Norepinephrine (noradrenaline): Drug information

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(For additional information see "Norepinephrine (noradrenaline): Patient drug information" and see
"Norepinephrine (noradrenaline): Pediatric drug information")
For abbreviations and symbols that may be used in Lexicomp (show table)

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.

Brand Names: U.S.

Levophed

Brand Names: Canada

Levophed

Pharmacologic Category

Alpha-/Beta- Agonist

Dosing: Adult
Administration requires the use of an infusion pump.
Note: Norepinephrine dosage is stated in terms of norepinephrine base.
Hypotension/shock: Continuous IV infusion:
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)

Dosing: Pediatric
(For additional information see "Norepinephrine (noradrenaline): Pediatric drug information")
Administration requires the use of an infusion pump.
Note: Norepinephrine dosage is stated in terms of norepinephrine base.
Hypotension/shock: Continuous IV infusion: Initial: 0.05-0.1 mcg/kg/minute; titrate to desired
effect; maximum dose: 2 mcg/kg/minute (AHA, 2010; Kleinman, 2007)

Dosing: Geriatric
Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment provided in manufacturers labeling.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturers labeling.

Dosage Forms: U.S.

Excipient information presented when available (limited, particularly for generics); consult specific
product labeling.
Solution, Injection [strength expressed as base]:
Levophed: 1 mg/mL (4 mL) [contains sodium metabisulfite]
Generic: 1 mg/mL (4 mL)
Solution, Injection [strength expressed as base, preservative free]:
Generic: 1 mg/mL (4 mL)

Generic Equivalent Available: U.S.

Yes

Administration
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 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 (no longer available in the US): Dilute 5-10 mg in 10-15 mL NS and administer
into extravasation site as soon as possible after extravasation (Peberdy, 2010) or dilute
5-10 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 3-10 mL) or 1 mg diluted in 1 mL NS (small/distal extravasation
site; administration volume varied from 0.5-1 mL) (Stier, 1999).

Usual Infusion Concentrations: Adult

IV infusion: 4 mg in 250 mL (concentration: 16 mcg/mL) or 8 mg in 250 mL (concentration:
32 mcg/mL) of D5W or NS

Usual Infusion Concentrations: Pediatric

IV infusion: 8 mcg/mL or 16 mcg/mL

Compatibility
Stable in D5LR, D51/2NS, D5NS, D5W, D10W, LR, NS; incompatible with alkaline solutions.
Y-site administration: Compatible: Amiodarone, anidulafungin, argatroban, bivalirudin,
caspofungin, cisatracurium, clonidine, dexmedetomidine, diltiazem, dobutamine, dopamine,
doripenem, epinephrine, esmolol, famotidine, fenoldopam, fentanyl, furosemide, haloperidol,
heparin, hetastarch in lactate electrolyte injection (Hextend), hydrocortisone sodium
succinate, hydromorphone, inamrinone, labetalol, lorazepam, meropenem, micafungin,
midazolam, milrinone, morphine, mycophenolate, nicardipine, nitroglycerin, nitroprusside,
potassium chloride, propofol, ranitidine, remifentanil, telavancin, tigecycline, vasopressin,
vecuronium, vitamin B complex with C.Incompatible: Drotrecogin alfa, insulin (regular),
thiopental. Variable (consult detailed reference): Furosemide, nesiritide, pantoprazole.
Compatibility in syringe: Incompatible: Pantoprazole.

Use
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)

Medication Safety Issues

Sound-alike/look-alike issues:
Levophed may be confused with levofloxacin
High alert medication:
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of
drugs which have a heightened risk of causing significant patient harm when used in
error.

Adverse Reactions Significant

Frequency not defined.
Cardiovascular: Arrhythmias, bradycardia, peripheral (digital) ischemia
Central nervous system: Anxiety, headache (transient)
Local: Skin necrosis (with extravasation)
Respiratory: Dyspnea, respiratory difficulty

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
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. [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 to prevent sloughing /necrosis.
Concurrent drug therapy issues:
Monoamine oxidase inhibitors (MAO-I): Use with extreme caution in patients taking MAOInhibitors; prolong hypertension may result from concurrent use.
Dosage form specific issues:
Sodium metabisulfite: Product may contain sodium metabisulfite.
Other warnings/precautions:

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

Metabolism/Transport Effects
Substrate of COMT

Drug Interactions
(For additional information: Launch Lexi-Interact Drug Interactions Program)
Alpha1-Blockers: May diminish the vasoconstricting effect of Alpha-/Beta-Agonists. Similarly,
Alpha-/Beta-Agonists may antagonize Alpha1-Blocker vasodilation. 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. Some beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (DirectActing), including anti-anaphylactic effects of epinephrine, may be diminished by BetaBlockers. 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
Cannabinoid-Containing Products: May enhance the tachycardic effect of
Sympathomimetics. Exceptions: Cannabidiol.Risk C: Monitor therapy
COMT Inhibitors: May decrease the metabolism of COMT Substrates. Risk C: Monitor therapy
Droxidopa: Norepinephrine may enhance the hypertensive effect of Droxidopa. Risk C: 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. Risk X: 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. Risk D: Consider therapy modification
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

Ioflupane I 123: Norepinephrine may diminish the diagnostic effect of Ioflupane I 123. Risk C:
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. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the hypertensive effect of
Norepinephrine. Exceptions: Tedizolid. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the tachycardic effect of Alpha-/BetaAgonists. 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
Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the
tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the vasopressor effect of Alpha-/Beta-Agonists (DirectActing). 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. Risk D:
Consider therapy modification

Pregnancy Risk Factor

C (show table)

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

Lactation
Excretion in breast milk unknown/use caution

Breast-Feeding Considerations
It is not known if norepinephrine is excreted in breast milk. The manufacturer recommends that
caution be exercised when administering norepinephrine to nursing women.

Pricing: U.S.
Solution (Levophed Injection)
1 mg/mL (4 mL): $17.88

Solution (Norepinephrine Bitartrate Injection)

1 mg/mL (4 mL): $4.29
Disclaimer: The pricing data provide a representative AWP and/or AAWP price from a single
manufacturer of the brand and/or generic product, respectively. The pricing data should be used for
benchmarking purposes only, and as such should not be used to set or adjudicate any prices for
reimbursement or purchasing functions. Pricing data is updated monthly.

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

Consult individual institutional policies and procedures.

International Brand Names

Adine (CL);

Adrenor (ES, IN);

Arespin (ID);

Arterenol (DE);

Cardiamed (MY);

Efrinalin (BR);

Fioritina (AR);

Levonor (PL, PY, UY, VN);

Levophed (GB, IE, LU);

Levophed Bitartrate (AE, AU, BE, BH, CY, EG, GR, IL, IQ, IR, JO, KR, KW, LB, LY, MY, NZ,
OM, PH, QA, SA, SG, SY, TH, TW, YE);

N-Epi (TH);

Noradrenalina (DO, GT, HN, PA);

Noradrenalina Tartrato (IT);

Noradrenaline (GB);

Noradrenaline Aguettant (FR);

Norepin (PH);

Norepine (TW);

Norphed (PH);

Norpin (KR, TH);

Rhinopront (LU);

Vascon (ID)

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 and Pharmacokinetics

Onset of action: IV: 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)
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