Brand name: Levophed
Drug class: alpha- and beta-Adrenergic Agonists
VA class: AU100
CAS number: 69815-49-2

Medically reviewed by Drugs.com on Mar 2, 2022. Written by ASHP.

Introduction

Norepinephrine is identical to the endogenous catecholamine that is synthesized in the adrenal medulla and in sympathetic nervous tissue; norepinephrine predominantly acts by a direct effect on α-adrenergic receptors.

Uses for Norepinephrine

Acute Hypotensive States

Used as adjunctive therapy to produce vasoconstriction and maintain BP in the management of certain acute hypotensive states (e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, MI, septicemia, blood transfusion, drug reactions).

Pressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes. Correct blood volume depletion as fully as possible before administration.

The Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock recommend norepinephrine as the vasopressor of choice in adults with septic shock; if adequate BP not achieved, vasopressin or epinephrine may be added. Vasopressin also may be given in conjunction with norepinephrine to reduce dosage requirements of norepinephrine.

Also used to provide vasopressor support in other types of shock (e.g., cardiogenic, hemorrhagic), generally as a temporary measure until underlying cause can be treated.

In patients who are hypotensive from blood volume deficits, manufacturer states to use norepinephrine only as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed.

Early revascularization is standard of care in patients with cardiogenic shock; individualize use of vasopressors in this setting.

Has been used to treat hypotension during spinal anesthesia; however, other vasopressors with a longer duration (e.g., phenylephrine) more commonly used.

Advanced Cardiovascular Life Support

Used adjunctively in the management of cardiac arrest to restore and maintain adequate BP after an effective heartbeat and ventilation have been established by other means.

High-quality CPR and defibrillation are the only proven interventions to increase survival to hospital discharge in ACLS. Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation.

Principal goal of pharmacologic therapy during cardiac arrest is to facilitate the return of spontaneous circulation (ROSC), and epinephrine is the drug of choice for this use. Vasoactive drugs such as norepinephrine may be used for hemodynamic support following resuscitation.

Norepinephrine Dosage and Administration

General

• Observe the effect of the initial dose on BP carefully and adjust the rate of flow to establish and maintain the desired BP.

• Do not leave the patient unattended; must closely monitor the infusion flow rate.

• Check BP every 2 minutes from the time the norepinephrine infusion is started until the desired effect is achieved, then every 5 minutes while the drug is being infused.

• Elevate BP to a low normal level to maintain circulation to vital organs.

• In previously normotensive patients, maintain SBP at 80–100 mm Hg; in previously hypertensive patients, maintain SBP at no more than 40 mm Hg below their preexisting BP.

• Continue therapy until adequate BP and tissue perfusion are maintained.

• When discontinuing therapy, slow infusion rate gradually and avoid abrupt withdrawal; observe patient carefully so that therapy may be resumed if the BP falls too rapidly.

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion using an infusion pump or other apparatus to control the rate of flow.

Infuse into the antecubital vein if possible, although the femoral vein may also be used. (See Extravasation under Cautions.)

Administer through a plastic catheter inserted deep into the vein.

A catheter tie-in technique should be avoided if possible because obstruction of blood flow around the tubing may cause stasis and increased local concentration of the drug.

Should not be administered in the same IV line as alkaline solutions, which may inactivate the drug.

Care must be taken to avoid extravasation because local necrosis may result. (See Extravasation under Cautions.)

Dilution

Must dilute commercially available concentrate for injection with a dextrose-containing solution (5% dextrose injection, with or without 0.9% sodium chloride injection); 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.

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.

Dosage

Available as norepinephrine bitartrate; dosage expressed in terms of norepinephrine.

Pediatric Patients

Acute Hypotensive States

IV

If norepinephrine is used in pediatric patients, some clinicians have recommended an initial infusion rate of 0.05–0.1 mcg/kg per minute, titrated to effect (up to a maximum of 2 mcg/kg per minute).

ACLS

IV

For postresuscitation stabilization in pediatric patients^{† [off-label]}, an infusion rate of 0.1–2 mcg/kg per minute, adjusted based on patient response, has been used.

Adults

Acute Hypotensive States

IV

Usual initial dosage: 8–12 mcg/minute; alternatively, some clinicians have suggested initial dosage of 0.5–1 mcg/minute, titrated to effect.

Adjust rate of flow to establish and maintain desired BP. (See General under Dosage and Administration.)

Administer in the lowest effective dosage for the shortest possible time.

Average adult maintenance dosage: 2–4 mcg/minute; however, there is wide variability in dosage range.

A few hypotensive patients have required much larger dosages (as much as 68 mg daily). Patients with refractory shock may require 8–30 mcg/minute.

ACLS

IV

If norepinephrine is used adjunctively to restore and maintain adequate BP during cardiac resuscitation, the manufacturer states to follow same dosage guidelines as for the treatment of acute hypotensive states. (See Acute Hypotensive States under Dosage and Administration.)

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

If used in geriatric patients, initial dosage usually should be at the low end of the dosage range and caution should be exercised since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group than in younger patients.

Cautions for Norepinephrine

Contraindications

• Generally contraindicated during anesthesia with cyclopropane or halogenated hydrocarbon general anesthetics. (See Specific Drugs under Interactions.)

• Use in patients who are hypotensive from blood volume deficits except as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed.

• Use in patients with mesenteric or peripheral vascular thrombosis, unless clinically necessary as a life-saving procedure.

• Use in patients with profound hypoxia or hypercapnia may be contraindicated. (See Arrhythmias under Cautions.)

Warnings/Precautions

Warnings

Severe Hypertension

To avoid the potential for dangerously high BP, monitor BP closely during administration. Headache may be a symptom of hypertension due to overdosage.

Hypovolemia

Pressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes. Correct blood volume depletion as fully as possible before administration.

May be used in an emergency as an adjunct to fluid volume replacement or as a temporary supportive measure to maintain coronary and cerebral artery perfusion until volume replacement therapy can be completed, but norepinephrine must not be used as sole therapy in hypovolemic patients.

Concomitant Drugs

Administer with extreme caution in patients receiving an MAO inhibitor or a triptyline- or imipramine-type antidepressant because severe, prolonged hypertension may result. (See Interactions.)

Extravasation

Because severe local adverse effects (e.g., tissue necrosis, sloughing at injection site) may occur as a result of local vasoconstriction, must avoid extravasation. (See Boxed Warning.)

Check site of infusion frequently for free flow and monitor infused vein for blanching.

Risk of tissue damage is apparently very slight if infused through a plastic catheter deep into an antecubital vein.

Avoid injection into leg veins, especially in geriatric patients or those with occlusive vascular diseases (e.g., arteriosclerosis, atherosclerosis, Buerger’s disease).

Impairment of circulation and sloughing of tissue may also occur without obvious extravasation.

If blanching is observed in the infused vein or if therapy is to be prolonged, consider changing the injection site periodically.

Sensitivity Reactions

Sulfite Sensitivity

Formulations of norepinephrine bitartrate injection contain sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.

General Precautions

Prolonged Administration

Has caused decreased cardiac output, edema, hemorrhage, focal myocarditis, subpericardial hemorrhage, necrosis of the intestine, or hepatic and renal necrosis. Generally occurs in patients with severe shock and it is not clear if the drug or the shock state itself was the cause.

Vasoconstriction

Can cause severe peripheral and visceral vasoconstriction, reducing blood flow and tissue perfusion to vital organs and resulting in possible tissue hypoxia, lactic acidosis, and ischemic injury; these effects are most likely to occur in hypovolemic patients if plasma volumes are not adequately corrected.

Cardiovascular Effects

May cause plasma volume depletion, which may result in hypotension when the drug is discontinued in the absence of blood volume replacement.

Cardiac output may be decreased following prolonged use of the drug or administration of large doses because venous return to the heart may be diminished because of increased peripheral vascular resistance; decreased cardiac output may be especially harmful to elderly patients or those with initially poor cerebral or coronary circulation.

Arrhythmias

May cause bradycardia (probably a reflex response to increased BP) as well as potentially fatal cardiac arrhythmias, including ventricular tachycardia and ventricular fibrillation.

Arrhythmias are especially likely to occur in patients with severe hypoxia, or hypercapnia, or those receiving other drugs that may increase cardiac irritability such as cyclopropane or halogenated hydrocarbon general anesthetics. (See Specific Drugs under Interactions.)

Hypoxia, Hypercapnia, and Acidosis

Hypoxia, hypercapnia, and acidosis may reduce the effectiveness and/or increase the incidence of adverse effects of norepinephrine, and must be identified and corrected prior to or concurrently with administration of the drug.

Specific Populations

Pregnancy

Category C. Use during pregnancy only if clearly indicated.

Lactation

Not known whether norepinephrine is distributed into milk. Use caution.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age. (See Geriatric Patients under Dosage and Administration.)

Do not infuse into leg veins in geriatric patients. (See Extravasation under Cautions.)

Common Adverse Effects

May cause headache, anxiety, arrhythmias, bradycardia, respiratory difficulty, ischemic injury, or extravasation at the infusion site.

Interactions for Norepinephrine

Specific Drugs

Norepinephrine Pharmacokinetics

Absorption

Bioavailability

Oral: Destroyed in the GI tract.

Sub-Q: Poorly absorbed.

Onset

IV: Pressor response occurs rapidly.

Duration

Short; 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 milk.

Elimination

Metabolism

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

Pharmacologic actions are terminated mainly by uptake and metabolism in sympathetic nerve endings.

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.

Stability

Storage

Parenteral

Injection

20–25°C; protect from light.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

IV infusion: Dilute norepinephrine with 5% dextrose injection with or without sodium chloride to protect against loss of potency caused by oxidation during IV infusion; do not use sodium chloride injection alone.

Following dilution with 5% dextrose, IV infusions containing norepinephrine 2.5 or 4 mcg/mL have been reported to be stable for at least 24 hours at room temperature if the pH is approximately 5.6.

Norepinephrine solutions containing 2.5 mcg/mL in 5% dextrose have been reported to lose 5% of their potency in 6 hours at pH 6.5 and in 4 hours at pH 7.5.

Use caution if diluted with 5% dextrose injections with a pH of >5.5–6 or if the drug is mixed with alkaline additives such as sodium bicarbonate, barbiturates, or alkaline buffered antibiotics which will result in pH >6; these solutions should be used immediately after preparation.

Should not be administered in the same IV line as alkaline solutions, which may inactivate the drug.

Administer whole blood or plasma, if indicated during therapy with norepinephrine, separately or via a Y-tube.

Solution CompatibilityHID

Drug Compatibility

Actions

• Acts predominantly by a direct effect on α-adrenergic receptors.

• Also stimulates β₁-adrenergic receptors but not β₂-adrenergic receptors.

• Main therapeutic effect is a clinically important increase in mean arterial pressure (MAP), with minimal change in heart rate or cardiac output.

• Constricts both arterial and venous blood vessels through its effect on α-adrenergic receptors.

• Systemic vascular resistance is increased, resulting in increased BP.

• Induces vasoconstriction in most vascular beds, potentially reducing blood flow to the renal, splanchnic, and cutaneous vasculature.

• Local vasoconstriction caused by the drug may result in hemostasis and/or necrosis.

• May reduce circulating plasma volume (especially with prolonged use).

• Acts on β₁-adrenergic receptors in the heart, producing a positive inotropic effect on the myocardium.

Advice to Patients

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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

Reload page with references included

Frequently asked questions

• Norepinephrine vs epinephrine: what's the difference?
• Strattera vs Adderall: What is the difference?
• What are some common side effects of antidepressants?

View more FAQ

Medical Disclaimer