Norepinephrine bitartrate

Norepinephrine bitartrate
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

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Black Box Warning

Important See full prescribing information for complete 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 mL to 15 mL of saline solution containing from 5 mg to 10 mg of Regitine® (brand 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.

Overview

Norepinephrine bitartrate is a vasopressor that is FDA approved for the treatment of acute hypotensive states (e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, myocardial infarction, septicemia, blood transfusion, and drug reactions). Norepinephrine is also indicated as an adjunct in the treatment of cardiac arrest and profound hypotension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bradyarrhythmia, hypertension, extravasation injury, necrosis, nausea, vomiting, confusion, headache, tremor, anxiety, restlessness, and urinary retention.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Norepinephrine Bitartrate Injection is a concentrated, potent drug which must be diluted in dextrose containing solutions prior to infusion. An infusion of Levophed should be given into a large vein.

Restoration of Blood Pressure in Acute Hypotensive States

• Blood volume depletion should always be corrected as fully as possible before any vasopressor is administered. When, as an emergency measure, intraaortic pressures must be maintained to prevent cerebral or coronary artery ischemia, Levophed can be administered before and concurrently with blood volume replacement.

• Diluent

• Levophed should be diluted in 5 percent dextrose injection or 5 percent dextrose and sodium chloride injections. These dextrose containing fluids are protection against significant loss of potency due to oxidation. Administration in saline solution alone is not recommended. Whole blood or plasma, if indicated to increase blood volume, should be administered separately (for example, by use of a Y-tube and individual containers if given simultaneously).

• Average Dosage

• Add a 4 mL ampul (4 mg) of Levophed to 1,000 mL of a 5 percent dextrose containing solution. Each mL of this dilution contains 4 mcg of the base of Levophed. Give this solution by intravenous infusion. Insert a plastic intravenous catheter through a suitable bore needle well advanced centrally into the vein and securely fixed with adhesive tape, avoiding, if possible, a catheter tie-in technique as this promotes stasis. An IV drip chamber or other suitable metering device is essential to permit an accurate estimation of the rate of flow in drops per minute. After observing the response to an initial dose of 2 mL to 3 mL (from 8 mcg to 12 mcg of base) per minute, adjust the rate of flow to establish and maintain a low normal blood pressure (usually 80 mm Hg to 100 mm Hg systolic) sufficient to maintain the circulation to vital organs. In previously hypertensive patients, it is recommended that the blood pressure should be raised no higher than 40 mm Hg below the preexisting systolic pressure. The average maintenance dose ranges from 0.5 mL to 1 mL per minute (from 2 mcg to 4 mcg of base).

• High Dosage

• Great individual variation occurs in the dose required to attain and maintain an adequate blood pressure. In all cases, dosage of Levophed should be titrated according to the response of the patient. Occasionally much larger or even enormous daily doses (as high as 68 mg base or 17 ampuls) may be necessary if the patient remains hypotensive, but occult blood volume depletion should always be suspected and corrected when present. Central venous pressure monitoring is usually helpful in detecting and treating this situation.

• Fluid Intake

• The degree of dilution depends on clinical fluid volume requirements. If large volumes of fluid (dextrose) are needed at a flow rate that would involve an excessive dose of the pressor agent per unit of time, a solution more dilute than 4 mcg per mL should be used. On the other hand, when large volumes of fluid are clinically undesirable, a concentration greater than 4 mcg per mL may be necessary.

• Duration of Therapy

• The infusion should be continued until adequate blood pressure and tissue perfusion are maintained without therapy. Infusions of Levophed should be reduced gradually, avoiding abrupt withdrawal. In some of the reported cases of vascular collapse due to acute myocardial infarction, treatment was required for up to six days.

Adjunctive Treatment in Cardiac Arrest

• Infusions of Levophed are usually administered intravenously during cardiac resuscitation to restore and maintain an adequate blood pressure after an effective heartbeat and ventilation have been established by other means. Levophed’s powerful beta-adrenergic stimulating action is also thought to increase the strength and effectiveness of systolic contractions once they occur.

• Average Dosage

• To maintain systemic blood pressure during the management of cardiac arrest, Levophed is used in the same manner as described under Restoration of Blood Pressure in Acute Hypotensive States.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use, whenever solution and container permit.
• Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate.
• Avoid contact with iron salts, alkalis, or oxidizing agents.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Norepinephrine bitartrate in adult patients.

Non–Guideline-Supported Use

Cardiopulmonary Bypass Operation

• Combined bi-atrial infusion of low-dose alprostadil and norepinephrine facilitates weaning from cardiopulmonary bypass of cardiac-surgery patients who developed acute pulmonary hypertension and low cardiac output syndrome post-operatively.

• Dosing Information

• Starting dose of alprostadil was 20 ng/kg/min, with incremental doses of 5 ng/kg/min over 5 min to maintain mean pulmonary artery pressure below 30 mmHg.
• Norepinephrine was started at 0.08 mcg/kg/min and titrated to a final dose of 0.11 mcg/kg/min.

Upper Gastrointestinal Hemorrhage

• Norepinephrine by intragastric administration was demonstrated to halt upper GI bleeding. Norepinephrine was given through a nasogastric tube at a dose of 8 mg in 100 mL of normal saline or 16 mg in 200 mL of normal saline.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Safety and effectiveness in pediatric patients has not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Norepinephrine bitartrate in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Norepinephrine bitartrate in pediatric patients.

Contraindications

• Levophed should not be given to patients who are hypotensive from blood volume deficits except as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed. If Levophed is continuously administered to maintain blood pressure in the absence of blood volume replacement, the following may occur: severe peripheral and visceral vasoconstriction, decreased renal perfusion and urine output, poor systemic blood flow despite normal blood pressure, tissue hypoxia, and lactate acidosis.
• Levophed should also not be given to patients with mesenteric or peripheral vascular thrombosis (because of the risk of increasing ischemia and extending the area of infarction) unless, in the opinion of the attending physician, the administration of Levophed is necessary as a life-saving procedure.
• Cyclopropane and halothane anesthetics increase cardiac autonomic irritability and therefore seem to sensitize the myocardium to the action of intravenously administered epinephrine or norepinephrine. Hence, the use of Levophed during cyclopropane and halothane anesthesia is generally considered contraindicated because of the risk of producing ventricular tachycardia or fibrillation.
• The same type of cardiac arrhythmias may result from the use of Levophed in patients with profound hypoxia or hypercarbia.

Warnings

Important See full prescribing information for complete 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 mL to 15 mL of saline solution containing from 5 mg to 10 mg of Regitine® (brand 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.

• Levophed should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe, prolonged hypertension may result.
• Levophed Bitartrate Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Precautions

• Avoid Hypertension

• Because of the potency of Levophed and because of varying response to pressor substances, the possibility always exists that dangerously high blood pressure may be produced with overdoses of this pressor agent. It is desirable, therefore, to record the blood pressure every two minutes from the time administration is started until the desired blood pressure is obtained, then every five minutes if administration is to be continued.
• The rate of flow must be watched constantly, and the patient should never be left unattended while receiving Levophed. Headache may be a symptom of hypertension due to overdosage.

• Site of Infusion

• Whenever possible, infusions of Levophed should be given into a large vein, particularly an antecubital vein because, when administered into this vein, the risk of necrosis of the overlying skin from prolonged vasoconstriction is apparently very slight. Some authors have indicated that the femoral vein is also an acceptable route of administration. A catheter tie-in technique should be avoided, if possible, since the obstruction to blood flow around the tubing may cause stasis and increased local concentration of the drug. Occlusive vascular diseases (for example, atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger's disease) are more likely to occur in the lower than in the upper extremity. Therefore, one should avoid the veins of the leg in elderly patients or in those suffering from such disorders. Gangrene has been reported in a lower extremity when infusions of Levophed were given in an ankle vein.

• Extravasation

• The infusion site should be checked frequently for free flow. Care should be taken to avoid extravasation of Levophed into the tissues, as local necrosis might ensue due to the vasoconstrictive action of the drug. Blanching along the course of the infused vein, sometimes without obvious extravasation, has been attributed to vasa vasorum constriction with increased permeability of the vein wall, permitting some leakage.
• This also may progress on rare occasions to superficial slough, particularly during infusion into leg veins in elderly patients or in those suffering from obliterative vascular disease. Hence, if blanching occurs, consideration should be given to the advisability of changing the infusion site at intervals to allow the effects of local vasoconstriction to subside.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Norepinephrine bitartrate in the drug label.

Postmarketing Experience

• Prolonged administration of any potent vasopressor may result in plasma volume depletion which should be continuously corrected by appropriate fluid and electrolyte replacement therapy. If plasma volumes are not corrected, hypotension may recur when Levophed is discontinued, or blood pressure may be maintained at the risk of severe peripheral and visceral vasoconstriction (e.g., decreased renal perfusion) with diminution in blood flow and tissue perfusion with subsequent tissue hypoxia and lactic acidosis and possible ischemic injury. Gangrene of extremities has been rarely reported.
• Overdoses or conventional doses in hypersensitive persons (e.g., hyperthyroid patients) cause severe hypertension with violent headache, photophobia, stabbing retrosternal pain, pallor, intense sweating, and vomiting.

Body as a Whole

Ischemic injury due to potent vasoconstrictor action and tissue hypoxia.

Cardiovascular

Bradycardia, probably as a reflex result of a rise in blood pressure, arrhythmias.

Neurologic

Anxiety, transient headache.

Respiratory

Respiratory difficulty.

Skin and Hypersensitivy Reactions

Extravasation necrosis at injection site.

Drug Interactions

• Cyclopropane and halothane anesthetics increase cardiac autonomic irritability and therefore seem to sensitize the myocardium to the action of intravenously administered epinephrine or norepinephrine. Hence, the use of Levophed during cyclopropane and halothane anesthesia is generally considered contraindicated because of the risk of producing ventricular tachycardia or fibrillation. The same type of cardiac arrhythmias may result from the use of Levophed in patients with profound hypoxia or hypercarbia.

• Levophed should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe, prolonged hypertension may result.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category C

• Animal reproduction studies have not been conducted with Levophed. It is also not known whether Levophed can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Levophed should be given to a pregnant woman only if clearly needed.

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Norepinephrine bitartrate in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Norepinephrine bitartrate during labor and delivery.

Nursing Mothers

• It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Levophed is administered to a nursing woman.

Pediatric Use

• Safety and effectiveness in pediatric patients has not been established.

Geriatic Use

• Clinical studies of Levophed did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

• Levophed infusions should not be administered into the veins in the leg in elderly patients.

Gender

There is no FDA guidance on the use of Norepinephrine bitartrate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Norepinephrine bitartrate with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Norepinephrine bitartrate in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Norepinephrine bitartrate in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Norepinephrine bitartrate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Norepinephrine bitartrate in patients who are immunocompromised.

Administration and Monitoring

Administration

• Intravenous

Monitoring

• In cases of refractory hypotension, occult blood volume depletion should always be suspected and corrected when present. Central venous pressure monitoring is usually helpful in detecting and treating this situation.

IV Compatibility

There is limited information regarding IV Compatibility of Norepinephrine bitartrate in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Overdosage with Levophed may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output.

Management

• In case of accidental overdosage, as evidenced by excessive blood pressure elevation, discontinue Levophed until the condition of the patient stabilizes.

Chronic Overdose

There is limited information regarding Chronic Overdose of Norepinephrine bitartrate in the drug label.

Pharmacology

Norepinephrine
Systematic (IUPAC) name
4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol
Identifiers
CAS number	51-41-2
ATC code	C01CA03
PubChem	439260
DrugBank	DB00368
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	169.18 g/mol
Synonyms	Noradrenaline (R)-(–)-Norepinephrine l-1-(3,4-Dihydroxyphenyl)-2-aminoethanol
Physical data
Density	1.397±0.06 g/cm³
Melt. point	217 °C (423 °F) (decomposes)
Boiling point	442.6 °C (829 °F) ±40.0°C
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic
Half life	?
Excretion	Urine (84-96%)
Therapeutic considerations
Licence data	US
Pregnancy cat.	B3(AU) C(US)
Legal status	Prescription Only (S4)(AU) ?(CA) POM(UK) [[Prescription drug|Template:Unicode-only]](US)
Routes	Intravenous

Mechanism of Action

• Levophed functions as a peripheral vasoconstrictor (alpha-adrenergic action) and as an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action).

Structure

• Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is a sympathomimetic amine which differs from epinephrine by the absence of a methyl group on the nitrogen atom.
• Norepinephrine Bitartrate is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate and has the following structural formula:

This image is provided by the National Library of Medicine.

• Levophed is supplied in sterile aqueous solution in the form of the bitartrate salt to be administered by intravenous infusion following dilution. Norepinephrine is sparingly soluble in water, very slightly soluble in alcohol and ether, and readily soluble in acids. Each mL contains the equivalent of 1 mg base of norepinephrine, sodium chloride for isotonicity, and not more than 2 mg of sodium metabisulfite as an antioxidant. It has a pH of 3 to 4.5. The air in the ampuls has been displaced by nitrogen gas.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Norepinephrine bitartrate in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Norepinephrine bitartrate in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Norepinephrine bitartrate in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Norepinephrine bitartrate in the drug label.

How Supplied

• Levophed, norepinephrine bitartrate injection, USP, contains the equivalent of 4 mg base of Levophed per each 4 mL ampul (1 mg/mL).

• Supplied as:

• Ampuls of 4 mL in boxes of 10, NDC 0409-1443-25

• Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from light.

Storage

There is limited information regarding Norepinephrine bitartrate Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Norepinephrine bitartrate in the drug label.

Precautions with Alcohol

• Alcohol-Norepinephrine bitartrate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Levophed®

Look-Alike Drug Names

• Levophed® — Levofloxacin

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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