Norepinephrine (Monograph)

Brand name: Levophed
Drug class: alpha- and beta-Adrenergic Agonists

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Endogenous catecholamine vasopressor that predominantly acts by a direct effect on α-adrenergic receptors and to a lesser extent on β-adrenergic receptors.

Uses for Norepinephrine

Acute Hypotensive States

Used to raise BP in adults with severe, acute hypotension.

Although not FDA-labeled in pediatric patients, also has been used for BP management in pediatric patients with fluid-refractory septic shock^{† [off-label]}.

Compared with other vasopressors, norepinephrine is associated with similar hemodynamic and mortality outcomes and lower risk for arrhythmia.

Guidelines for treatment of sepsis and septic shock generally recommend norepinephrine as a first-line vasopressor for hemodynamic management.

The American Heart Association (AHA) states that in cardiogenic shock, norepinephrine may be the vasopressor of choice in many patients, although the optimal first-line vasopressor in this setting remains unclear.

Prolongation of Anesthesia

Has been added to solutions of some local anesthetics to decrease the rate of vascular absorption of the anesthetic and prolong the duration of anesthesia^{† [off-label]}. However, epinephrine is more commonly used for this purpose.

Norepinephrine Dosage and Administration

General

Pretreatment Screening

Correct hypovolemia prior to initiating norepinephrine.

Patient Monitoring

Monitor BP every 2 minutes until the desired hemodynamic effect is achieved, and then monitor BP every 5 minutes throughout the infusion.
Monitor for changes to the skin or the extremities in patients susceptible to tissue ischemia.
Monitor for signs of extravasation.
Perform continuous cardiac monitoring in patients with arrhythmias.
Monitor cardiac rhythm in patients treated with halogenated anesthetics.
Monitor for hypertension in patients receiving concomitant treatment with drugs that can cause hypertension (e.g., monoamine oxidase inhibitors, tricyclic antidepressants).
Monitor glucose concentration in patients treated with antidiabetic agents.

Dispensing and Administration Precautions

Based on the Institute for Safe Medication Practices (ISMP), norepinephrine is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

IV Administration

Administer by IV infusion.

To minimize risk of necrosis, infuse into a large vein; avoid infusions into the veins of the leg in elderly patients or in patients with occlusive vascular disease of the legs.

Care must be taken to avoid extravasation because local necrosis may result.

Avoid contact of the drug with iron salts, alkalies, or oxidizing agents.

Must dilute commercially available injection concentrate (e.g., Levophed) prior to administration; alternatively, may use commercially available premixed norepinephrine solutions in 5% dextrose or 0.9% sodium chloride injection without dilution.

Dilution

Must dilute commercially available concentrate for injection with a dextrose-containing solution (5% dextrose injection, with or without 0.9% sodium chloride injection); manufacturer states that dilution with 0.9% sodium chloride injection alone is not recommended.

Concentration of norepinephrine and the infusion rate depend on the drug and fluid requirements of the individual patient; use higher concentration solutions in patients requiring fluid restriction.

Infusion solution usually prepared by adding 4 mg of norepinephrine (4 mL of the commercially available injection) to 1 L of a 5% dextrose-containing solution to produce a concentration of 4 mcg/mL; a more dilute or concentrated solution may be prepared depending on the fluid requirements of the patient.

Standardize 4 Safety

Standardize 4 safety (S4S) is a national, multidisciplinary, patient safety initiative to standardize drug concentrations to reduce medication errors, especially during transitions of care. Recommendations developed to date through this initiative are available at [Web].

Table 1: Standardize 4 Safety Continuous Infusion Standards for Norepinephrine249250
Patient Population	Concentration Standard	Dosing Units
Adults	16 mcg/mL 32 mcg/mL 128 mcg/mL	mcg/kg/min
Pediatric patients (<50 kg)	16 mcg/mL 32 mcg/mL 64 mcg/mL	mcg/kg/min

Dosage

Avoid abrupt withdrawal of norepinephrine infusion; discontinue by reducing the flow rate gradually.

Pediatric Patients

Acute Hypotensive States

IV

If norepinephrine is used in pediatric patients, some clinicians have recommended an infusion rate of 0.05–2.5 mcg/kg per minute, titrated to effect.

Adults

Acute Hypotensive States

IV

Usual initial dosage is 8–12 mcg/minute; typical maintenance IV dosage is 2–4 mcg/minute. Other experts have described common dosage ranges of norepinephrine as 0.01–0.5 mcg/kg per minute. Adjust dosage to maintain desired hemodynamic effect.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations. 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.

Cautions for Norepinephrine

Contraindications

None.

Warnings/Precautions

Tissue Ischemia

In patients with hypovolemia-related hypotension, can cause severe peripheral and visceral vasoconstriction, decreased renal perfusion and reduced urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow, even in patients with “normal” blood pressure. Address hypovolemia prior to initiating norepinephrine. Avoid in patients with mesenteric or peripheral vascular thrombosis, which may increase ischemic risk and extend the area of infarction.

Extravasation may occur. To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the extravasated area with 10–15 mL of sodium chloride solution containing 5–10 mg of phentolamine mesylate using a syringe with a fine hypodermic needle. Administer phentolamine as soon as possible after extravasation.

Hypotension after Abrupt Discontinuation

Abrupt cessation can cause marked hypotension. When discontinuing infusion, gradually reduce infusion rate while expanding blood volume with IV fluids.

Cardiac Arrhythmias

May cause arrhythmias, particularly in patients with hypoxia or hypercarbia. Perform continuous cardiac monitoring of patients with arrhythmias.

Allergic Reactions Associated with Sulfite

Injection concentrate (Levophed )contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. Such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Specific Populations

Pregnancy

Limited data have not identified increased risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Delaying necessary treatment in pregnant women 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.

Lactation

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 of norepinephrine in the infant is unlikely.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age.

Do not infuse into leg veins in geriatric patients.

Common Adverse Effects

Most common adverse effects: ischemic injury, bradycardia, anxiety, transient headache, respiratory difficulty, extravasation necrosis at injection site.

Drug Interactions

Specific Drugs

Drug	Interaction	Comments
Anesthetics, halogenated	Concomitant use may result in arrhythmias	Manufacturer states to monitor cardiac rhythm in patients receiving concomitant halogenated anesthetics
Antidepressants, tricyclic (e.g., imipramine)	May potentiate the pressor effects of norepinephrine, resulting in severe, prolonged hypertension	Manufacturer states to monitor for hypertension if coadministration cannot be avoided
Antidepressants, MAO inhibitors or drugs with MAO-inhibiting properties (e.g., linezolid)	Risk of severe, prolonged hypertension	Manufacturer states to monitor for hypertension if coadministration cannot be avoided
Antidiabetics	May decrease insulin sensitivity and raise blood glucose concentrations	Manufacturer states to monitor glucose and consider dosage adjustment of antidiabetic drugs

Norepinephrine Pharmacokinetics

Absorption

Onset

Steady-state plasma concentration achieved within 5 minutes of IV infusion.

Duration

Pressor action stops within 1–2 minutes after the infusion is discontinued.

Distribution

Extent

Localizes mainly in sympathetic nervous tissue.

Crosses the placenta. Does not cross the blood-brain barrier.

Not known if distributes into human milk.

Plasma Protein Binding

Approximately 25% bound to plasma protein, mainly to albumin and to a lesser extent alpha 1-acid glycoprotein.

Elimination

Metabolism

Via the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and MAO.

Major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive.

Elimination Route

Metabolites are excreted in urine mainly as the sulfate conjugates and, to a lesser extent, as the glucuronide conjugates; only small quantities of norepinephrine are excreted unchanged.

Half-life

Mean half-life is approximately 2.4 minutes.

Stability

Storage

Parenteral

Injection

20–25°C (excursions permitted to 15–30°C); protect from light. Diluted norepinephrine solution may be stored for up to 24 hours at room temperature prior to use.

Actions

Acts predominantly by a direct effect on α-adrenergic receptors and to a lesser extent, β-adrenergic receptors.
Causes increased inotropic effect, dilation of coronary arteries, and increased coronary blood flow; has minimal effect on cardiac output and chronotropy.
Induces vasoconstriction in most vascular beds, potentially reducing blood flow to the major abdominal organs and skeletal muscle.

Advice to Patients

Advise the patient, family, or caregiver to report signs of extravasation urgently.
Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.
Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Norepinephrine Bitartrate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection concentrate, for IV infusion	1 mg (of norepinephrine) per mL*	Levophed	Hospira
			Norepinephrine Bitartrate Injection

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Norepinephrine Bitartrate in Dextrose
Routes	Dosage Forms	Strengths	Brand Names
Parenteral	Injection, for IV infusion	16 mcg/mL norepinephrine (4 mg) in 5% dextrose*	Norepinephrine Bitartrate in Dextrose 5%
		32 mcg/mL norepinephrine (8 mg) in 5% dextrose*	Norepinephrine Bitartrate in Dextrose 5%
		64 mcg/mL norepinephrine (16 mg) in 5% dextrose*	Norepinephrine Bitartrate in Dextrose 5%

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Norepinephrine Bitartrate in Sodium Chloride
Routes	Dosage Forms	Strengths	Brand Names
Parenteral	Injection, for IV infusion	16 mcg/mL norepinephrine (4 mg) in 0.9% sodium chloride*	Norepinephrine Bitartrate in Sodium Chloride Injection
		32 mcg/mL norepinephrine (8 mg) in 0.9% sodium chloride*	Norepinephrine Bitartrate in Sodium Chloride Injection
		64 mcg/mL norepinephrine (16 mg) in 0.9% sodium chloride*	Norepinephrine Bitartrate in Sodium Chloride Injection