Norepinephrine

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)

Pharmacology

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)

Pharmacokinetics/Pharmacodynamics

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

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

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

Dosage and Administration

Dosing: Adult

Note: Dose is stated in terms of norepinephrine base.

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).

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.

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 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

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 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

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

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

Solriamfetol: Sympathomimetics may enhance the hypertensive 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. [US Boxed Warning]: If extravasation occurs, infiltrate the area with diluted phentolamine (5 to 10 mg in 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

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.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• 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, edema, burning, or irritation
• Signs of a significant reaction like 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. 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 brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.