2.1 Important Dosage and Administration Instructions

2.2 Dosage

After an initial dosage of 8 to 12 mcg per minute via intravenous infusion, assess patient response and adjust dosage to maintain desired hemodynamic effect. Monitor blood pressure every two minutes until the desired hemodynamic effect is achieved, and then monitor blood pressure every five minutes for the duration of the infusion.

Typical maintenance intravenous dosage is 2 to 4 mcg per minute.

2.3 Preparation of Diluted Solution

Visually inspect LEVOPHED for particulate matter and discoloration prior to administration (the solution is colorless). Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate.

Add the content of one LEVOPHED vial or ampule (4 mg in 4 mL) to 1,000 mL of 5% Dextrose Injection, USP or Sodium Chloride Injection solutions that contain 5% dextrose to produce a 4 mcg per mL dilution. Dextrose reduces loss of potency due to oxidation. Administration in saline solution alone is not recommended.

Use higher concentration solutions in patients requiring fluid restriction. Prior to use, store the diluted LEVOPHED solution for up to 24 hours at room temperature [20°C to 25°C (68°F to 77°F)] and protect from light.

2.4 Drug Incompatibilities

Avoid contact with iron salts, alkalis, or oxidizing agents.

Whole blood or plasma, if indicated to increase blood volume, should be administered separately.

5.1 Tissue Ischemia

Administration of LEVOPHED 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. Address hypovolemia prior to initiating LEVOPHED [see Dosage and Administration (2.1)]. Avoid LEVOPHED in patients with mesenteric or peripheral vascular thrombosis, as this may increase ischemia and extend the area of infarction.

Gangrene of the extremities has occurred in patients with occlusive or thrombotic vascular disease or who received prolonged or high dose infusions. Monitor for changes to the skin of the extremities in susceptible patients.

Extravasation of LEVOPHED may cause 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 [see Dosage and Administration (2.1)].

5.2 Hypotension after Abrupt Discontinuation

Sudden cessation of the infusion rate may result in marked hypotension. When discontinuing the infusion, gradually reduce the LEVOPHED infusion rate while expanding blood volume with intravenous fluids.

5.3 Cardiac Arrhythmias

LEVOPHED elevates intracellular calcium concentrations and may cause arrhythmias, particularly in the setting of hypoxia or hypercarbia. Perform continuous cardiac monitoring of patients with arrhythmias.

5.4 Allergic Reactions Associated with Sulfite

LEVOPHED 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 non-asthmatic people.

7.1 MAO-Inhibiting Drugs

Co-administration of LEVOPHED with monoamine oxidase (MAO) inhibitors or other drugs with MAO-inhibiting properties (e.g., linezolid) can cause severe, prolonged hypertension.

If administration of LEVOPHED cannot be avoided in patients who recently have received any of these drugs and in whom, after discontinuation, MAO activity has not yet sufficiently recovered, monitor for hypertension.

7.2 Tricyclic Antidepressants

Co-administration of LEVOPHED with tricyclic antidepressants (including amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can cause severe, prolonged hypertension. If administration of LEVOPHED cannot be avoided in these patients, monitor for hypertension.

7.3 Antidiabetics

LEVOPHED can decrease insulin sensitivity and raise blood glucose. Monitor glucose and consider dosage adjustment of antidiabetic drugs.

7.4 Halogenated Anesthetics

Concomitant use of LEVOPHED with halogenated anesthetics (e.g., cyclopropane, desflurane, enflurane, isoflurane, and sevoflurane) may lead to ventricular tachycardia or ventricular fibrillation. Monitor cardiac rhythm in patients receiving concomitant halogenated anesthetics.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric 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.

Avoid administration of LEVOPHED into the veins in the leg in elderly patients [see Warnings and Precautions (5.1)].

12.1 Mechanism of Action

Norepinephrine is a peripheral vasoconstrictor (alpha-adrenergic action) and an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action).

12.2 Pharmacodynamics

The primary pharmacodynamic effects of norepinephrine are cardiac stimulation and vasoconstriction. Cardiac output is generally unaffected, although it can be decreased, and total peripheral 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. Coronary blood flow is substantially increased secondary to the indirect effects of alpha stimulation. After intravenous administration, a pressor response occurs rapidly and reaches steady state within 5 minutes. The pharmacologic actions of norepinephrine are terminated primarily by uptake and metabolism in sympathetic nerve endings. The pressor action stops within 1–2 minutes after the infusion is discontinued.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, mutagenesis, and fertility studies have not been performed.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]

Store in original carton until time of administration to protect from light. Discard unused portion.

Risk of Tissue Damage

Advise the patient, family, or caregiver to report signs of extravasation urgently [see Warnings and Precautions (5.1)].