norepinephrine bitartrate (formerly levarterenol bitartrate)
Levophed

Available forms
Available by prescription only
Injection: 1 mg/ml parenteral

Indications and dosages
 To maintain blood pressure in acute hypotensive states. Adults: Initially, 8 to 12 mcg/minute I.V. infusion, adjusted to maintain desired blood pressure. Maintenance dosage, 2 to 4 mcg/minute.
Children: Initially, 2 mcg/minute or 2 mcg/m²/minute by I.V. infusion, adjusted to maintain desired blood pressure. For advanced cardiac life support, initial infusion rate is 0.1 mcg/kg/minute adjusted to maximum of 2 mcg/kg/minute.
 GI bleeding ◇. Adults: 8 mg in 250 ml normal saline solution given intraperitoneally. Or, 8 mg in 100 ml of normal saline solution given via a nasogastric tube q hour for 6 to 8 hours and then q 2 hours for 4 to 6 hours.

Pharmacodynamics
Vasopressor action: Norepinephrine acts mainly by direct stimulation of alpha-adrenergic receptors, constricting both capacitance and resistance blood vessels. This results in increased total peripheral resistance; increased systolic and diastolic blood pressure; decreased blood flow to vital organs, skin, and skeletal muscle; and constriction of renal blood vessels, which reduces renal blood flow. It also has a direct stimulating effect on beta₁ receptors of the heart, producing a positive inotropic response. Its main therapeutic effects are vasoconstriction and cardiac stimulation.

Pharmacokinetics
Absorption: Administered I.V.
Distribution: Localizes in sympathetic nerve tissues. It crosses the placental barrier but not the blood-brain barrier.
Metabolism: Metabolized in the liver and other tissues to inactive compounds.
Excretion: Excreted in urine primarily as sulfate and glucuronide conjugates. Small amounts are excreted unchanged in urine.

Contraindications and precautions
Contraindicated in patients with mesenteric or peripheral vascular thrombosis, profound hypoxia, hypercapnia, or hypotension resulting from blood volume deficit and during cyclopropane and halothane anesthesia.
  Use cautiously in patients with sulfite allergies or in those receiving MAO inhibitors or triptyline- or imipramine-type antidepressants.

Interactions
Drug-drug. Antihistamines (some), ergot alkaloids (parenteral), guanethidine, linezolid, MAO inhibitors, methyldopa, oxytocic drugs, tricyclic antidepressants: Causes severe, prolonged hypertension. Avoid use together.
Atropine: Blocks the reflex bradycardia caused by norepinephrine and enhances its pressor effects. Use together cautiously.
Beta blockers: Increases risk of hypertension. Propranolol may be used to treat arrhythmias occurring during norepinephrine administration. Use together cautiously.
Furosemide, other diuretics: May decrease arterial responsiveness. Monitor blood pressure for effect.
General anesthetics: May increase occurrence of arrhythmias. Use together cautiously.

Adverse reactions
CNS: anxiety, weakness, dizziness, tremor, restlessness, insomnia.
CV: bradycardia, severe hypertension, arrhythmias.
Respiratory: respiratory difficulties, asthmatic episodes.
Skin: irritation or necrosis with extravasation.
Other: anaphylaxis.

Effects on lab test results
None reported.

Overdose and treatment
Signs and symptoms of overdose include severe hypertension, photophobia, retrosternal or pharyngeal pain, intense sweating, vomiting, cerebral hemorrhage, seizures, and arrhythmias. Monitor vital signs closely.
 Treatment includes supportive and symptomatic measures. Use atropine for reflex bradycardia, phentolamine for extravasation, and propranolol for tachyarrhythmias.

Special considerations
• Correct blood volume depletion before administration. Norepinephrine isn’t a substitute for blood, plasma, fluid, or electrolyte replacement.
• Select injection site carefully. Administration by I.V. infusion requires an infusion pump or other device to control flow rate. If possible, infuse into antecubital vein of the arm or the femoral vein. Change injection sites for prolonged therapy. Dilute before use with 5% dextrose or with saline (dilution with saline alone isn’t recommended). Monitor infusion rate. Withdraw drug gradually; recurrent hypotension may follow abrupt withdrawal.
• Prepare infusion solution by adding 4 mg norepinephrine to 1 L of D₅W. The resulting solution contains 4 mcg/ml.
• To treat extravasation, infiltrate site promptly with 10 to 15 ml saline solution containing 5 to 10 mg phentolamine, using a fine needle.
• In patients with previously normal blood pressure, adjust flow rate to maintain blood pressure at low normal (usually 80 to 100 mm Hg systolic); in hypertensive patients, maintain systolic no more than 40 mm Hg below preexisting pressure level.
• Observe patient constantly during norepinephrine administration. Obtain baseline blood pressure and pulse before therapy, and repeat every 2 minutes until stabilization. Repeat every 5 minutes during administration.
• In addition to vital signs, monitor patient’s mental state, skin temperature of limbs, and skin color (especially earlobes, lips, and nail beds).
• Monitor intake and output. Norepinephrine reduces renal blood flow, which may cause decreased urine output initially.
• Avoid contact of drug with iron salts, alkalies, or oxidizing agents.
• Protect solution from light. Discard solution that’s discolored or contains a precipitate.
Pediatric patients
• Use cautiously in children.
Geriatric patients
• Drug hasn’t been evaluated systematically in patients age 65 or older. Start with low dose and adjust based on response.

Patient education
• Inform patient of need for frequent monitoring of vital signs.
• Advise patient to report adverse reactions.
• Advise patient to report if I.V. site feels cool or painful.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use