, such as nitrates • diuretics • antihypertensives • ergot alkaloids • phenothiazine antipsychotics 7.2 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 7.3 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 [see warnings and precautions (5.5) and adverse reactions (6) ] . • β-blockers, such as propranolol • cyclopropane or halogenated hydrocarbon anesthetics, such as halothane • antihistamines • thyroid hormones • diuretics • cardiac glycosides, such as digitalis glycosides • quinidine 7.4 drugs potentiating hypokalemic effects of epinephrine • potassium depleting diuretics • corticosteroids • theophylline

soconstriction, which may result in pulmonary edema. 5.3 cardiac arrhythmias and ischemia epinephrine may induce cardiac arrhythmias and myocardial ischemia in patients, especially patients with coronary artery disease, or cardiomyopathy [see adverse reactions and drug interactions (7.3) ] . 5.4 extravasation and tissue necrosis with intravenous infusion avoid extravasation of epinephrine into the tissues, to prevent local necrosis. when epinephrine injection is administered intravenously, check the infusion site frequently for free flow. 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 a superficial slough. hence, if blanching occurs, consider changing the infusion site at intervals to allow the effects of local vasoconstriction to subside. there is potential for gangrene in a lower extremity when infusions of catecholamine are given in an ankle vein. 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. 5.5 renal impairment epinephrine constricts renal blood vessels, which may result in oliguria or renal impairment. 5.6 allergic reactions associated with sulfite epinephrine injection contains sodium metabisulfite which may cause mild to severe allergic reactions including anaphylaxis or asthmatic episodes, particularly in patients with a history of allergies. the presence of sodium metabisulfite in this product should not preclude its use for the treatment of hypotension associated with septic shock even if the patient is sulfite-sensitive, as the alternatives to using epinephrine in a life-threatening situation may not be satisfactory. in susceptible patients, consider using a formulation of epinephrine or another vasoconstrictor that does not contain sodium metabisulfite.

commended. if indicated, administer whole blood or plasma separately. 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. avoid the veins of the leg in elderly patients or in those suffering from occlusive vascular diseases. 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 – 15 minutes, in increments of 0.05 mcg/kg/min to 0.2 mcg/kg/min, to achieve the desired blood pressure goal. after hemodynamic stabilization, wean incrementally over time, such as by decreasing doses of epinephrine every 30 minutes over a 12- to 24-hour period.

tion, limb ischemia, pulmonary edema, hypertension gastrointestinal disorders : nausea, vomiting general disorders and administrative site conditions : extravasation metabolic : insulin resistance, hypokalemia, lactic acidosis nervous system disorders : headache, paresthesia, tremor, stroke, central nervous system bleeding, weakness, dizziness, disorientation, impaired memory, panic, psychomotor agitation, somnolence psychiatric disorders : excitability, anxiety, apprehensiveness, nervousness, restlessness renal disorders : renal insufficiency respiratory : rales skin and subcutaneous tissue disorders : diaphoresis, pallor, piloerection, skin blanching, skin necrosis with extravasation. most common adverse reactions to systemically administered epinephrine are headache; anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; diaphoresis; nausea/vomiting; and/or respiratory difficulties. arrhythmias, including fatal ventricular fibrillation, rapid rises in blood pressure producing cerebral hemorrhage, and angina have occurred. ( 6 ) to report suspected adverse reactions, contact hospira, inc. at 1-800-441-4100, or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

, such as nitrates • diuretics • antihypertensives • ergot alkaloids • phenothiazine antipsychotics 7.2 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 7.3 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 [see warnings and precautions (5.5) and adverse reactions (6) ] . • β-blockers, such as propranolol • cyclopropane or halogenated hydrocarbon anesthetics, such as halothane • antihistamines • thyroid hormones • diuretics • cardiac glycosides, such as digitalis glycosides • quinidine 7.4 drugs potentiating hypokalemic effects of epinephrine • potassium depleting diuretics • corticosteroids • theophylline

2 times, respectively, the maximum recommended daily intramuscular or subcutaneous dose (see data ) . all pregnancies have a background risk of birth defects, loss, or other adverse outcomes. the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypotension associated with septic shock is a 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. do not withhold life-sustaining therapy for a pregnant woman. 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. although epinephrine improves maternal hypotension associated with anaphylaxis, it may result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia. data animal data in a study in pregnant rabbits administered 1.2 mg/kg/day epinephrine (approximately 15 times the maximum recommended intramuscular or subcutaneous dose on a mg/m 2 basis) subcutaneously during organogenesis (on days 3 to 5, 6 to 7 or 7 to 9 of gestation), epinephrine caused teratogenic effects (including gastroschisis). animals treated on days 6 to 7 had decreased number of implantations. in a teratology study, pregnant mice were subcutaneously administered epinephrine (0.1 to 10 mg/kg/day) on gestation days 6 to 15. teratogenic effects, embryonic lethality, and delays in skeletal ossification were observed at approximately 3 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at maternal subcutaneous dose of 1 mg/kg/day for 10 days). these effects were not seen in mice at approximately 2 times the maximum recommended daily intramuscular or subcutaneous dose (on a mg/m 2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days). subcutaneous administration of epinephrine to pregnant hamsters at a dose of 0.5 mg/kg/day (approximately 2 times the maximum recommended intramuscular or subcutaneous dose on a mg/m 2 basis) on gestation days 7 to 10 resulted in delayed skeletal ossification and a reduction in litter size. 8.2 lactation risk summary 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. the lack of clinical data during lactation precludes a clear determination of the risk of epinephrine to a breastfed infant. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 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.

miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypotension associated with septic shock is a 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. do not withhold life-sustaining therapy for a pregnant woman. 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. although epinephrine improves maternal hypotension associated with anaphylaxis, it may result in uterine vasoconstriction, decreased uterine blood flow, and fetal anoxia. data animal data in a study in pregnant rabbits administered 1.2 mg/kg/day epinephrine (approximately 15 times the maximum recommended intramuscular or subcutaneous dose on a mg/m 2 basis) subcutaneously during organogenesis (on days 3 to 5, 6 to 7 or 7 to 9 of gestation), epinephrine caused teratogenic effects (including gastroschisis). animals treated on days 6 to 7 had decreased number of implantations. in a teratology study, pregnant mice were subcutaneously administered epinephrine (0.1 to 10 mg/kg/day) on gestation days 6 to 15. teratogenic effects, embryonic lethality, and delays in skeletal ossification were observed at approximately 3 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at maternal subcutaneous dose of 1 mg/kg/day for 10 days). these effects were not seen in mice at approximately 2 times the maximum recommended daily intramuscular or subcutaneous dose (on a mg/m 2 basis at a subcutaneous maternal dose of 0.5 mg/kg/day for 10 days). subcutaneous administration of epinephrine to pregnant hamsters at a dose of 0.5 mg/kg/day (approximately 2 times the maximum recommended intramuscular or subcutaneous dose on a mg/m 2 basis) on gestation days 7 to 10 resulted in delayed skeletal ossification and a reduction in litter size.

e constricted including renal, splanchnic, mucosal and skin. epinephrine increases glycogenolysis, reduces glucose up take by tissues, and inhibits insulin release in the pancreas, resulting in hyperglycemia and increased blood lactic acid. 12.3 pharmacokinetics when administered parenterally epinephrine has a 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. a pharmacokinetic steady state following continuous intravenous infusion is achieved within 10–15 min. in patients with septic shock, epinephrine displays dose-proportional pharmacokinetics in the infusion dose range of 0.03 to 1.7 mcg/kg/min. epinephrine is extensively metabolized with only a 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%). specific populations elderly in a 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 a 14.3 ng/kg/min infusion). body weight body weight has been found to influence epinephrine pharmacokinetics. higher body weight was associated with a higher plasma epinephrine clearance and a lower concentration plateau.

harmacokinetic 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 a 14.3 ng/kg/min infusion). body weight body weight has been found to influence epinephrine pharmacokinetics. higher body weight was associated with a higher plasma epinephrine clearance and a lower concentration plateau.

eptic 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).