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:
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 0.2 mg of sodium metabisulfite as an antioxidant. It
has a pH of 3 to 4.5. The air in the vials has been displaced by nitrogen
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).
As 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.
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
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
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.
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
: 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.
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.
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
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 established.
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 (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,
System: Anxiety, transient headache.
Respiratory System: Respiratory
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.
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.
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 patient stabilizes.
DOSAGE AND ADMINISTRATION
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).
Restoration 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 the content of the
vial (4 mg/4 mL) 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 vials) 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.
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
LEVOPHED (norepinephrine bitartrate) injection, USP,
contains the equivalent of 1 mg base of LEVOPHED per 1 mL (4
5 mL vials (4 mL fill, 4 mg/4 mL) in boxes of 10 (NDC No. 0409–3375–04)
Store at 20 to 25°C (68 to 77°F); excursions
permitted to 15 to 30°C (59 to 86°F). [See USP Controlled