NOREPINEPHRINE BITARTRATE IN SODIUM CHLORIDE

Norepinephrine Bitartrate in Sodium Chloride Injection contains the active pharmaceutical ingredient norepinephrine, a catecholamine, in the form of bitartrate salt (monohydrate). Norepinephrine is sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine which differs from epinephrine by the absence of a methyl group on the nitrogen atom. The chemical name for norepinephrine bitartrate (monohydrate) 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 (monohydrate) is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Norepinephrine Bitartrate in 0.9% Sodium Chloride Injection is supplied as a sterile aqueous ready-to-use solution in 250 mL transparent intravenous bags. Each mL contains 32 mcg, 64 mcg, 128 mcg or 256 mcg of norepinephrine bitartrate monohydrate, equivalent to 16 mcg, 32 mcg, 64 mcg or 128 mcg of norepinephrine base, respectively. Each mL also contains 9 mg of Sodium Chloride USP as a tonicity agent, and may contain Hydrochloric Acid NF and Sodium Hydroxide NF as pH adjusters, for a pH range of 3.4 to 4.0, in Water for Injection. structural formula

Norepinephrine Bitartrate in Sodium Chloride Injection is indicated to raise blood pressure in adult patients with severe, acute hypotension. Norepinephrine Bitartrate in Sodium Chloride Injection is a catecholamine indicated for restoration of blood pressure in adult patients with acute hypotensive states. ( 1 )

• Initiate 8 to 12 mcg/min and adjust the rate to maintain blood pressure sufficient to maintain the circulation of vital organs. ( 2.2 ) • The average maintenance dose ranges from 2 to 4 mcg/min. ( 2.2 ) 2.1 Important Dosage and Administration Instructions Correct Hypovolemia Address hypovolemia before initiation of Norepinephrine Bitartrate in Sodium Chloride Injection therapy. If the patient does not respond to therapy, suspect occult hypovolemia [see Warnings and Precautions (5.1) ] . Administration Norepinephrine Bitartrate in Sodium Chloride Injection is a ready to administer product that requires no further dilution prior to infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Infuse Norepinephrine Bitartrate in Sodium Chloride 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. Discard unused portion. 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. 2.4 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.

None. None. ( 4 )

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 WG Critical Care, LLC at 1-866-562-4708, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Monoamine oxidase inhibitors (MAOI) or tricyclic antidepressants of the triptyline or imipramine types may result in hypertension. ( 7.1 , 7.2) • Antidiabetics: Norepinephrine can decrease insulin sensitivity and raise blood glucose. ( 7.3) • Cyclopropane and halothane anesthetics increase cardiac autonomic irritability. ( 7.4 ) 7.1 MAO-Inhibiting Drugs Co-administration of Norepinephrine Bitartrate in Sodium Chloride 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 in Sodium Chloride 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 in Sodium Chloride Injection with tricyclic antidepressants (including amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can cause severe, prolonged hypertension. If administration of Norepinephrine Bitartrate in Sodium Chloride Injection cannot be avoided in these patients, monitor for hypertension. 7.3 Antidiabetics Norepinephrine Bitartrate in Sodium Chloride 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 in Sodium Chloride 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.