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Norepinephrine

Pronunciation

Pronunciation

(nor ep i NEF rin)

Index Terms

  • Levarterenol Bitartrate
  • Noradrenaline
  • Noradrenaline Acid Tartrate
  • Norepinephrine Bitartrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [strength expressed as base]:

Levophed: 1 mg/mL (4 mL) [contains sodium metabisulfite]

Generic: 1 mg/mL (4 mL)

Solution, Intravenous [strength expressed as base, preservative free]:

Generic: 1 mg/mL (4 mL)

Brand Names: U.S.

  • Levophed

Pharmacologic Category

  • Alpha/Beta Agonist

Pharmacology

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)

Metabolism

Via catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO)

Excretion

Urine (as inactive metabolites)

Onset of Action

Very rapid acting

Duration of Action

Vasopressor: 1 to 2 minutes

Use: Labeled Indications

Hypotension/shock: Treatment of shock which persists after adequate fluid volume replacement; severe hypotension

Note: Recommended as the first-choice vasopressor for the treatment of sepsis and septic shock in adult patients (Dellinger 2013)

Contraindications

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 US) or halothane (not available in US) anesthesia

Documentation of allergenic cross-reactivity for vasopressors is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity can not be ruled out with certainty

Dosing: Adult

Note: Dose is stated in terms of norepinephrine base.

Hypotension/shock: Continuous IV infusion:

Initial: 8 to 12 mcg/minute; titrate to desired response. Usual maintenance range: 2 to 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 to 0.5 mcg/kg/minute (7 to 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 to 3 mcg/kg/minute (0.7 to 210 mcg/minute in a 70 kg patient) (Hollenberg 2004)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Dose is stated in terms of norepinephrine base.

Hypotension/shock (off-label use): Infants, Children, and Adolescents: Continuous IV infusion: Initial: 0.05 to 0.1 mcg/kg/minute; titrate to desired effect; usual maximum dose: 2 mcg/kg/minute (Fuhrman 2011; PALS [Kleinman 2010]; Park 2014)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Continuous IV infusion: Dilute with D5W, D5NS, or NS; dilution in NS is not recommended by the manufacturer; however, stability in NS has been demonstrated (Tremblay 2008). Concentrations ranging from 4 to 16 mcg/mL are typically used in clinical practice (Phillips 2011).

Administration

Administer as a continuous infusion via an infusion pump. Dilute prior to use. Central line administration is preferred; extravasation may cause severe ischemic necrosis. Do not administer sodium bicarbonate (or any alkaline solution) through an IV line containing norepinephrine; inactivation of norepinephrine may occur.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Initiate phentolamine (or alternative) antidote. Apply dry warm compresses (Hurst 2004).

Phentolamine: Dilute 5 to 10 mg in 10 to 5 mL NS and administer into extravasation site as soon as possible after extravasation (Peberdy 2010) or dilute 5 to 10 mg in 10 mL NS and administer into extravasation area (within 12 hours of extravasation).

Alternatives to phentolamine:

Nitroglycerin topical 2% ointment (based on limited case reports in neonates/infants): Apply 4 mm/kg as a thin ribbon to the affected areas; may repeat after 8 hours if needed (Wong 1992) or apply a 1-inch strip on the affected site (Denkler 1989).

Terbutaline (based on limited case reports): Infiltrate extravasation area using a solution of terbutaline 1 mg diluted to 10 mL in NS (large extravasation site; administration volume varied from 3 to 10 mL) or 1 mg diluted in 1 mL NS (small/distal extravasation site; administration volume varied from 0.5 to 1 mL) (Stier 1999).

Compatibility

Stable in D5LR, D51/2NS, D5NS, D5W, D10W, LR, NS; incompatible with alkaline solutions.

Y-site administration: Incompatible with drotrecogin alfa, insulin (regular), thiopental.

Compatibility in syringe: Incompatible with pantoprazole.

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Alpha1-Blockers: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Similarly, Alpha-/Beta-Agonists may antagonize Alpha1-Blocker vasodilation. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. 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. 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. Some beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (Direct-Acting), including anti-anaphylactic effects of epinephrine, may be diminished by Beta-Blockers. 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. Consider therapy modification

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Exceptions: Cannabidiol. Monitor therapy

COMT Inhibitors: May decrease the metabolism of COMT Substrates. Monitor therapy

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Droxidopa: Norepinephrine may enhance the hypertensive effect of Droxidopa. Monitor therapy

Ergot Derivatives: May enhance the hypertensive effect of Alpha-/Beta-Agonists. Ergot Derivatives may enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Exceptions: Ergoloid Mesylates; Nicergoline. Avoid combination

Hyaluronidase: May enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of alpha-/beta-agonists. Use of hyaluronidase for other purposes in patients receiving alpha-/beta-agonists may be considered as clinically indicated. Consider therapy modification

Inhalational Anesthetics: May enhance the arrhythmogenic effect of Norepinephrine. Avoid combination

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ioflupane I 123: Norepinephrine may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

MAO Inhibitors: May enhance the hypertensive effect of Norepinephrine. Exceptions: Tedizolid. Monitor therapy

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. Consider therapy modification

Spironolactone: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Management: Avoid, if possible, the use of direct-acting alpha-/beta-agonists in patients receiving tricyclic antidepressants. If combined, monitor for evidence of increased pressor effects and consider reductions in initial dosages of the alpha-/beta-agonist. Consider therapy modification

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

ALERT: U.S. Boxed Warning

Antidote for extravasation ischemia:

To prevent sloughing and necrosis in areas in which extravasation has taken place, the area should be infiltrated as soon as possible with 10 to 15 mL of saline solution containing from 5 to 10 mg of phentolamine, an adrenergic blocking agent. A syringe with a fine hypodermic needle should be used, with the solution being infiltrated liberally throughout the area, which is easily identified by its cold, hard, and pallid appearance. 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.

Warnings/Precautions

Concerns related to adverse effects:

• Extravasation: Vesicant; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation; infuse into a large vein if possible. Avoid infusion into leg veins. Monitor IV site closely. [US Boxed Warning]: If extravasation occurs, infiltrate the area with diluted phentolamine (5 to 10 mg in 10 to 15 mL of saline) with a fine hypodermic needle. Phentolamine should be administered as soon as possible after extravasation is noted to prevent sloughing /necrosis.

Disease-related concerns:

• Hypoxia/hypercarbia: Use in patients with profound hypoxia or hypercarbia may produce ventricular tachycardia or fibrillation; use with extreme caution.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Sodium metabisulfite: Product may contain sodium metabisulfite; use caution in patients with asthma or a sulfite allergy.

Other warnings/precautions:

• Administration: Administer infusions into a large vein, particularly an antecubital vein; some clinicians have indicated that the femoral vein is also an acceptable route. Avoid catheter tie-in technique, if possible. Avoid leg veins in elderly patients or in those suffering from occlusive disorders (eg, atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger disease). Gangrene has been reported in a lower extremity when infusions were given in an ankle vein.

• Appropriate use: Assure adequate circulatory volume to minimize need for vasoconstrictors. Avoid hypertension; monitor blood pressure closely and adjust infusion rate.

Monitoring Parameters

Blood pressure (or mean arterial pressure), heart rate; cardiac output (as appropriate), intravascular volume status, pulmonary capillary wedge pressure (as appropriate); urine output, peripheral perfusion; monitor infusion site closely

Consult individual institutional policies and procedures.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Norepinephrine is an endogenous catecholamine and crosses the placenta (Minzter 2010; Wang 1999).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, nausea, or anxiety. Have patient report immediately to prescriber significant injection site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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