bitartrate injection cannot be avoided in these patients, monitor for hypertension. 7.3 antidiabetics norepinephrine bitartrate injection can decrease insulin sensitivity and raise blood glucose. monitor glucose and consider dosage adjustment of antidiabetic drugs. 7.4 halogenated anesthetics concomitant use of norepinephrine bitartrate injection with halogenated anesthetics (e.g., cyclopropane, desflurane, enflurane, isoflurane, and sevoflurane) may lead to ventricular tachycardia or ventricular fibrillation. monitor cardiac rhythm in patients receiving concomitant halogenated anesthetics.

( 5.4 ) 5.1 tissue ischemia administration of norepinephrine bitartrate injection to patients who are hypotensive from hypovolemia can result in severe peripheral and visceral vasoconstriction, decreased renal perfusion and reduced urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow despite “normal” blood pressure. address hypovolemia prior to initiating norepinephrine bitartrate injection [see dosage and administration (2.1) ]. avoid norepinephrine bitartrate injection in patients with mesenteric or peripheral vascular thrombosis, as this may increase ischemia and extend the area of infarction. gangrene of the extremities has occurred in patients with occlusive or thrombotic vascular disease or who received prolonged or high dose infusions. monitor for changes to the skin of the extremities in susceptible patients. extravasation of norepinephrine bitartrate injection may cause necrosis and sloughing of surrounding tissue. to reduce the risk of extravasation, infuse into a large vein, check the infusion site frequently for free flow, and monitor for signs of extravasation [see dosage and administration (2.1) ]. emergency treatment of extravasation to prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using a syringe with a fine hypodermic needle with 5 to 10 mg of phentolamine mesylate in 10 to 15 ml of 0.9% sodium chloride injection in adults. sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours. 5.2 hypotension after abrupt discontinuation sudden cessation of the infusion rate may result in marked hypotension. when discontinuing the infusion, gradually reduce the norepinephrine bitartrate injection infusion rate while expanding blood volume with intravenous fluids. 5.3 cardiac arrhythmias norepinephrine bitartrate injection elevates intracellular calcium concentrations and may cause arrhythmias, particularly in the setting of hypoxia or hypercarbia. perform continuous cardiac monitoring of patients with arrhythmias. 5.4 allergic reactions associated with sulfite norepinephrine bitartrate injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. the overall prevalence of sulfite sensitivity in the general population is unknown. sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

) ]. avoid using a catheter-tie-in technique . discontinuation when discontinuing the infusion, reduce the flow rate gradually. avoid abrupt withdrawal. 2.2 dosage after an initial dosage of 8 to 12 mcg per minute via intravenous infusion, assess patient response and adjust dosage to maintain desired hemodynamic effect. monitor blood pressure every two minutes until the desired hemodynamic effect is achieved, and then monitor blood pressure every five minutes for the duration of the infusion. typical maintenance intravenous dosage is 2 to 4 mcg per minute. 2.3 preparation of diluted solution visually inspect norepinephrine bitartrate injection for particulate matter and discoloration prior to administration (the solution is colorless) . do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate. add the content of one norepinephrine bitartrate injection vial (4 mg in 4 ml) to 1,000 ml of 5% dextrose injection, usp or sodium chloride injection solutions that contain 5% dextrose to produce a 4 mcg per ml dilution. dextrose reduces loss of potency due to oxidation. administration in saline solution alone is not recommended. use higher concentration solutions in patients requiring fluid restriction. prior to use, store the diluted norepinephrine bitartrate injection solution for up to 24 hours at room temperature [20°c to 25°c (68°f to 77°f)] and protect from light. 2.4 drug incompatibilities avoid contact with iron salts, alkalis, or oxidizing agents. whole blood or plasma, if indicated to increase blood volume, should be administered separately.

bitartrate injection cannot be avoided in these patients, monitor for hypertension. 7.3 antidiabetics norepinephrine bitartrate injection can decrease insulin sensitivity and raise blood glucose. monitor glucose and consider dosage adjustment of antidiabetic drugs. 7.4 halogenated anesthetics concomitant use of norepinephrine bitartrate injection with halogenated anesthetics (e.g., cyclopropane, desflurane, enflurane, isoflurane, and sevoflurane) may lead to ventricular tachycardia or ventricular fibrillation. monitor cardiac rhythm in patients receiving concomitant halogenated anesthetics.

injections at approximately 2 times the maximum recommended dose on a mg/m 3 basis for four days during organogenesis ( see data ) . the estimated background risk for major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15−20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypotension associated with septic shock, myocardial infarction, and stroke are medical emergencies in pregnancy which can be fatal if left untreated. delaying treatment in pregnant women with hypotension associated with septic shock, myocardial infarction and stroke 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 norepinephrine on the fetus. data animal data a study in pregnant sheep receiving high doses of intravenous norepinephrine (40 mcg/min, at approximately 10 times the average maintenance dose of 2-4 mcg/min in human, on a mg/kg basis) exhibited a significant decrease in maternal placental blood flow. decreases in fetal oxygenation, urine and lung liquid flow were also observed. norepinephrine administration to pregnant rats on gestation day 16 or 17 resulted in cataract production in rat fetuses. in hamsters, an increased number of resorptions (29.1% in study group vs. 3.4% in control group), fetal microscopic liver abnormalities and delayed skeletal ossification were observed at approximately 2 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day from gestation day 7-10). 8.2 lactation risk summary there are no data on the presence of norepinephrine in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. clinically relevant exposure to the infant is not expected based on the short half-life and poor oral bioavailability of norepinephrine. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use clinical studies of norepinephrine bitartrate injection 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. avoid administration of norepinephrine bitartrate injection into the veins in the leg in elderly patients [see warnings and precautions ( 5.1 )] .

genesis ( see data ) . the estimated background risk for major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15−20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk hypotension associated with septic shock, myocardial infarction, and stroke are medical emergencies in pregnancy which can be fatal if left untreated. delaying treatment in pregnant women with hypotension associated with septic shock, myocardial infarction and stroke 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 norepinephrine on the fetus. data animal data a study in pregnant sheep receiving high doses of intravenous norepinephrine (40 mcg/min, at approximately 10 times the average maintenance dose of 2-4 mcg/min in human, on a mg/kg basis) exhibited a significant decrease in maternal placental blood flow. decreases in fetal oxygenation, urine and lung liquid flow were also observed. norepinephrine administration to pregnant rats on gestation day 16 or 17 resulted in cataract production in rat fetuses. in hamsters, an increased number of resorptions (29.1% in study group vs. 3.4% in control group), fetal microscopic liver abnormalities and delayed skeletal ossification were observed at approximately 2 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day from gestation day 7-10).

ly by uptake and metabolism in sympathetic nerve endings. the pressor action stops within 1-2 minutes after the infusion is discontinued. 12.3 pharmacokinetics absorption following initiation of intravenous infusion, the steady state plasma concentration is achieved in 5 min. distribution plasma protein binding of norepinephrine is approximately 25%. it is mainly bound to plasma albumin and to a smaller extent to prealbumin and alpha 1-acid glycoprotein. the volume of distribution is 8.8 l. norepinephrine localizes mainly in sympathetic nervous tissue. it crosses the placenta but not the blood-brain barrier. elimination the mean half-life of norepinephrine is approximately 2.4 min. the average metabolic clearance is 3.1 l/min. metabolism norepinephrine is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-o-methyltransferase (comt) and mao. the major metabolites are normetanephrine and 3­ methoxyl-4-hydroxy mandelic acid (vanillylmandelic acid, vma), both of which are inactive. other inactive metabolites include 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxymandelic acid, and 3,4­ dihydroxyphenylglycol. excretion noradrenaline metabolites are excreted in urine primarily as sulphate conjugates and, to a lesser extent, as glucuronide conjugates. only small quantities of norepinephrine are excreted unchanged.

acid, and 3,4­ dihydroxyphenylglycol. excretion noradrenaline metabolites are excreted in urine primarily as sulphate conjugates and, to a lesser extent, as glucuronide conjugates. only small quantities of norepinephrine are excreted unchanged.