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Norepinephrine

Medically reviewed by Drugs.com. Last updated on Jun 15, 2020.

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:

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

Generic: 1 mg/mL (4 mL)

Solution, Intravenous [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)

Distribution

Vd: 8.8 L.

Metabolism

Via catechol-o-methyltransferase and monoamine oxidase.

Excretion

Urine (as inactive metabolites; small amounts as unchanged drug).

Onset of Action

Very rapid acting.

Time to Peak

Steady state: 5 minutes.

Duration of Action

Vasopressor: 1 to 2 minutes.

Half-Life Elimination

Mean: ~2.4 minutes.

Protein Binding

25% mainly albumin with smaller extent to prealbumin and alpha 1-acid glycoprotein.

Use: Labeled Indications

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

Guideline recommendations:

Cardiogenic shock: The 2017 American Heart Association (AHA) scientific statement for the Contemporary Management of Cardiogenic Shock recommends norepinephrine as the vasopressor of choice for initial management in patients with hemodynamic instability (eg, systolic blood pressure <90 mm Hg or evidence of end organ hypoperfusion) or the following etiologies of cardiogenic shock: right ventricular failure, mitral regurgitation, ventricular septal defect after myocardial infarction, or pericardial tamponade (AHA [van Diepen 2017]).

Septic shock: The 2016 Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock recommends norepinephrine as the first-choice vasopressor for management of septic shock (SCCM [Rhodes 2017]).

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Additional contraindications (not in US labeling): 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 or halothane 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 cannot be ruled out with certainty.

Dosing: Adult

Note: Dose is stated in terms of norepinephrine base.

Hypotension/shock: Note: Vasopressors should be used if patient is hypotensive during or after fluid resuscitation to maintain goal mean arterial pressure ≥65 mm Hg (AHA [Peberdy 2010]; Levy 2018; SCCM [Rhodes 2017]). Titrate to lowest effective dose. Institutional protocols may vary with weight-based or nonweight dose regimens.

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).

Cardiogenic shock (off-label dose): 0.05 to 0.4 mcg/kg/minute (AHA [van Diepen 2017]).

Septic shock (weight-based dosing): Initial: 0.01 to 0.15 mcg/kg/minute; usual dose range: 0.025 to 0.3 mcg/kg/minute; refractory shock dose: 0.5 to 3.3 mcg/kg/minute (De Backer 2010; Hollenberg 2004; Hollenberg 2011; Khanna 2017; Manaker 2020; Martin 1990; Russell 2008).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Dose stated in terms of norepinephrine base.

Hypotension/shock: 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). A retrospective, descriptive study in pediatric patients (n=144; median age: 25 months; IQR: 9 to 83 months) receiving norepinephrine for septic shock reported the mean initial dose as 0.5 ± 0.4 mcg/kg/minute up to a maximum mean dose of 2.5 ± 2.2 mcg/kg/minute; the maximum individual reported rate: 10.5 mcg/kg/minute (Lampin 2012).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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

IV: 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. Avoid abrupt withdrawal; reduce infusion flow rate slowly.

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; Reynolds 2014).

Phentolamine: Dilute 5 to 10 mg in 10 to 20 mL NS and administer into extravasation site as soon as possible after extravasation; may readminister if patient remains symptomatic (Reynolds 2014) 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 data): Apply a 1-inch strip to the site of ischemia; may repeat every 8 hours as necessary (Reynolds 2014).

Terbutaline (based on limited case reports): Infiltrate extravasation area using a solution of terbutaline 1 mg diluted in 10 mL 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) (Reynolds 2014; Stier 1999).

Storage

Store intact vials in original container at 20°C to 25°C (68°F to 77°F); excursion permitted to 15°C to 30°C (59°F to 86°F). Diluted solution may be stored at room temperature for up to 24 hours. 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

Bretylium: May enhance the therapeutic effect of Alpha-/Beta-Agonists (Direct-Acting). Monitor therapy

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

Chloroprocaine: May enhance the hypertensive effect of Alpha-/Beta-Agonists. Monitor therapy

CloZAPine: May diminish the therapeutic effect of Alpha-/Beta-Agonists. Monitor therapy

Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

COMT Inhibitors: May increase the serum concentration 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

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy

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

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

Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of Norepinephrine. Monitor therapy

Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Management: Concomitant use of ozanimod with sympathomimetic agents is not recommended. If combined, monitor patients closely for the development of hypertension, including hypertensive crises. Consider therapy modification

Procarbazine: May enhance the adverse/toxic effect of Sympathomimetics. Management: Consider alternatives to this combination when possible. Procarbazine prescribing information states that this combination should be avoided. 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. Management: If possible, avoid coadministration of direct-acting alpha-/beta-agonists and serotonin/norepinephrine reuptake inhibitors. If coadministered, monitor for increased sympathomimetic effects (eg, increased blood pressure, chest pain, headache). Consider therapy modification

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

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. Management: Avoid, if possible, the use of 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: Bradycardia, cardiac arrhythmia, cardiomyopathy (stress), peripheral vascular insufficiency

Central nervous system: Anxiety, transient headache

Respiratory: Dyspnea

<1%, postmarketing, and/or case reports: Peripheral gangrene, peripheral ischemia (digital [Daroca-Pérez 2017])

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. If extravasation occurs, infiltrate the area with diluted phentolamine (5 to 10 mg in 10 to 20 mL 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:

• Hypovolemia: Address hypovolemia before initiating therapy; patients who are hypotensive from hypovolemia may experience severe peripheral and visceral vasoconstriction, decreased renal perfusion and reduced urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow despite normal BP.

• 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; allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic episodes, may occur.

Other warnings/precautions:

• Abrupt discontinuation: Gradually reduce infusion rate while expanding blood volume with IV fluids during discontinuation of therapy; severe hypotension may occur with abrupt discontinuation.

• 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 of the extremities has occurred in patients with occlusive or thrombotic vascular disease or with prolonged or high-dose infusions.

• Appropriate use: Assure adequate circulatory volume to minimize need for vasoconstrictors. Avoid hypertension; monitor BP closely and adjust infusion rate. Avoid in patients with mesenteric or peripheral vascular thrombosis; use may increase ischemia and extend the area of infarction.

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 Considerations

Norepinephrine is an endogenous catecholamine and crosses the placenta (Minzter 2010; Wang 1999).

Medications used for the treatment of cardiac arrest in pregnancy are the same as in the non-pregnant woman. Appropriate medications should not be withheld due to concerns of fetal teratogenicity. Norepinephrine use during the post-resuscitation phase may be considered; however, the effects of vasoactive medications on the fetus should also be considered. Doses and indications should follow current Advanced Cardiovascular Life Support guidelines (Jeejeebhoy [AHA] 2015).

Patient Education

What is this drug used for?

• It is used to treat low blood pressure.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Severe headache

• Dizziness

• Passing out

• Vision changes

• Slow heartbeat

• Abnormal heartbeat

• Anxiety

• Shortness of breath

• Excessive weight gain

• Swelling of arms or legs

• Severe injection site pain, swelling, burning, or irritation

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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