephrine clearance and lower concentration plateau.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drugs antagonizing pressor effects of epinephrine-blockers, such as phentolamineVasodilators, such as nitratesDiureticsAntihypertensivesErgot alkaloidsDrugs potentiating pressor effects of epinephrineSympathomimetics-blockers, such as propranololTricyclic anti-depressantsMonoamine oxidase (MAO) inhibitorsCatechol-O-methyl transferase (COMT) inhibitors, such as entacaponeClonidineDoxapramOxytocinDrugs potentiating arrhythmogenic effects of epinephrinePatients who are concomitantly receiving any of the following drugs should be observed carefully for the development of cardiac arrhythmias [see Warnings and Precautions (5.6) and Adverse Reactions (6)].-blockers, such as propranololCyclopropane or halogenated hydrocarbon anesthetics, such as halothaneAntihistaminesThyroid hormonesDiureticsCardiac glycosides, such as digitalis glycosidesQuinidineDrugs potentiating hypokalemic effects of epinephrinePotassium depleting diureticsCorticosteroidsTheophyllineEpinephrine should not be used to counteract circulatory collapse or hypotension caused by phenothiazines, as 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.. -blockers, such as phentolamine. Vasodilators, such as nitrates. Diuretics. Antihypertensives. Ergot alkaloids. Sympathomimetics. -blockers, such as propranolol. Tricyclic anti-depressants. Monoamine oxidase (MAO) inhibitors. Catechol-O-methyl transferase (COMT) inhibitors, such as entacapone. Clonidine. Doxapram. Oxytocin. -blockers, such as propranolol. Cyclopropane or halogenated hydrocarbon anesthetics, such as halothane. Antihistamines. Thyroid hormones. Diuretics. Cardiac glycosides, such as digitalis glycosides. Quinidine. Potassium depleting diuretics. Corticosteroids. Theophylline. Drugs that counter the pressor effects of epinephrine include alpha blockers, vasodilators such as nitrates, diuretics, antihypertensives, and ergot alkaloids. (7)Drugs that potentiate the effects of epinephrine include sympathomimetics, beta blockers, tricyclic antidepressants, MAO inhibitors, COMT inhibitors, clonidine, doxapram, oxytocin, levothyroxine sodium, and certain antihistamines. (7)Drugs that increase the arrhythmogenic potential of epinephrine include beta blockers, cyclopropane and halogenated hydrocarbon anesthetics, quinidine, antihistamines, exogenous thyroid hormones, diuretics, and cardiac glycosides. Observe for development of cardiac arrhythmias. (7)Potassium-depleting drugs, including corticosteroids, diuretics, and theophylline, potentiate the hypokalemic effects of epinephrine. (7). Drugs that counter the pressor effects of epinephrine include alpha blockers, vasodilators such as nitrates, diuretics, antihypertensives, and ergot alkaloids. (7). Drugs that potentiate the effects of epinephrine include sympathomimetics, beta blockers, tricyclic antidepressants, MAO inhibitors, COMT inhibitors, clonidine, doxapram, oxytocin, levothyroxine sodium, and certain antihistamines. (7). Drugs that increase the arrhythmogenic potential of epinephrine include beta blockers, cyclopropane and halogenated hydrocarbon anesthetics, quinidine, antihistamines, exogenous thyroid hormones, diuretics, and cardiac glycosides. Observe for development of cardiac arrhythmias. (7). Potassium-depleting drugs, including corticosteroids, diuretics, and theophylline, potentiate the hypokalemic effects of epinephrine. (7).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Epinephrine is non-selective alpha and beta adrenergic agonist indicated:To increase mean arterial blood pressure in adult patients with hypotension associated with septic shock (1.1)For emergency treatment of allergic reactions (Type 1), including anaphylaxis (1.2). To increase mean arterial blood pressure in adult patients with hypotension associated with septic shock (1.1). For emergency treatment of allergic reactions (Type 1), including anaphylaxis (1.2). 1.1 Hypotension associated with Septic Shock. Epinephrine Injection mg/mL is indicated to increase mean arterial blood pressure in adult patients with hypotension associated with septic shock.. 1.2 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients or their caregivers about common adverse reactions associated with the use of epinephrine, including an increase in heart rate, the sensation of more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These symptoms and signs usually subside rapidly, especially with rest, quiet and recumbent positioning.Warn patients with good response to initial treatment about the possibility of recurrence of anaphylaxis symptoms and instruct patients to obtain medical attention if symptoms return.Advise patients with diabetes that they may develop increased blood glucose levels following epinephrine administration.Rare cases of serious skin and soft tissue infections, including necrotizing fasciitis and myonecrosis caused by Clostridia (gas gangrene), have been reported at the injection site following epinephrine injection for anaphylaxis. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the epinephrine injection site [see Warnings and Precautions (5.7 )].Manufactured by:HIKMA FARMACEUTICA (PORTUGAL), S.A.Estrada do Rio da Mo, 8, 8A 8B Fervenca 2705-906 Terrugem SNT, PORTUGALDistributed by:Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922Revised: February 2026PIN691-WES/1.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term studies to evaluate the carcinogenic potential of epinephrine have not been conducted.Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro. Epinephrine was positive in the Salmonella bacterial reverse mutation assay, positive in the mouse lymphoma assay, and negative in the in vivo micronucleus assay. Epinephrine is an oxidative mutagen based on the E. coli WP2 Mutoxitest bacterial reverse mutation assay. This should not prevent the use of epinephrine under the conditions noted under the Indications and Usage (1).The potential for epinephrine to impair reproductive performance has not been evaluated, but epinephrine has been shown to decrease implantation in female rabbits dosed subcutaneously with 1.2 mg/kg/day (15-fold the highest human intramuscular or subcutaneous daily dose) during gestation days to 9.. 13.2 Animal Toxicology and/or Pharmacology. Epinephrine was associated with metabolic effects, decreased mesentery, coronary and renal conductance in sheep model of septic shock. Data from hemolysis study have shown that epinephrine at 1:1000 dilution is non-hemolytic. Epinephrine infusion significantly increased the MAP (69 vs. 86 mmHg) and cardiac output (6.4 vs. 7.1 L/min) and decreased renal blood flow (330 vs. 247 mL/min).

OVERDOSAGE SECTION.

10 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 rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support. Treatment of arrhythmias consists of administration of 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Intravenous use for hypotension associated with septic shockFollowing intravenous administration of epinephrine, increases in systolic blood pressure and heart rate are observed. Decreases in systemic vascular resistance and diastolic blood pressure are observed at low doses of epinephrine because of 2-mediated vasodilation, but are overtaken by 1-mediated peripheral vasoconstriction at higher doses leading to increase in diastolic blood pressure. The onset of blood pressure increase following an intravenous dose of epinephrine is 5 minutes and the time to offset blood pressure response occurs within 20 min. Most vascular beds are constricted including renal, splanchnic, mucosal and skin.Intramuscular and subcutaneous use for anaphylaxisThrough its action on alpha-adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension.Through its action on beta-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation and helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis.Epinephrine also alleviates pruritus, urticaria, and angioedema and may relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus and urinary bladder.Epinephrine increases glycogenolysis, reduces glucose up take by tissues, and inhibits insulin release in the pancreas, resulting in hyperglycemia and increased blood lactic acid [see Warnings and Precautions (5.8 )].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. When administered parenterally, epinephrine has rapid onset and short duration of action.Following intravenous injection, epinephrine is rapidly cleared from the plasma with an effective half-life of 5 min. pharmacokinetic steady state following continuous intravenous infusion is achieved within 10 to 15 min. In patients with septic shock, epinephrine displays dose-proportional pharmacokinetics in the infusion dose range of 0.03 mcg/kg/min to 1.7 mcg/kg/min.Epinephrine is extensively metabolized with only small amount excreted unchanged.Epinephrine is rapidly degraded to vanillylmandelic acid, an inactive metabolite, by monoamine oxidase and catechol-O-methyltransferase that are abundantly expressed in the liver, kidneys and other extraneuronal tissues. The tissues with the highest contribution to removal of circulating exogenous epinephrine are the liver (32%), kidneys (25%), skeletal muscle (20%), and mesenteric organs (12%).Special PopulationsElderlyIn pharmacokinetic study of 45-minute epinephrine infusions given to healthy men aged 20 to 25 years and healthy men aged 60 to 65 years, the mean plasma metabolic clearance rate of epinephrine at steady state was greater among the older men (144.8 versus 78 mL/kg/min for 14.3 ng/kg/min infusion).Body WeightBody weight has been found to influence epinephrine pharmacokinetics. Higher body weight was associated with higher plasma epinephrine clearance and lower concentration plateau.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryProlonged experience with epinephrine use in pregnant women over several decades, based on published literature, does not identify 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 (see Clinical Considerations). In animal reproduction studies, epinephrine administered by the subcutaneous route to pregnant rabbits, mice, and hamsters, during the period of organogenesis, resulted in adverse developmental effects (including gastroschisis, embryonic lethality, and delayed skeletal ossification) at doses approximately times the maximum recommended daily intramuscular, subcutaneous, or intravenous dose (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskDuring pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. The prevalence of anaphylaxis occurring during pregnancy is reported to be approximately cases per 100,000 deliveries.Management of anaphylaxis during pregnancy is similar to management in the general population. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in pregnant and non-pregnant patients. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care.Hypotension associated with septic shock is medical emergency in pregnancy which can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic shock may increase the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of epinephrine on the fetus.Labor or DeliveryEpinephrine 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 prolonged period of uterine atony with hemorrhage. Avoid epinephrine in obstetrics when maternal blood pressure exceeds 130/80 mmHg.Although epinephrine may improve maternal hypotension associated with septic shock and anaphylaxis, it may result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia.DataAnimal Data In an embryofetal development study with pregnant rabbits dosed during the period of organogenesis (on days to 5, to 7, or to of gestation), epinephrine caused teratogenic effects (including gastroschisis) at doses approximately 15 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on mg/m2 basis at maternal subcutaneous dose of 1.2 mg/kg/day for to days). Animals treated on days to had decreased number of implantations.In an embryofetal development study, pregnant mice were administered epinephrine (0.1 to 10 mg/kg/day) on Gestation Days to 15. Teratogenic effects, embryonic lethality, and delays in skeletal ossification were observed at approximately times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on mg/m2 basis at maternal subcutaneous dose of mg/kg/day for 10 days). These effects were not seen in mice at approximately times the maximum recommended daily intramuscular or subcutaneous dose (on mg/m2 basis at subcutaneous maternal dose of 0.5 mg/kg/day for 10 days).In an embryofetal development study with pregnant hamsters dosed during the period of organogenesis from gestation days to 10, epinephrine produced reductions in litter size and delayed skeletal ossification at doses approximately times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on mg/m2 basis at maternal subcutaneous dose of 0.5 mg/kg/day).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: May cause fetal harm. (8.1)Elderly patients and pregnant women may be at greater risk of developing adverse reactions when epinephrine is administered parenterally. (8.1, 8.5). Pregnancy: May cause fetal harm. (8.1). Elderly patients and pregnant women may be at greater risk of developing adverse reactions when epinephrine is administered parenterally. (8.1, 8.5). 8.1 Pregnancy. Risk SummaryProlonged experience with epinephrine use in pregnant women over several decades, based on published literature, does not identify 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 (see Clinical Considerations). In animal reproduction studies, epinephrine administered by the subcutaneous route to pregnant rabbits, mice, and hamsters, during the period of organogenesis, resulted in adverse developmental effects (including gastroschisis, embryonic lethality, and delayed skeletal ossification) at doses approximately times the maximum recommended daily intramuscular, subcutaneous, or intravenous dose (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskDuring pregnancy, anaphylaxis can be catastrophic and can lead to hypoxic-ischemic encephalopathy and permanent central nervous system damage or death in the mother and, more commonly, in the fetus or neonate. The prevalence of anaphylaxis occurring during pregnancy is reported to be approximately cases per 100,000 deliveries.Management of anaphylaxis during pregnancy is similar to management in the general population. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in pregnant and non-pregnant patients. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care.Hypotension associated with septic shock is medical emergency in pregnancy which can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic shock may increase the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of epinephrine on the fetus.Labor or DeliveryEpinephrine 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 prolonged period of uterine atony with hemorrhage. Avoid epinephrine in obstetrics when maternal blood pressure exceeds 130/80 mmHg.Although epinephrine may improve maternal hypotension associated with septic shock and anaphylaxis, it may result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia.DataAnimal Data In an embryofetal development study with pregnant rabbits dosed during the period of organogenesis (on days to 5, to 7, or to of gestation), epinephrine caused teratogenic effects (including gastroschisis) at doses approximately 15 times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on mg/m2 basis at maternal subcutaneous dose of 1.2 mg/kg/day for to days). Animals treated on days to had decreased number of implantations.In an embryofetal development study, pregnant mice were administered epinephrine (0.1 to 10 mg/kg/day) on Gestation Days to 15. Teratogenic effects, embryonic lethality, and delays in skeletal ossification were observed at approximately times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on mg/m2 basis at maternal subcutaneous dose of mg/kg/day for 10 days). These effects were not seen in mice at approximately times the maximum recommended daily intramuscular or subcutaneous dose (on mg/m2 basis at subcutaneous maternal dose of 0.5 mg/kg/day for 10 days).In an embryofetal development study with pregnant hamsters dosed during the period of organogenesis from gestation days to 10, epinephrine produced reductions in litter size and delayed skeletal ossification at doses approximately times the maximum recommended intramuscular, subcutaneous, or intravenous dose (on mg/m2 basis at maternal subcutaneous dose of 0.5 mg/kg/day).. 8.2 Lactation. Risk SummaryThere 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.. 8.4 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.. 8.5 Geriatric Use. Clinical studies of epinephrine for the treatment of hypotension associated with septic shock did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.Clinical studies for the treatment of anaphylaxis have not been performed in subjects aged 65 and over to determine whether they respond differently from younger subjects. However, other reported clinical experience with use of epinephrine for the treatment of anaphylaxis has identified that geriatric patients may be particularly sensitive to the effects of epinephrine.Therefore, for the treatment of anaphylaxis, consider starting with lower dose to take into account potential concomitant disease or other drug therapy.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Monitor patient for acute severe hypertension. (5.1)Avoid extravasation into tissues, which can cause local necrosis. (5.2)Do not inject into buttocks, digits, hands, or feet. (5.3)Potential for pulmonary edema, which may be fatal. (5.4)May constrict renal blood vessels and decrease urine formation. (5.5)May induce potentially serious cardiac arrhythmias or aggravate angina pectoris, particularly in patients with underlying heart disease. (5.6)Presence of sulfite in this product should not deter use. (5.9). Monitor patient for acute severe hypertension. (5.1). Avoid extravasation into tissues, which can cause local necrosis. (5.2). Do not inject into buttocks, digits, hands, or feet. (5.3). Potential for pulmonary edema, which may be fatal. (5.4). May constrict renal blood vessels and decrease urine formation. (5.5). May induce potentially serious cardiac arrhythmias or aggravate angina pectoris, particularly in patients with underlying heart disease. (5.6). Presence of sulfite in this product should not deter use. (5.9). 5.1 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 [see Drug Interactions (7)].. 5.2 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. This also may progress on rare occasions to superficial slough. Hence, if blanching occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside.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 mg to 10 mg of phentolamine, an adrenergic blocking agent. Use syringe with 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.. 5.3 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 administer repeated injections of epinephrine at the same site, as the resulting vasoconstriction may cause tissue necrosis.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 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.. 5.4 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 rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support.. 5.5 Renal Impairment. Intravenously administered epinephrine initially may produce constriction of renal blood vessels and decrease urine formation.. 5.6 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 [see Adverse Reactions (6) and Drug Interactions (7)]. Treatment of arrhythmias consists of administration of beta-adrenergic blocking drug (such as propranolol).. 5.7 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 [see Warnings and Precautions (5.3)]. Advise patients to seek medical care if they develop signs or symptoms of infection, such as persistent redness, warmth, swelling, or tenderness, at the epinephrine injection site.. 5.8 Other Disease Interactions. Epinephrine should be administered with caution to patients with hyperthyroidism, Parkinsons disease, diabetes mellitus, pheochromocytoma, elderly individuals, and pregnant women.Patients with Parkinsons disease may experience psychomotor agitation or notice temporary worsening of symptoms. Diabetic patients may experience transient increases in blood sugar. Despite these concerns, the presence of these conditions is not contraindication to epinephrine administration in an acute, life-threatening situation.. 5.9 Allergic Reactions Associated with Sulfite. Epinephrine is the preferred treatment for serious allergic or other emergency situations even though this product contains sodium metabisulfite, sulfite that may in other products cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in life- threatening situation may not be satisfactory. The presence of sulfite(s) in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations.