LEVOPHED (Brand for NOREPINEPHRINE BITARTRATE)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration 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.
Intravenous Administration
-Address hypovolemia before initiation of norepinephrine therapy.
-Administer whole blood or plasma, if indicated to increase blood volume, separately.
-Norepinephrine is inactivated in alkaline solutions; do not mix with bicarbonate.

Dilution
-Dilute norepinephrine 4 mg in 1,000 mL of 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection for a concentration of 4 mcg/mL.
--Dextrose-containing fluids offer protection against loss of potency due to oxidation; therefore, 5% Dextrose Injection or 5% Dextrose and 0.9% Sodium Chloride Injection are generally the preferred diluents. Although FDA-approved labeling states that dilution of norepinephrine in 0.9% Sodium Chloride Injection alone is not recommended, data support the stability of norepinephrine in 0.9% Sodium Chloride Injection at concentrations up to 16 mcg/mL.

-ISMP Recommended Standard Concentration for Neonatal Infusions: 16 mcg/mL
-A single children's medical center reports the use of standard norepinephrine concentrations of 8 mcg/mL and 64 mcg/mL for infusions via "smart-pumps".
-A concentration of 100 mcg/mL in 5% Dextrose Injection was used in a small study of neonates with hypotension due to septic shock refractory to fluid resuscitation and dopamine or dobutamine infusion. Central catheters were used for the infusion.
-Storage: Stable for up to 7 days at room temperature in 5% Dextrose Injection or 0.9% Sodium Chloride Injection at concentrations of 4 mcg/mL or 16 mcg/mL.

Continuous IV Infusion
-May administer initially via peripheral IV and change to central line administration as soon as possible. Infuse into a large vein. Avoid infusions into the veins of the leg in patients with occlusive vascular disease of the legs.
-Avoid using a catheter-tie-in technique.
-Monitor blood pressure every 2 minutes until the desired hemodynamic effect is achieved, then monitor blood pressure every 5 minutes for the duration of the infusion.
-Check the infusion site frequently for free flow, and monitor for signs of extravasation.
-When discontinuing the infusion, reduce the flow rate gradually. Avoid abrupt withdrawal.

Extravasation Management
-Extravasation management instructions are provided in FDA-approved labeling; instructions are not specific to pediatric patients and may require adjustments for some patients (e.g., smaller volumes for neonates and infants).
-To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using a syringe with a fine hypodermic needle with phentolamine 5 to 10 mg in 10 to 15 mL of 0.9% Sodium Chloride Injection.
-Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours.

Nervous system adverse effects that can occur with norepinephrine use include anxiety and headache.

Hypertension and bradycardia are the most common adverse reactions associated with norepinephrine. Norepinephrine increases intracellular calcium concentrations and may cause arrhythmias, particularly in the setting of hypoxemia or hypercarbia.

Administration of norepinephrine to patients who are hypotensive from hypovolemia can result in severe visceral and peripheral vasoconstriction, decreased renal perfusion and reduced urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow despite normal blood pressure. Gangrene of the extremities has occurred in patients with occlusive or thrombotic vascular disease or who received prolonged or high dose infusions of norepinephrine. Extravasation of norepinephrine may cause tissue necrosis and sloughing of surrounding tissue. To reduce the risk of extravasation, infuse into a large vein, check the infusion site frequently for free flow, and monitor for signs of extravasation. To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using a syringe with a fine hypodermic needle with phentolamine 5 to 10 mg in 10 to 15 mL of 0.9% Sodium Chloride Injection in adults. Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours.

Respiratory adverse effects that can occur with norepinephrine use include respiratory difficulty and pulmonary edema.

Correct hypovolemia before starting norepinephrine. Administration of norepinephrine to patients who are hypotensive from hypovolemia can result in severe peripheral and visceral vasoconstriction, decreased renal perfusion and reduced urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow despite normal blood pressure.

Avoid norepinephrine in patients with peripheral vascular or mesenteric thrombosis, as this may increase ischemia and extend the area of infarction.

Perform continuous cardiac monitoring of patients with cardiac arrhythmias. Norepinephrine increases intracellular calcium concentrations and may cause arrhythmias, particularly in the setting of hypoxemia or hypercarbia.

When discontinuing norepinephrine, gradually reduce the infusion rate while expanding blood volume with intravenous fluids. Abrupt discontinuation of norepinephrine may result in marked hypotension.

Avoid infusion of norepinephrine into the veins of the leg in patients with occlusive peripheral vascular disease of the legs. Gangrene of the extremities has occurred in patients with occlusive or thrombotic vascular disease or who received prolonged or high dose infusions of norepinephrine. Monitor for changes to the skin of the extremities in susceptible patients. Extravasation of norepinephrine may cause tissue necrosis and sloughing of surrounding tissue. To reduce the risk of extravasation, infuse into a large vein, check the infusion site frequently for free flow, and monitor for signs of extravasation.

Avoid administration of norepinephrine with monoamine oxidase (MAO) inhibitors or other drugs with MAO-inhibiting properties (e.g., linezolid). If administration of norepinephrine cannot be avoided in patients who recently have received MAOI therapy and in whom, after discontinuation, MAO activity has not yet sufficiently recovered, monitor for hypertension. Coadministration of norepinephrine with these drugs can cause severe, prolonged hypertension.

Certain formulations of norepinephrine contain sodium metabisulfite. Sodium metabisulfite is a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe episodes in certain susceptible people, such as patients with sulfite hypersensitivity or asthma.

Description: Norepinephrine is an intravenous catecholamine used for restoration of blood pressure in patients with acute hypotensive states. It is an endogenous catecholamine synthesized in the adrenal medulla and is the biochemical precursor of epinephrine. Norepinephrine is the transmitter of most sympathetic postganglionic fibers of the central nervous system. Norepinephrine is a potent alpha-adrenergic receptor agonist with modest beta-agonist activity. Administration of norepinephrine to patients who are hypotensive from hypovolemia can result in severe visceral and peripheral vasoconstriction, decreased renal perfusion and reduced urine output, tissue hypoxia, lactic acidosis, and reduced systemic blood flow despite normal blood pressure; therefore, hypovolemia must be corrected before starting norepinephrine. Gangrene of the extremities has occurred in patients with occlusive or thrombotic vascular disease or who received prolonged or high dose infusions of norepinephrine. Guidelines recommend norepinephrine and epinephrine as first-line vasopressors for pediatric patients with fluid-refractory septic shock. Norepinephrine is generally chosen to increase systemic vascular resistance. Pediatric Advanced Life Support guidelines state that norepinephrine may be preferable to dopamine in pediatric patients, especially infants, with marked circulatory instability and decompensated shock. Although not FDA-approved, norepinephrine has been used in pediatric patients as young as neonates.

For the treatment of acute hypotension*, cardiogenic shock*, or septic shock*:
Intravenous dosage:
Neonates: 0.1 to 0.5 mcg/kg/minute continuous IV infusion; titrate every 30 minutes to attain hemodynamic goals (Usual Max: 2 mcg/kg/minute). The norepinephrine infusion rate required to correct hypotension ranged from 0.2 to 2 mcg/kg/minute (mean 0.5 mcg/kg/minute), and the individual maximum infusion rate to sustain normal systolic blood pressure ranged from 0.2 to 7.1 mcg/kg/minute in an observational study of 22 neonates (gestational age older than 35 weeks) with hypotension due to septic shock refractory to fluid resuscitation and dopamine or dobutamine. When discontinuing norepinephrine, reduce the infusion rate gradually; avoid abrupt withdrawal.
Infants, Children, and Adolescents: 0.1 mcg/kg/minute continuous IV infusion; titrate to attain hemodynamic goals (Usual Max: 2 mcg/kg/minute). When discontinuing norepinephrine, reduce the infusion rate gradually; avoid abrupt withdrawal.

Maximum Dosage Limits:
Safety and efficacy have not been established. Although dosage is titrated to effect, 2 mcg/kg/minute IV continuous infusion is often used as an upper limit.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments are not available; however, the rate of metabolism of norepinephrine may be decreased in individual patients with hepatic impairment. Titrate to attain clinical goals.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments are not available; it appears that no dosage adjustments are needed. Titrate to attain clinical goals.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Norepinephrine acts predominantly on alpha-adrenergic receptors to produce constriction of resistance and capacitance vessels, thereby increasing systemic blood pressure and coronary artery blood flow. Norepinephrine also acts on beta1-receptors, although quantitatively less than either epinephrine or isoproterenol. In relatively lower doses, the cardiac-stimulant effect of norepinephrine is predominant; with larger doses, the vasoconstrictor effect predominates.

Similar to epinephrine, norepinephrine has direct agonist effects on effector cells that contain alpha- and beta-receptors. As with other catecholamines, the intracellular action of norepinephrine is mediated via cyclic adenosine monophosphate (cAMP), the production of which is augmented by beta stimulation and attenuated by alpha stimulation.

The primary pharmacodynamic effects of norepinephrine are cardiac stimulation, particularly at lower doses, and vasoconstriction, which tends to predominate with moderate to higher doses of the drug. Metabolic effects observed with epinephrine, such as glycogenolysis, inhibition of insulin release, and lipolysis, also occur with norepinephrine but are much less pronounced.

The hemodynamic consequences of norepinephrine's cardiovascular stimulation include increases in systolic, diastolic, and pulse pressures. Peripheral vascular resistance is also elevated. The elevation in resistance and pressure result in reflex vagal activity, which slows the heart rate and increases stroke volume. The elevation in vascular tone or resistance reduces blood flow to the major abdominal organs as well as to skeletal muscle. As with epinephrine, however, coronary blood flow is substantially increased secondary to the indirect effects of alpha stimulation. Therefore, norepinephrine does not significantly increase myocardial oxygen consumption.

Pharmacokinetics: Norepinephrine is administered intravenously. Plasma protein binding of norepinephrine is approximately 25%. It is mainly bound to plasma albumin and to a smaller extent to prealbumin and alpha 1-acid glycoprotein. The Vd is 8.8 L. Norepinephrine localizes mainly in sympathetic nervous tissue. It does not cross the blood-brain barrier. Norepinephrine is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The major metabolites are normetanephrine and 3-methoxyl-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Other inactive metabolites include 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylglycol. Noradrenaline metabolites are excreted in urine primarily as sulphate conjugates and, to a lesser extent, as glucuronide conjugates. Only small quantities of norepinephrine are excreted unchanged. In adults, the average metabolic clearance is 3.1 L/minute, and the mean half-life of norepinephrine is approximately 2.4 minutes.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Intravenous Route
After initiation of an intravenous norepinephrine infusion, onset of activity is rapid (less than 30 seconds); steady-state plasma concentration is achieved in 5 minutes, and duration persists less than 10 minutes after discontinuation of the infusion.