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.^{101 173}

Uses for Norepinephrine

Acute Hypotensive States

Used to raise BP in adults with severe, acute hypotension.^{101 153 154 157 163 174 175}

Although not FDA-labeled in pediatric patients, also has been used for BP management in pediatric patients with fluid-refractory septic shock^{† [off-label]}.⁴⁰⁷

Compared with other vasopressors, norepinephrine is associated with similar hemodynamic and mortality outcomes and lower risk for arrhythmia.^{176 177 178 179}

Guidelines for treatment of sepsis and septic shock generally recommend norepinephrine as a first-line vasopressor for hemodynamic management.^{153 407}

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.¹⁸⁰

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]}.^{165 166 167} However, epinephrine is more commonly used for this purpose.^{165 166 167}

Norepinephrine Dosage and Administration

General

Pretreatment Screening

• Correct hypovolemia prior to initiating norepinephrine.¹⁰¹

Patient Monitoring

• Monitor BP every 2 minutes until the desired hemodynamic effect is achieved, and then monitor BP every 5 minutes throughout the infusion.¹⁰¹

• Monitor for changes to the skin or the extremities in patients susceptible to tissue ischemia.¹⁰¹

• Monitor for signs of extravasation.¹⁰¹

• Perform continuous cardiac monitoring in patients with arrhythmias.¹⁰¹

• Monitor cardiac rhythm in patients treated with halogenated anesthetics.¹⁰¹

• Monitor for hypertension in patients receiving concomitant treatment with drugs that can cause hypertension (e.g., monoamine oxidase inhibitors, tricyclic antidepressants).¹⁰¹

• Monitor glucose concentration in patients treated with antidiabetic agents.¹⁰¹

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.¹⁸²

Administration

IV Administration

Administer by IV infusion.¹⁰¹

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.¹⁰¹

Care must be taken to avoid extravasation because local necrosis may result. ¹⁰¹

Avoid contact of the drug with iron salts, alkalies, or oxidizing agents.¹⁰¹

Must dilute commercially available injection concentrate (e.g., Levophed) prior to administration;¹⁰¹ alternatively, may use commercially available premixed norepinephrine solutions in 5% dextrose or 0.9% sodium chloride injection without dilution.^{102 103}

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.¹⁰¹

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.¹⁰¹

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.¹⁰¹

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.^{249 250} Recommendations developed to date through this initiative are available at [Web].^{249 250}

Dosage

Avoid abrupt withdrawal of norepinephrine infusion; discontinue by reducing the flow rate gradually.¹⁰¹

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.¹⁷⁵

Adults

Acute Hypotensive States

IV

Usual initial dosage is 8–12 mcg/minute; typical maintenance IV dosage is 2–4 mcg/minute.¹⁰¹ Other experts have described common dosage ranges of norepinephrine as 0.01–0.5 mcg/kg per minute.¹⁷³ Adjust dosage to maintain desired hemodynamic effect.¹⁰¹

Special Populations

Hepatic Impairment

No specific dosage recommendations.¹⁰¹

Renal Impairment

No specific dosage recommendations.¹⁰¹

Geriatric Patients

No specific dosage recommendations.¹⁰¹ 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.¹⁰¹

Cautions for Norepinephrine

Contraindications

• None.¹⁰¹

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.¹⁰¹ Address hypovolemia prior to initiating norepinephrine.¹⁰¹ Avoid in patients with mesenteric or peripheral vascular thrombosis, which may increase ischemic risk and extend the area of infarction.¹⁰¹

Extravasation may occur.¹⁰¹ 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.¹⁰¹ Administer phentolamine as soon as possible after extravasation.¹⁰¹

Hypotension after Abrupt Discontinuation

Abrupt cessation can cause marked hypotension.¹⁰¹ When discontinuing infusion, gradually reduce infusion rate while expanding blood volume with IV fluids.¹⁰¹

Cardiac Arrhythmias

May cause arrhythmias, particularly in patients with hypoxia or hypercarbia.¹⁰¹ Perform continuous cardiac monitoring of patients with arrhythmias.¹⁰¹

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.¹⁰¹ Such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.¹⁰¹

Specific Populations

Pregnancy

Limited data have not identified increased risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.¹⁰¹ Delaying necessary treatment in pregnant women may increase the risk of maternal and fetal morbidity and mortality.¹⁰¹ Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of norepinephrine on the fetus.¹⁰¹

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.¹⁰¹ Clinically relevant exposure of norepinephrine in the infant is unlikely.¹⁰¹

Pediatric Use

Safety and efficacy not established.¹⁰¹

Geriatric Use

Insufficient experience in patients ≥65 years of age.¹⁰¹

Do not infuse into leg veins in geriatric patients.¹⁰¹

Common Adverse Effects

Most common adverse effects: ischemic injury, bradycardia, anxiety, transient headache, respiratory difficulty, extravasation necrosis at injection site.¹⁰¹

Drug Interactions

Specific Drugs

Norepinephrine Pharmacokinetics

Absorption

Onset

Steady-state plasma concentration achieved within 5 minutes of IV infusion.¹⁰¹

Duration

Pressor action stops within 1–2 minutes after the infusion is discontinued.¹⁰¹

Distribution

Extent

Localizes mainly in sympathetic nervous tissue.¹⁰¹

Crosses the placenta.¹⁰¹ Does not cross the blood-brain barrier.¹⁰¹

Not known if distributes into human milk.¹⁰¹

Plasma Protein Binding

Approximately 25% bound to plasma protein, mainly to albumin and to a lesser extent alpha 1-acid glycoprotein.¹⁰¹

Elimination

Metabolism

Via the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and MAO.¹⁰¹

Major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive.¹⁰¹

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.¹⁰¹

Half-life

Mean half-life is approximately 2.4 minutes.¹⁰¹

Stability

Storage

Parenteral

Injection

20–25°C (excursions permitted to 15–30°C); protect from light.¹⁰¹ Diluted norepinephrine solution may be stored for up to 24 hours at room temperature prior to use.¹⁰¹

Actions

• Acts predominantly by a direct effect on α-adrenergic receptors and to a lesser extent, β-adrenergic receptors.¹⁰¹

• Causes increased inotropic effect, dilation of coronary arteries, and increased coronary blood flow; has minimal effect on cardiac output and chronotropy.^{101 173 181}

• Induces vasoconstriction in most vascular beds, potentially reducing blood flow to the major abdominal organs and skeletal muscle.¹⁰¹

Advice to Patients

• Advise the patient, family, or caregiver to report signs of extravasation urgently.¹⁰¹

• Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.¹⁰¹

• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.¹⁰¹

• Inform patients of other important precautionary information.¹⁰¹

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

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

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

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