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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(nor ep i NEF rin)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of shock which persists after adequate fluid volume replacement; severe hypotension
Pregnancy Risk Factor
C
Lactation
Excretion in breast milk unknown
Contraindications
Hypersensitivity to norepinephrine, bisulfites (contains metabisulfite), or any component of the formulation; hypotension from hypovolemia except as an emergency measure to maintain coronary and cerebral perfusion until volume could be replaced; mesenteric or peripheral vascular thrombosis unless it is a lifesaving procedure; during anesthesia with cyclopropane (not available in U.S.) or halothane (not available in U.S.) anesthesia (risk of ventricular arrhythmias)
Warnings/Precautions
Boxed warnings:
• Extravasation: See “Other warnings/precautions” below.
Concurrent drug therapy issues:
• Monoamine oxidase inhibitors (MAO-I): Use with extreme caution in patients taking MAO-Inhibitors; prolong hypertension may result from concurrent use.
Dosage form specific issues:
• Sodium metasulfite: Product may contain sodium metasulfite.
Other warnings/precautions:
• Appropriate use: Assure adequate circulatory volume to minimize need for vasoconstrictors. Avoid hypertension; monitor blood pressure closely and adjust infusion rate.
• Extravasation: Avoid extravasation; infuse into a large vein if possible. Avoid infusion into leg veins. Watch I.V. site closely. [U.S. Boxed Warning]: If extravasation occurs, infiltrate the area with diluted phentolamine (5-10 mg in 10-15 mL of saline) with a fine hypodermic needle. Phentolamine should be administered as soon as possible after extravasation is noted.
Adverse Reactions
Frequency not defined.
Cardiovascular: Arrhythmias, bradycardia, peripheral (digital) ischemia
Central nervous system: Anxiety, headache (transient)
Local: Skin necrosis (with extravasation)
Respiratory: Dyspnea, respiratory difficulty
Drug Interactions
Antacids: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Aluminum Hydroxide. Risk C: Monitor therapy
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Benzylpenicilloyl Polylysine: Alpha-/Beta-Agonists may diminish the diagnostic effect of Benzylpenicilloyl Polylysine. Management: Consider use of a histamine skin test as a positive control to assess a patient's ability to mount a wheal and flare response. Risk D: Consider therapy modification
Beta-Blockers: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Risk D: Consider therapy modification
Bromocriptine: Alpha-/Beta-Agonists may enhance the adverse/toxic effect of Bromocriptine. Including increased blood pressure, ventricular arrhythmias, and seizure. Risk C: Monitor therapy
Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Carbonic Anhydrase Inhibitors: May decrease the excretion of Alpha-/Beta-Agonists. Exceptions: Brinzolamide; Dorzolamide. Risk C: Monitor therapy
COMT Inhibitors: May decrease the metabolism of COMT Substrates. Risk C: Monitor therapy
Inhalational Anesthetics: May enhance the arrhythmogenic effect of Norepinephrine. Risk X: Avoid combination
Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination
MAO Inhibitors: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Primarily with oral administration of phenylephrine. Risk D: Consider therapy modification
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Risk D: Consider therapy modification
Spironolactone: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Risk D: Consider therapy modification
Storage
Readily oxidized. Protect from light. Do not use if brown coloration. Stability of parenteral admixture at room temperature (25°C) is 24 hours.
Reconstitution
Dilute with D5W, D5NS, or NS; dilution in NS is not recommended by the manufacturer; however, stability in NS has been demonstrated (Tremblay, 2008).
Compatibility
Stable in D5NS, D5W, LR, NS; incompatible with alkaline solutions.
Y-site administration: Compatible: Amiodarone, cisatracurium, diltiazem, dobutamine, dopamine, epinephrine, esmolol, famotidine, fentanyl, haloperidol, heparin, hydrocortisone sodium succinate, hydromorphone, inamrinone, labetalol, lorazepam, meropenem, midazolam, milrinone, morphine, nicardipine, nitroglycerin, potassium chloride, propofol, ranitidine, remifentanil, vecuronium, vitamin B complex with C. Incompatible: Insulin (regular), thiopental. Variable (consult detailed reference):Furosemide.
Compatibility in syringe: Compatible: Heparin.
Mechanism of Action
Stimulates beta1-adrenergic receptors and alpha-adrenergic receptors causing increased contractility and heart rate as well as vasoconstriction, thereby increasing systemic blood pressure and coronary blood flow; clinically, alpha effects (vasoconstriction) are greater than beta effects (inotropic and chronotropic effects)
Pharmacodynamics/Kinetics
Onset of action: I.V.: Very rapid-acting
Duration: vasopressor: 1-2 minutes
Metabolism: Via catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO)
Excretion: Urine (84% to 96% as inactive metabolites)
Dosage
Administration requires the use of an infusion pump.
Note: Norepinephrine dosage is stated in terms of norepinephrine base.
Continuous I.V. infusion:
Children: Initial: 0.05-0.1 mcg/kg/minute; titrate to desired effect; maximum dose: 2 mcg/kg/minute (Kliegman, 2007; AHA, 2010)
Adults: Initial: 8-12 mcg/minute; titrate to desired response. Usual maintenance range: 2-4 mcg/minute; dosage range varies greatly depending on clinical situation. If patient remains hypotensive despite large doses, evaluate for occult hypovolemia and provide fluid resuscitation as appropriate.
ACLS dosing range (weight-based dosing): Post cardiac arrest care: Initial: 0.1-0.5 mcg/kg/minute (7-35 mcg/minute in a 70 kg patient); titrate to desired response (AHA, 2010)
Sepsis and septic shock (weight-based dosing): Range from clinical trials: 0.01-3 mcg/kg/minute (0.7-210 mcg/minute in a 70 kg patient) (Hollenberg, 2004)
Administration: I.V.
Administer as a continuous infusion with the use of an infusion pump. Dilute prior to use. Administration via central line recommended; may cause severe ischemic necrosis if extravasated. Do not administer sodium bicarbonate (or any alkaline solution) through an I.V. line containing norepinephrine; inactivation of norepinephrine may occur.
Patient Education
This drug is used in emergency situations. Patient information is based on patient condition.
Additional Information
Norepinephrine dosage is stated in terms of norepinephrine base. Although the intravenous product vial designates the contents as norepinephrine bitartrate, the actual concentration shown is in terms of norepinephrine base 1 mg/mL.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Norepinephrine is effective at increasing arterial blood pressure through vasoconstriction with little change in heart rate or cardiac output. Adequate fluid resuscitation is essential to the success of norepinephrine in raising blood pressure; may successfully increase blood pressure without causing a deterioration in cardiac index or organ function in patients with septic shock. It should be used early and not withheld as a last resort. The 2008 Surviving Sepsis Campaign guidelines recommend that either norepinephrine or dopamine is the first-choice vasopressor agent in adult patients (Grade 1C). Norepinephrine is more potent than dopamine and may be more effective at reversing hypotension in septic shock.
Extravasation Management: Antidote for peripheral ischemia caused by norepinephrine extravasation: To prevent sloughing and necrosis in ischemic areas, the area should be infiltrated as soon as possible with 5-10 mg of Regitine® (phentolamine), an adrenergic blocking agent, diluted in 10-15 mL of saline. A syringe with a fine hypodermic needle should be used and the solution liberally infiltrated throughout the ischemic area. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours. Therefore, phentolamine should be given as soon as possible after the extravasation is noted, as phentolamine may be ineffective if given >12 hours after extravasation.
Evidence-Based Information: The 2008 Surviving Sepsis Campaign guidelines recommend that either norepinephrine or dopamine is the first-choice vasopressor agent in adult patients (Grade 1C). Norepinephrine is more potent than dopamine and may be more effective at reversing hypotension in septic shock.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause anxiety, dizziness, or insomnia
Mental Health: Effects on Psychiatric Treatment
Monitor for increased pressor effect when used with TCAs, MAO inhibitors, and antihistamines
Nursing: Physical Assessment/Monitoring
Monitor blood pressure and cardiac status, CNS status, skin temperature, and color during and following infusion. Monitor fluid status. Assess infusion site frequently for extravasation. Blanching along vein pathway is a preliminary sign of extravasation.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [strength expressed as base]: 1 mg/mL (4 mL)
Levophed®: 1 mg/mL (4 mL) [contains sodium metabisulfite]
References
Aron DC, Bravo EL, and Kapcala LP, “Erroneous Plasma Norepinephrine Levels With Radioimmunoassay,” Ann Intern Med, 1983, 98(6):1023.
Brierley J, Carcillo JA, Choong K, et al, “Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock: 2007 Update from the American College of Critical Care Medicine,” Crit Care Med, 2009, 37(2):666-88.
Cryer PE, “Physiology and Pathophysiology of the Human Sympathoadrenal Neuroendocrine System,” N Engl J Med, 1980, 303(8):436-44.
Dellinger RP, Levy MM, Carlet JM, et al, “Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008,” [published correction appears in Crit Care Med, 2008, 36(4):1394-6], Crit Care Med, 2008, 36(1):296-327.
Field JM, Hazinski MF, Sayre MR, et al, “Part 1: Executive Summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,” Circulation, 2010, 122 (18 Suppl 3):640-56.
Hollenberg SM, Ahrens TS, Annane D, et al, “Practice Parameters for Hemodynamic Support of Sepsis in Adult Patients: 2004 Update,” Crit Care Med, 2004, 32(9):1928-48.
Kleinman ME, Chameides L, Schexnayder SM, et al, “Part 14: Pediatric Advanced Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,” Circulation, 2010, 122(18 Suppl 3):876-908.
Martin C, Papazian L, Perrin G, et al, “Norepinephrine or Dopamine for the Treatment of Hyperdynamic Septic Shock?” Chest, 1993, 103(6):1826-31.
Nelson Textbook of Pediatrics, 18th ed, Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds, Philadelphia, PA: WB Saunders Co, 2007.
Peberdy MA, Callaway CW, Neumar RW, et al, “Part 9: Post Cardiac Arrest Care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care,” Circulation, 2010, 122(18 Suppl 3):768-86.
Tremblay M, Lessard MR, Trépanier CA, et al, “Stability of Norepinephrine Infusions Prepared in Dextrose and Normal Saline Solutions,” Can J Anaesth, 2008, 55(3):163-7.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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