These Highlights Do Not Include All The Information Needed To Use Norepinephrine In Sodium Chloride Injection Safely And Effectively. See Full Prescribing Information For Norepinephrine In Sodium Chloride Injection.

Correct Hypovolemia

Address hypovolemia before initiation of Norepinephrine in Sodium Chloride Injection therapy. If the patient does not respond to therapy, suspect occult hypovolemia [see Warnings and Precautions (5.1)].

Principal Display Panel – 4 mg Pouch Label

NDC: 81298-9659-1

Rx only

1 x 250 mL

Norepinephrine

in 0.9% Sodium Chloride injection

4 mg per 250 mL

(16 mcg/mL)

Keep in sealed overwrap until time of use.

LONG GROVE

PHARMACEUTICALS™

After an initial dose 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 or continuously until the desired hemodynamic effect is achieved, and then monitor blood pressure every five minutes for the duration of the infusion.

Recommended Average Maintenance Dosage:

Typical maintenance intravenous dosage is 2 to 4 mcg per minute.

Overdosage with Norepinephrine in Sodium Chloride Injection may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output.

In case of accidental overdosage, discontinue Norepinephrine in Sodium Chloride Injection until the condition of the patient stabilizes.

Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is a catecholamine which differs from epinephrine by the absence of a methyl group on the nitrogen atom.

Chemically, 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 in Sodium Chloride Injection is a clear, colorless, single dose sterile solution supplied as a ready-to-use intravenous infusion bag for intravenous use and does not require further dilution. Each mL contains the equivalent of 16 or 32 or 64 micrograms of norepinephrine base supplied as 31.90 or 63.80 or 127.6 micrograms per mL of norepinephrine bitartrate monohydrate. In addition, each mL of solution contains 0.01 mg edetate disodium dihydrate as a metal chelator and 9.0 mg sodium chloride for isotonicity. It has a pH of 3.5 to 4.5.

Norepinephrine in Sodium Chloride Injection can decrease insulin sensitivity and raise blood glucose. Monitor glucose and consider dosage adjustment of antidiabetic drugs.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of Norepinephrine in Sodium Chloride 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 in Sodium Chloride Injection into the veins in the leg in elderly patients [see Warnings and Precautions (5.1)].

None.

Administration of Norepinephrine in Sodium Chloride 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 in Sodium Chloride Injection [see Dosage and Administration (2.1)]. Avoid Norepinephrine in Sodium Chloride 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 in Sodium Chloride 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)].

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

• 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)

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.

Norepinephrine in Sodium Chloride Injection is indicated to raise blood pressure in adult patients with severe, acute hypotension.

Norepinephrine in Sodium Chloride 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.

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

Co-administration of Norepinephrine 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 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.

Avoid contact with iron salts and alkalizing and oxidizing agents.

Whole blood or plasma, if indicated to increase blood volume, should be administered separately.

• Tissue Ischemia: Avoid extravasation into tissues, which can cause local necrosis (5.1)
• Hypotension After Abrupt Discontinuation: Sudden cessation of the infusion rate may result in marked hypotension. Reduce the Norepinephrine in Sodium Chloride Injection infusion rate gradually. (5.2)
• Cardiac Arrhythmias: Norepinephrine in Sodium Chloride Injection may cause arrhythmias. Monitor cardiac function in patients with underlying heart disease. (5.3)

• No further dilution prior to infusion is required (2.1)
• Initial intravenous infusion rate of 8 to 12 mcg per minute, adjust the rate of flow to establish and maintain a low to normal blood pressure (usually 80 to 100 mm Hg) sufficient to maintain the circulation of vital organs (2.2)
• The average maintenance dose ranges from 2 to 4 mcg per minute. (2.2)

Concomitant use of Norepinephrine 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.

Injection: Norepinephrine is a clear, colorless sterile solution in the premixed, ready-to-use single dose intravenous infusion bags available as:

• 4 mg/250 mL (16 mcg/mL) of norepinephrine in 0.9% Sodium Chloride
• 8 mg/250 mL (32 mcg/mL) of norepinephrine in 0.9% Sodium Chloride
• 16 mg/250 mL (64 mcg/mL) of norepinephrine in 0.9% Sodium Chloride

Co-administration of Norepinephrine in Sodium Chloride Injection with tricyclic antidepressants (including amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can cause severe, prolonged hypertension. If administration of Norepinephrine in Sodium Chloride Injection cannot be avoided in these patients, monitor for hypertension.

• Elderly patients may be at greater risk of developing adverse reactions. (8.5)

Norepinephrine in Sodium Chloride Injection (norepinephrine bitartrate) is supplied as a clear, colorless sterile solution in a 250 mL non-PVC infusion bag with single function connector system consisting of a port and cap, packaged individually in an aluminum foil pouch with an oxygen scavenger. Supplied as:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Protect from light. Once the overwrap is removed, the bag can be stored at room temperature for up to 45 days.

Sudden cessation of the infusion rate may result in marked hypotension. When discontinuing the infusion, gradually reduce the Norepinephrine in Sodium Chloride Injection infusion rate while expanding blood volume with intravenous fluids.

Carcinogenesis, mutagenesis, and fertility studies have not been performed.

Correct Hypovolemia

Address hypovolemia before initiation of Norepinephrine in Sodium Chloride Injection therapy. If the patient does not respond to therapy, suspect occult hypovolemia [see Warnings and Precautions (5.1)].

Principal Display Panel – 4 mg Pouch Label

NDC: 81298-9659-1

Rx only

1 x 250 mL

Norepinephrine

in 0.9% Sodium Chloride injection

4 mg per 250 mL

(16 mcg/mL)

Keep in sealed overwrap until time of use.

LONG GROVE

PHARMACEUTICALS™

After an initial dose 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 or continuously until the desired hemodynamic effect is achieved, and then monitor blood pressure every five minutes for the duration of the infusion.

Recommended Average Maintenance Dosage:

Typical maintenance intravenous dosage is 2 to 4 mcg per minute.

Overdosage with Norepinephrine in Sodium Chloride Injection may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output.

In case of accidental overdosage, discontinue Norepinephrine in Sodium Chloride Injection until the condition of the patient stabilizes.

Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is a catecholamine which differs from epinephrine by the absence of a methyl group on the nitrogen atom.

Chemically, 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 in Sodium Chloride Injection is a clear, colorless, single dose sterile solution supplied as a ready-to-use intravenous infusion bag for intravenous use and does not require further dilution. Each mL contains the equivalent of 16 or 32 or 64 micrograms of norepinephrine base supplied as 31.90 or 63.80 or 127.6 micrograms per mL of norepinephrine bitartrate monohydrate. In addition, each mL of solution contains 0.01 mg edetate disodium dihydrate as a metal chelator and 9.0 mg sodium chloride for isotonicity. It has a pH of 3.5 to 4.5.

Norepinephrine in Sodium Chloride Injection can decrease insulin sensitivity and raise blood glucose. Monitor glucose and consider dosage adjustment of antidiabetic drugs.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of Norepinephrine in Sodium Chloride 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 in Sodium Chloride Injection into the veins in the leg in elderly patients [see Warnings and Precautions (5.1)].

None.

Administration of Norepinephrine in Sodium Chloride 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 in Sodium Chloride Injection [see Dosage and Administration (2.1)]. Avoid Norepinephrine in Sodium Chloride 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 in Sodium Chloride 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)].

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

• 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)

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.

Norepinephrine in Sodium Chloride Injection is indicated to raise blood pressure in adult patients with severe, acute hypotension.

Norepinephrine in Sodium Chloride 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.

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

Co-administration of Norepinephrine 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 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.

Avoid contact with iron salts and alkalizing and oxidizing agents.

Whole blood or plasma, if indicated to increase blood volume, should be administered separately.

• Tissue Ischemia: Avoid extravasation into tissues, which can cause local necrosis (5.1)
• Hypotension After Abrupt Discontinuation: Sudden cessation of the infusion rate may result in marked hypotension. Reduce the Norepinephrine in Sodium Chloride Injection infusion rate gradually. (5.2)
• Cardiac Arrhythmias: Norepinephrine in Sodium Chloride Injection may cause arrhythmias. Monitor cardiac function in patients with underlying heart disease. (5.3)

• No further dilution prior to infusion is required (2.1)
• Initial intravenous infusion rate of 8 to 12 mcg per minute, adjust the rate of flow to establish and maintain a low to normal blood pressure (usually 80 to 100 mm Hg) sufficient to maintain the circulation of vital organs (2.2)
• The average maintenance dose ranges from 2 to 4 mcg per minute. (2.2)

Concomitant use of Norepinephrine 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.

Injection: Norepinephrine is a clear, colorless sterile solution in the premixed, ready-to-use single dose intravenous infusion bags available as:

• 4 mg/250 mL (16 mcg/mL) of norepinephrine in 0.9% Sodium Chloride
• 8 mg/250 mL (32 mcg/mL) of norepinephrine in 0.9% Sodium Chloride
• 16 mg/250 mL (64 mcg/mL) of norepinephrine in 0.9% Sodium Chloride

Co-administration of Norepinephrine in Sodium Chloride Injection with tricyclic antidepressants (including amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can cause severe, prolonged hypertension. If administration of Norepinephrine in Sodium Chloride Injection cannot be avoided in these patients, monitor for hypertension.

• Elderly patients may be at greater risk of developing adverse reactions. (8.5)

Norepinephrine in Sodium Chloride Injection (norepinephrine bitartrate) is supplied as a clear, colorless sterile solution in a 250 mL non-PVC infusion bag with single function connector system consisting of a port and cap, packaged individually in an aluminum foil pouch with an oxygen scavenger. Supplied as:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Protect from light. Once the overwrap is removed, the bag can be stored at room temperature for up to 45 days.

Sudden cessation of the infusion rate may result in marked hypotension. When discontinuing the infusion, gradually reduce the Norepinephrine in Sodium Chloride Injection infusion rate while expanding blood volume with intravenous fluids.

Carcinogenesis, mutagenesis, and fertility studies have not been performed.