Dosage guidance:
Dosing: Dose stated in terms of norepinephrine base.
Septic shock, refractory: Limited data available: Preterm and term neonates: Continuous IV infusion: Usual initial dose: 0.02 to 0.1 mcg/kg/minute; titrate to desired effect; usual maximum dose: 1 to 2 mcg/kg/minute (Ref). Studies in neonates (GA ≥23 weeks) with refractory septic shock show norepinephrine improves blood pressure and may improve organ perfusion (Ref).
Circulatory failure (pulmonary hypertension, persistent [PPHN] induced); refractory: Limited data available:
GA ≥35 weeks: Continuous IV infusion: Usual initial dose: 0.02 to 0.5 mcg/kg/minute; titrate to desired effect; usual maximum dose: 1.5 mcg/kg/minute; doses up to 3.3 mcg/kg/minute have been reported (Ref). Usual dose range: 0.02 to 1 mcg/kg/minute (Ref).
Dosage guidance:
Dosing: Dose stated in terms of norepinephrine base.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Norepinephrine (noradrenaline): Drug information")
Cardiogenic shock:
Note: Optimal goal of therapy not well established, but typically titrate to maintain end-organ perfusion. Institutional protocols may vary with weight-based or non-weight-based dose regimens (Ref).
Continuous infusion:
Weight-based dosing: IV: Initial: 0.05 mcg/kg/minute; titrate based on clinical end point (eg, BP, end-organ perfusion); usual dosage range: 0.05 to 0.4 mcg/kg/minute (Ref).
Non–weight-based dosing (based on ~80 kg patient): IV: Initial: 5 mcg/minute; titrate based on clinical end point (eg, BP, end-organ perfusion); usual dosage range: 5 to 30 mcg/minute (doses calculated and rounded for an 80 kg patient based on weight-based dosing using the referenced sources (Ref).
Hepatorenal syndrome type 1 or acute kidney injury, treatment (alternative agent) (off-label use): Note: Alternative to terlipressin. Use in combination with albumin (Ref).
Continuous infusion :
Non–weight-based dosing: IV: Initial: 5 to 8 mcg/minute; dose may be increased every 4 hours based on clinical end points (eg, increase mean arterial pressure of ~10 mm Hg from baseline, improved urine output); maximum dose: 10 mcg/minute non-ICU; 50 mcg/minute in ICU (Ref).
Post–cardiac arrest shock:
Note: Optimal goal of therapy not well established, but typically titrate to mean arterial BP (MAP) >65 mm Hg and preferably systolic BP of 80 to 100 mm Hg to optimize cerebral and end-organ perfusion. Institutional protocols may vary with weight-based or non-weight-based dose regimens (Ref).
Continuous infusion:
Weight-based dosing: IV: Initial: 0.05 to 0.15 mcg/kg/minute; titrate based on clinical end points (eg, MAP, end-organ perfusion); usual dosing range: 0.05 to 1 mcg/kg/minute; maximum dose range for refractory shock: 1 to 3.3 mcg/kg/minute (Ref).
Non–weight-based dosing (based on ~80 kg patient): IV: Initial: 5 to 15 mcg/minute; titrate based on clinical end points (eg, MAP, end-organ perfusion); usual dosing range: 5 to 80 mcg/minute; maximum dose range for refractory shock: 80 to 250 mcg/minute (doses calculated and rounded for an 80 kg patient based on weight-based dosing using the referenced sources (Ref).
Septic shock and other vasodilatory shock states:
Note: In general, used to maintain goal MAP (eg, ~65 mm Hg); consider use if patient is in shock or has hypoperfusion during or after fluid resuscitation (Ref). Institutional protocols may vary with weight-based or non-weight-based dose regimens.
Continuous infusion:
Weight-based dosing: IV: Initial: 0.05 to 0.15 mcg/kg/minute; titrate to goal MAP; usual dose range: 0.025 to 1 mcg/kg/minute; maximum dose range for refractory shock: 1 to 3.3 mcg/kg/minute (Ref). Note: While available data describe a wide range of initial dosing (0.01 to 0.5 mcg/kg/minute), initial dosing provided is a reasonable starting point for most patients.
Non–weight-based dosing (based on ~80 kg patient): IV: Initial: 5 to 15 mcg/minute; titrate to goal MAP; usual dose range: 2 to 80 mcg/minute; maximum dose range for refractory shock: 80 to 250 mcg/minute (doses calculated and rounded for an 80 kg patient based on weight-based dosing using the referenced sources (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (only small amount excreted by kidney unchanged) (Ref).
Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2):
Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).
No dosage adjustment necessary (Ref).
Hemodialysis, intermittent (thrice weekly): Likely to be dialyzable (Ref): No supplemental dose or dosage adjustment necessary since norepinephrine is titrated to clinical targets (Ref).
Peritoneal dialysis: No dosage adjustment necessary (Ref).
CRRT: Unlikely to be significantly dialyzable (Ref): No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
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])
There are no contraindications listed in the US manufacturer's labeling.
Canadian 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.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 mL saline in adult patients) with a fine hypodermic needle. Phentolamine should be administered as soon as possible after extravasation is noted to prevent sloughing/necrosis (Stefanos 2023).
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.
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.
• 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.
Norepinephrine dosage is stated in terms of norepinephrine base. Although the IV product vial designates the contents as norepinephrine bitartrate, the actual concentration shown is in terms of norepinephrine base 1 mg/mL.
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); 16 mg/250 mL in NaCl 0.9% (250 mL); 4 mg/250 mL in NaCl 0.9% (250 mL); 8 mg/250 mL in NaCl 0.9% (250 mL)
Solution, Intravenous [preservative free]:
Levophed: 1 mg/mL (4 mL) [contains sodium metabisulfite]
Generic: 1 mg/mL (4 mL); 16 mg/250 mL in Dextrose 5% (250 mL); 4 mg/250 mL in Dextrose 5% (250 mL); 8 mg/250 mL in Dextrose 5% (250 mL)
Yes
Solution (Levophed Intravenous)
1 mg/mL (per mL): $6.74
Solution (Norepinephrine Bitartrate Intravenous)
1 mg/mL (per mL): $0.99 - $5.69
Solution (Norepinephrine-Dextrose Intravenous)
4MG/250ML 5% (per mL): $0.12
8MG/250ML 5% (per mL): $0.17
16MG/250ML 5% (per mL): $0.34
Solution (Norepinephrine-Sodium Chloride Intravenous)
4MG/250ML 0.9% (per mL): $0.18
8MG/250ML 0.9% (per mL): $0.24
16MG/250ML 0.9% (per mL): $0.31 - $0.38
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
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); 4 mg/250 mL in Dextrose 5% (250 mL); 8 mg/250 mL in Dextrose 5% (250 mL)
Parenteral: Continuous IV infusion: Administer as a continuous infusion via an infusion pump. Vials must be diluted prior to administration; premixed IV solutions (16 mcg/mL and 32 mcg/mL) are available. Central line administration is preferred; extravasation may cause severe ischemic necrosis. If central line is not available, may administer for a short duration through a peripheral IV catheter placed in a large vein or via intraosseous access using a more dilute solution or with a second carrier fluid (Ref); frequent monitoring of the IV catheter site is recommended to rapidly identify extravasation (Ref). Note: Refer to institutional policies and procedures; catheter placement/size and vasopressor concentration may vary depending on institution. Do not administer sodium bicarbonate (or any alkaline solution) through an IV line containing norepinephrine; inactivation of norepinephrine may occur (Ref). Avoid abrupt withdrawal; reduce infusion flow rate slowly.
Rate of infusion (mL/hour) = dose (mcg/kg/minute) x weight (kg) x 60 minutes/hour divided by the concentration (mcg/mL)
Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. If extravasation occurs, stop infusion immediately; leave cannula/needle in place temporarily but do NOT flush the line; gently aspirate extravasated solution, then remove needle/cannula unless needed for IV antidote; elevate extremity; apply dry, warm compresses. Initiate phentolamine (or alternative antidote) (Ref).
IV: Administer as a continuous infusion via an infusion pump. Dilute vials prior to use; premixed solutions are also available for IV infusion. Central line administration is preferred; extravasation may cause severe ischemic necrosis. If central line is not available, may administer for a short duration (<72 hours) through a peripheral IV catheter placed in a large vein at a proximal site (eg, in or proximal to antecubital fossa). Frequent monitoring of the IV catheter site is recommended to rapidly identify extravasation (Ref). Refer to institutional policies and procedures; catheter placement/size and vasopressor concentration may vary depending on institution. Administration through midline catheters may also be an option (Ref). 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; leave cannula/needle in place temporarily but do NOT flush the line; gently aspirate extravasated solution, then remove needle/cannula; elevate extremity; apply dry warm compresses; initiate phentolamine (or alternative) antidote (Ref).
Phentolamine: SUBQ: Dilute 5 to 10 mg in 10 mL NS and administer into extravasation site as soon as possible after extravasation; if IV catheter remains in place, administer initial dose IV through infiltrated catheter; may repeat in 60 minutes if patient remains symptomatic (Ref).
Alternatives to phentolamine:
Nitroglycerin topical 2% ointment: Apply a 1-inch strip to the site of ischemia to cover the affected area; may repeat every 8 hours as necessary (Ref).
Terbutaline:
Large extravasations: SUBQ: Infiltrate affected extravasation area with terbutaline 1 mg using a solution of terbutaline 1 mg diluted in 10 mL NS; may repeat dose after 15 minutes (Ref).
Small extravasations: SUBQ: Infiltrate affected extravasation area with terbutaline 0.5 mg using a solution of terbutaline 1 mg diluted in 1 mL NS; may repeat dose after 15 minutes (Ref).
Note: Premixed solutions are available.
IV infusion: 4 mcg/mL or 16 mcg/mL.
Note: Premixed solutions are available.
IV infusion: 16 mcg/mL, 32 mcg/mL, or 64 mcg/mL.
Premixed solution in D5W:
Refrigerated product: Store in protective overwrap at 2°C to 8°C (36°F to 46°F); protect from light. Once removed from refrigerator, may be stored in overwrap at room temperature (up to 25°C [77°F]) for up to 90 days and the overwrap should be marked to indicate the revised 90-day expiration date. Do not return product to the refrigerator after it has been stored at room temperature. Once overwrap is removed, may be stored for up to 30 days at room temperature.
Room temperature product: Store in protective overwrap at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Once overwrap is removed, may be stored for up to 30 days at room temperature.
Premixed solution in NS: Store in protective overwrap at 20°C to 25°C (68°F to 77°F). Protect from light. Once overwrap is removed, may be stored for up to 7 days at room temperature.
Vials: 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.
Treatment of severe, acute hypotension (FDA approved in adults); has also been used for shock and in neonates with persistent pulmonary hypertension (PPHN)-induced circulatory failure.
Levophed may be confused with levofloxacin
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (adrenergic agonist, IV) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care Settings).
Substrate of COMT
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
Alpha1-Blockers: May diminish the therapeutic effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Azosemide: May diminish the therapeutic effect of Norepinephrine. 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
Bretylium: May enhance the therapeutic effect of Alpha-/Beta-Agonists (Direct-Acting). Risk C: Monitor therapy
Bromocriptine: May enhance the hypertensive effect of Alpha-/Beta-Agonists. Management: Consider alternatives to this combination when possible. If combined, monitor for hypertension and tachycardia, and do not coadminister these agents for more than 10 days. Risk D: Consider therapy modification
Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Chloroprocaine (Systemic): May enhance the hypertensive effect of Alpha-/Beta-Agonists. Risk C: Monitor therapy
CloZAPine: May diminish the therapeutic effect of Alpha-/Beta-Agonists. Risk C: 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. Risk D: Consider therapy modification
COMT Inhibitors: May increase the serum concentration of COMT Substrates. Risk C: Monitor therapy
Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Risk C: Monitor therapy
Droxidopa: Norepinephrine may enhance the hypertensive effect of Droxidopa. Risk C: Monitor therapy
Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates): May enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Risk X: Avoid combination
Furosemide: May diminish the therapeutic effect of Norepinephrine. Risk C: Monitor therapy
Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
Hyaluronidase: May enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Management: Do not use hyaluronidase to enhance the 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 C: Monitor therapy
Kratom: May enhance the adverse/toxic effect of Sympathomimetics. Risk X: Avoid combination
Levothyroxine: May enhance the adverse/toxic effect of Sympathomimetics. Specifically, the risk of coronary insufficiency may be increased in patients with coronary artery disease. Levothyroxine may enhance the therapeutic effect of Sympathomimetics. Sympathomimetics may enhance the therapeutic effect of Levothyroxine. Risk C: Monitor therapy
Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Consider initial dose reductions of sympathomimetic agents, and closely monitor for enhanced blood pressure elevations, in patients receiving linezolid. Risk D: Consider therapy modification
Lisuride: May enhance the hypertensive effect of Alpha-/Beta-Agonists. Risk X: Avoid combination
Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of Norepinephrine. Risk C: Monitor therapy
Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
Pergolide: May enhance the hypertensive effect of Alpha-/Beta-Agonists. Risk C: 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. 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). Risk D: Consider therapy modification
Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy
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. 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. Risk D: Consider therapy modification
Vasopressin: Alpha-/Beta-Agonists (Direct-Acting) may enhance the hypertensive effect of Vasopressin. The effect of other hemodynamic parameters may also be enhanced. Risk C: Monitor therapy
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).
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.
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)
Onset of action: Very rapid acting.
Duration: Vasopressor: 1 to 2 minutes.
Distribution: Vd: 8.8 L.
Protein binding: 25% mainly albumin with smaller extent to prealbumin and alpha 1-acid glycoprotein.
Metabolism: Via catechol-o-methyltransferase and monoamine oxidase.
Half-life elimination: Mean: ~2.4 minutes.
Time to peak, serum: Steady state: 5 minutes.
Excretion: Urine (as inactive metabolites; small amounts as unchanged drug).
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