NOREPINEPHRINE BITARTRATE

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: • Tissue Ischemia [see Warnings and Precautions ( 5.1 )] • Hypotension [see Warnings and Precautions ( 5.2 )] • Cardiac Arrhythmias [see Warnings and Precautions ( 5.3 )] The most common adverse reactions are hypertension and bradycardia. The following adverse reactions can occur: Nervous system disorders: Anxiety, headache Respiratory disorders: Respiratory difficulty, pulmonary edema Most common adverse reactions are ischemic injury, bradycardia, anxiety, transient headache, respiratory difficulty, and extravasation necrosis at injection site. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine ) is a sympathomimetic amine which differs from epinephrine by the absence of a methyl group on the nitrogen atom. Norepinephrine bitartrate is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate (molecular weight 337.3 g/mol) and has the following structural formula: Norepinephrine bitartrate injection, USP is supplied in a sterile aqueous solution in the form of the bitartrate salt to be administered by intravenous infusion following dilution. Norepinephrine is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Each mL contains the equivalent of 1 mg base of norepinephrine, sodium chloride for isotonicity, and not more than 0.2 mg of sodium metabisulfite as an antioxidant. It has a pH of 3 to 4.5. The air in the vials has been displaced by nitrogen gas. chemical-structure

2 DOSAGE AND ADMINISTRATION • Initial dose of 0.25 mL to 0.375 mL (from 8 mcg to 12 mcg of base) per minute, adjust the rate of flow to establish and maintain a low to normal blood pressure (usually 80 mm Hg to 100 mm Hg systolic) sufficient to maintain the circulation of vital organs. ( 2.2 ) • The average maintenance dose ranges from 0.0625 mL to 0.125 mL per minute (from 2 mcg to 4 mcg of base). ( 2.2 ) 2.1 Important Dosage and Administration Instructions Correct Hypovolemia Address hypovolemia before initiation of norepinephrine bitartrate injection therapy. If the patient does not respond to therapy, suspect occult hypovolemia [see Warnings and Precautions ( 5.1 )] . Administration Dilute norepinephrine bitartrate injection prior to use [see Dosage and Administration ( 2.3 )] . Infuse norepinephrine bitartrate injection into a large vein. Avoid infusions into the veins of the leg in the elderly or in patients with occlusive vascular disease of the legs [see Warnings and Precautions ( 5.1 )] . 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.

1 INDICATIONS AND USAGE Norepinephrine bitartrate injection is indicated to raise blood pressure in adult patients with severe, acute hypotension. Norepinephrine bitartrate injection is a catecholamine, indicated for restoration of blood pressure in adult patients with acute hypotensive states. ( 1 )

10 OVERDOSAGE Overdosage with norepinephrine bitartrate injection may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output. In case of overdosage, discontinue norepinephrine bitartrate injection until the condition of the patient stabilizes.

7 DRUG INTERACTIONS • Monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types may result in hypertension. ( 7.1 ) • Cyclopropane and halothane anesthetics increase cardiac autonomic irritability. ( 7.4 ) 7.1 MAO-Inhibiting Drugs Co-administration of norepinephrine bitartrate injection with monoamine oxidase (MAO) inhibitors or other drugs with MAO-inhibiting properties (e.g., linezolid) can cause severe, prolonged hypertension. If administration of norepinephrine bitartrate injection cannot be avoided in patients who recently have received any of these drugs and in whom, after discontinuation, MAO activity has not yet sufficiently recovered, monitor for hypertension. 7.2 Tricyclic Antidepressants Co-administration of norepinephrine bitartrate injection with tricyclic antidepressants (including amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can cause severe, prolonged hypertension. If administration of norepinephrine 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Norepinephrine is a peripheral vasoconstrictor (alpha-adrenergic action) and an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action). 12.2 Pharmacodynamics The primary pharmacodynamic effects of norepinephrine are cardiac stimulation and vasoconstriction. Cardiac output is generally unaffected, although it can be decreased, and total peripheral resistance is also elevated. The elevation in resistance and pressure result in reflex vagal activity, which slows the heart rate and increases stroke volume. The elevation in vascular tone or resistance reduces blood flow to the major abdominal organs as well as to skeletal muscle. Coronary blood flow is substantially increased secondary to the indirect effects of alpha stimulation. After intravenous administration, a pressor response occurs rapidly and reaches steady state within 5 minutes. The pharmacologic actions of norepinephrine are terminated primarily 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.

12.1 Mechanism of Action Norepinephrine is a peripheral vasoconstrictor (alpha-adrenergic action) and an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action).

12.2 Pharmacodynamics The primary pharmacodynamic effects of norepinephrine are cardiac stimulation and vasoconstriction. Cardiac output is generally unaffected, although it can be decreased, and total peripheral resistance is also elevated. The elevation in resistance and pressure result in reflex vagal activity, which slows the heart rate and increases stroke volume. The elevation in vascular tone or resistance reduces blood flow to the major abdominal organs as well as to skeletal muscle. Coronary blood flow is substantially increased secondary to the indirect effects of alpha stimulation. After intravenous administration, a pressor response occurs rapidly and reaches steady state within 5 minutes. The pharmacologic actions of norepinephrine are terminated primarily 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.

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3 DOSAGE FORMS AND STRENGTHS Injection: 4 mg/4 mL (1 mg/mL norepinephrine base) sterile, colorless solution in a single-dose amber glass vial. Injection: 4 mg/4 mL (1 mg/mL) norepinephrine base in single-dose glass vial. ( 3 )

NOREPINEPHRINE BITARTRATE Norepinephrine Bitartrate NOREPINEPHRINE BITARTRATE NOREPINEPHRINE SODIUM CHLORIDE SODIUM METABISULFITE

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, mutagenesis, and fertility studies have not been performed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, mutagenesis, and fertility studies have not been performed.

ANDA211359

NOREPINEPHRINE BITARTRATE

Norepinephrine Bitartrate

72572-481

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 72572-481-10 Norepinephrine Bitartrate Injection, USP 4mg/4mL* (1mg/mL) FOR INTRAVENOUS INFUSION ONLY Warning: Contains Sulfites. Rx Only 10 x 4 mL Single-Dose Vials CIVICA carton

17 PATIENT COUNSELING INFORMATION Risk of Tissue Damage Advise the patient, family, or caregiver to report signs of extravasation urgently [see Warnings and Precautions ( 5.1 )]. Manufactured for: Civica, Inc., Lehi, Utah 84043 Manufactured by: Delpharm Boucherville Canada Inc. 145 Rue Jules-Leger Street Boucherville, QC, J4B 7K8 46327077

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 )].

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Limited published data consisting of a small number of case reports and multiple small trials involving the use of norepinephrine in pregnant women at the time of delivery have not identified an increased risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus from hypotension associated with septic shock, myocardial infarction and stroke which are medical emergencies in pregnancy and can be fatal if left untreated ( see Clinical Considerations ). In animal reproduction studies, using high doses of intravenous norepinephrine resulted in lowered maternal placental blood flow. Clinical relevance to changes in the human fetus is unknown since the average maintenance dose is ten times lower ( see Data ). Increased fetal reabsorptions were observed in pregnant hamsters after receiving daily 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 USE IN SPECIFIC POPULATIONS • Elderly patients may be at greater risk of developing adverse reactions. ( 8.5 ) 8.1 Pregnancy Risk Summary Limited published data consisting of a small number of case reports and multiple small trials involving the use of norepinephrine in pregnant women at the time of delivery have not identified an increased risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus from hypotension associated with septic shock, myocardial infarction and stroke which are medical emergencies in pregnancy and can be fatal if left untreated ( see Clinical Considerations ). In animal reproduction studies, using high doses of intravenous norepinephrine resulted in lowered maternal placental blood flow. Clinical relevance to changes in the human fetus is unknown since the average maintenance dose is ten times lower ( see Data ). Increased fetal reabsorptions were observed in pregnant hamsters after receiving daily 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 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Norepinephrine bitartrate injection, USP is a sterile, colorless solution for injection intended for intravenous use. It contains the equivalent of 1 mg of norepinephrine base per 1 mL (4 mg/4 mL). It is available as 4 mg/4 mL in single-dose amber glass vials. Supplied as: 4 mg/4 mL Single-dose Vials in boxes of 10 (NDC 72572-481-10) Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Store in original carton until time of administration to protect from light. Discard unused portion.