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.
is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt)
monohydrate and has the following structural formula:
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.
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).
INDICATIONS AND USAGE
For blood pressure control in certain acute hypotensive states
(e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia,
myocardial infarction, septicemia, blood transfusion, and drug reactions).
an adjunct in the treatment of cardiac arrest and profound hypotension.
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.
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.
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.
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.
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.
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
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.
IMPORTANT ―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.
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.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Studies have not been performed.
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.
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.
Safety and effectiveness in pediatric patients has not been
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
LEVOPHED infusions should not be administered
into the veins in the leg in elderly patients (see PRECAUTIONS, General).
The following reactions can occur:
Body As A Whole: Ischemic injury due to potent
vasoconstrictor action and tissue hypoxia.
Cardiovascular System: Bradycardia, probably
as a reflex result of a rise in blood pressure, arrhythmias.
Nervous System: Anxiety, transient headache.
Respiratory System: Respiratory difficulty.
Skin and Appendages: Extravasation necrosis
at injection site.
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.
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.
Overdosage with LEVOPHED may result in headache, severe hypertension,
reflex bradycardia, marked increase in peripheral resistance, and decreased
cardiac output. In case of accidental overdosage, as evidenced by excessive
blood pressure elevation, discontinue LEVOPHED until the condition of the
DOSAGE AND ADMINISTRATION
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 (see PRECAUTIONS).
of Blood Pressure in Acute Hypotensive States
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.
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.
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
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.
drug products should be inspected visually for particulate matter and discoloration
prior to use, whenever solution and container permit.
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.
LEVOPHED, norepinephrine bitartrate injection, USP, contains
the equivalent of 4 mg base of LEVOPHED per each 4 mL ampul (1 mg/mL).
Ampuls of 4 mL in boxes of 10 (List 1443)
at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F).