Norepinephrine Bitartrate

Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection is indicated to raise blood pressure in adult patients with severe, acute hypotension. Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection is a catecholamine indicated for restoration of blood pressure in adult patients with acute hypotensive states. ( 1 )

Injection: Norepinephrine bitartrate in either 5% Dextrose or 0.9% Sodium Chloride is a colorless to slightly yellow solution for intravenous infusion, supplied in 250-mL single dose containers as:

• 4 mg equivalent of norepinephrine (16 mcg/mL).
• 8 mg equivalent of norepinephrine (32 mcg/mL).
• 16 mg equivalent of norepinephrine (64 mcg/mL). Injection: 250-mL single dose-containers with
• 4 mg equivalent of norepinephrine (16 mcg/mL) in 5% Dextrose or 0.9% Sodium Chloride.
• 8 mg equivalent of norepinephrine (32 mcg/mL) in 5% Dextrose or 0.9% Sodium Chloride.
• 16 mg equivalent of norepinephrine (64 mcg/mL) in 5% Dextrose or 0.9% Sodium Chloride.

None.

• None. ( 4 )

• Tissue Ischemia : Infuse Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection into a large vein. To prevent sloughing and necrosis in areas in with extravasation, infiltrate the area with an adrenergic blocking agent in saline. ( 5.1 )
• Hypotension After Abrupt Discontinuation: Gradually taper a norepinephrine infusion to prevent hypotension. ( 5.2 )
• Cardiac Arrhythmias: Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection may cause arrhythmias. Monitor cardiac function in patients with underlying heart disease. ( 5.3 )
• Allergic Reactions with Sulfite : Norepinephrine Bitartrate in Sodium Chloride Injection contains sodium metabisulfite: Sulfite may cause allergic-type reactions. ( 5.4 )

5.1 Tissue Ischemia Administration of Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection 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 Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection [see Dosage and Administration (2.1) ]. Avoid Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection 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 Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection 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) ]. Emergency Treatment 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 5 mg to 10 mg of phentolamine mesylate in 10 mL 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.

5.2 Hypotension after Abrupt Discontinuation Sudden cessation of the infusion rate may result in marked hypotension. When discontinuing the infusion, gradually reduce the Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection infusion rate while expanding blood volume with intravenous fluids.

5.3 Cardiac Arrhythmias Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection 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 This product 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 and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

The following serious adverse reactions are described in greater detail in other sections:

• Tissue Ischemia [see Warnings and Precautions (5.1) ]
• Hypotension [see Warnings and Precautions (5.2) ]
• Cardiac Arrhythmias [see Warnings and Precautions (5.3) ]
• Allergic Reactions associated with Sulfite [see Warnings and Precautions (5.4 )] The most common adverse reactions are hypertension and bradycardia. The following adverse reactions can occur: Nervous system disorders: Anxiety, headache Respiratory disorders: Respiratory difficulty, pulmonary edema General disorders and administration site conditions : Extravasation, injection site necrosis [see Warnings and Precautions (5.1)] . Most common adverse reactions are hypertension, bradycardia, ischemic injury, anxiety, headache, respiratory difficulty, pulmonary edema, and extravasation necrosis at injection site. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Monoamine oxidase inhibitors (MAOI) or tricyclic antidepressants of the triptyline or imipramine types may result in hypertension. ( 7.1 , 7.2 )
• Antidiabetics: Norepinephrine can decrease insulin sensitivity and raise blood glucose ( 7.3 )
• Cyclopropane and halothane anesthetics increase cardiac autonomic irritability. ( 7.4 ) 7.1 MAO-Inhibiting Drugs Co-administration of Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection with monoamine oxidase (MAO) inhibitors or other drugs with MAO-inhibiting properties (e.g., linezolid) can cause severe, prolonged hypertension. If administration of Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection 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 Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection with tricyclic antidepressants (including amitriptyline, nortriptyline, protriptyline, clomipramine, desipramine, imipramine) can cause severe, prolonged hypertension. If administration of Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection cannot be avoided in these patients, monitor for hypertension.

7.3 Antidiabetics Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection can decrease insulin sensitivity and raise blood glucose. Monitor glucose and consider dosage adjustment of antidiabetic drugs.

7.4 Halogenated Anesthetics Concomitant use of Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection 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.

• Elderly patients may be at greater risk of developing adverse reactions ( 8.5 )

8.1 Pregnancy Risk Summary Limited published data consisting of a small number of case reports and multiple small trials involving the use of norepinephrine in pregnant women at the time of delivery have not identified an increased risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus from hypotension associated with septic shock, myocardial infarction and stroke which are medical emergencies in pregnancy and can be fatal if left untreated. (see Clinical Considerations). In animal reproduction studies, using high doses of intravenous norepinephrine resulted in lowered maternal placental blood flow. Clinical relevance to changes in the human fetus is unknown since the average maintenance dose is ten times lower (see Data). Increased fetal reabsorptions were observed in pregnant hamsters after receiving daily injections at approximately 2 times the maximum recommended dose on a mg/m 3 basis for four days during organogenesis (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypotension associated with septic shock, myocardial infarction, and stroke are medical emergencies in pregnancy which can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic shock, myocardial infarction and stroke may increase the risk of maternal and fetal morbidity and mortality. Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of norepinephrine on the fetus. Data Animal Data A study in pregnant sheep receiving high doses of intravenous norepinephrine (40 mcg/min, at approximately 10 times the average maintenance dose of 2 mcg/min -4 mcg/min in human, on a mg/kg basis) exhibited a significant decrease in maternal placental blood flow. Decreases in fetal oxygenation, urine and lung liquid flow were also observed. Norepinephrine administration to pregnant rats on Gestation Day 16 or 17 resulted in cataract production in rat fetuses. In hamsters, an increased number of resorptions (29.1% in study group vs. 3.4% in control group), fetal microscopic liver abnormalities and delayed skeletal ossification were observed at approximately 2 times the maximum recommended intramuscular or subcutaneous dose (on a mg/m 2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day from Gestation Day 7-10).

8.2 Lactation Risk Summary There are no data on the presence of norepinephrine in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Clinically relevant exposure to the infant is not expected based on the short half-life and poor oral bioavailability of norepinephrine.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of norepinephrine 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 Norepinephrine Bitartrate in Dextrose Injection or Norepinephrine Bitartrate in Sodium Chloride Injection into the veins in the leg in elderly patients [see Warnings and Precautions (5.1) ].

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