ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The following reactions can occur:Body As Whole: Ischemic injury due to potent vasoconstrictor action and tissue hypoxia.Cardiovascular System: Bradycardia, probably as reflex result of rise in blood pressure, arrhythmias, and stress cardiomyopathy.Nervous System: Anxiety, transient headache.Respiratory System: Respiratory difficulty.Skin 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.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. LEVOPHED functions as peripheral vasoconstrictor (alpha-adrenergic action) and as an inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action).

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. 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.LEVOPHED 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 life-saving procedure.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.

DESCRIPTION SECTION.

DESCRIPTION. Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is sympathomimetic amine which differs from epinephrine by the absence of methyl group on the nitrogen atom.Norepinephrine Bitartrate is (-)--(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 mg base of norepinephrine, sodium chloride for isotonicity, and not more than 0.2 mg of sodium metabisulfite as an antioxidant. It has pH of to 4.5. The air in the vials has been displaced by nitrogen gas.. Levophed Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Norepinephrine Bitartrate Injection is concentrated, potent drug which must be diluted in dextrose containing solutions prior to infusion. An infusion of LEVOPHED should be given into large vein (see PRECAUTIONS).Restoration of Blood Pressure in Acute Hypotensive StatesBlood 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 percent dextrose injection or 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 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 5 percent dextrose containing solution. Each mL of this dilution contains mcg of the base of LEVOPHED. Give this solution by intravenous infusion. Insert plastic intravenous catheter through suitable bore needle well advanced centrally into the vein and securely fixed with adhesive tape, avoiding, if possible, 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 mL to mL (from mcg to 12 mcg of base) per minute, adjust the rate of flow to establish and maintain 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 mL per minute (from mcg to 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 flow rate that would involve an excessive dose of the pressor agent per unit of time, solution more dilute than mcg per mL should be used. On the other hand, when large volumes of fluid are clinically undesirable, concentration greater than 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 ArrestInfusions 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. [LEVOPHEDs 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.Parenteral 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 precipitate.Avoid contact with iron salts, alkalis, or oxidizing agents.

HOW SUPPLIED SECTION.

HOW SUPPLIED. LEVOPHED (norepinephrine bitartrate) injection, USP, contains the equivalent of mg base of LEVOPHED per mL (4 mg/4 mL).Supplied as:Unit of SaleConcentrationNDC 0409-3375-044 mg/4 mL10 in Carton(1 mg/mL)Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F). [See USP Controlled Room Temperature.]Protect from light.Regitine, trademark, CIBA Pharmaceuticals Company.Distributed by Hospira, Inc., Lake Forest, IL 60045 USALAB-1150-2.0Revised: 08/2018. Levophed Structural Formula.

INDICATIONS & USAGE SECTION.

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.

OVERDOSAGE SECTION.

OVERDOSAGE. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 4 mL Vial Label. mL Fill in mL VialSingle dose Fliptop VialNDC 0409-3375-04LV45Levophed(R) norepinephrine bitartrateinjection, USP4 mg/4mL (1 mg/mL)FOR IV INFUSION ONLYWarning: Contains Sulfites.Hospira, Inc., Lake Forest, IL 60045 USARx only. PRINCIPAL DISPLAY PANEL 4 mL Vial Label.

PRECAUTIONS SECTION.

PRECAUTIONS. GeneralAvoid 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 symptom of hypertension due to overdosage.Site of Infusion: Whenever possible, infusions of LEVOPHED should be given into 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. 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, Buergers 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 lower extremity when infusions of LEVOPHED were given in an ankle vein.Extravasation: 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.This also 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 mg to 10 mg of Regitine(R) (brand of phentolamine), an adrenergic blocking agent. syringe with 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.Drug Interactions: 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 may result.Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies have not been performed.Pregnancy: Animal reproduction studies have not been conducted with LEVOPHED. It is also not known whether LEVOPHED can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. LEVOPHED should be given to pregnant woman only if clearly needed.Nursing Mothers: 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 nursing woman.Pediatric Use: Safety and effectiveness in pediatric patients has not been established.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.LEVOPHED infusions should not be administered into the veins in the leg in elderly patients (see PRECAUTIONS, General).

SPL UNCLASSIFIED SECTION.

Norepinephrine BitartrateInjection, USPRx only.

WARNINGS SECTION.

WARNINGS. 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 may result.LEVOPHED Bitartrate Injection contains sodium metabisulfite, 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: mg/4 mL (1 mg/mL norepinephrine base) sterile, colorless solution in single-dose amber glass vial.Injection: mg/4 mL (1 mg/mL norepinephrine base) sterile, colorless solution in single-dose clear glass ampule.. Injection: mg/4 mL (1 mg/mL) norepinephrine base in single-dose glass vial or ampule. (3).

STORAGE AND HANDLING SECTION.

Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F). [See USP Controlled Room Temperature.]Store in original carton until time of administration to protect from light. Discard unused portion.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Elderly patients may be at greater risk of developing adverse reactions. (8.5). Elderly patients may be at greater risk of developing adverse reactions. (8.5). 8.1 Pregnancy. Risk SummaryLimited published data consisting of 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 times the maximum recommended dose on mg/m3 basis for four days during organogenesis (see Data ).The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 the clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskHypotension 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 DataA study in pregnant sheep receiving high doses of intravenous norepinephrine (40 mcg/min, at approximately 10 times the average maintenance dose of 2-4 mcg/min in human, on mg/kg basis) exhibited 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 times the maximum recommended intramuscular or subcutaneous dose (on mg/m2 basis at maternal subcutaneous dose of 0.5 mg/kg/day from Gestation Day 7-10).. 8.2 Lactation. Risk SummaryThere 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 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)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis, mutagenesis, and fertility studies have not been performed.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types may result in hypertension. (7.1)Cyclopropane and halothane anesthetics increase cardiac autonomic irritability. (7.4). Monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types may result in hypertension. (7.1). Cyclopropane and halothane anesthetics increase cardiac autonomic irritability. (7.4). 7.1MAO-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.. 7.3Antidiabetics. LEVOPHED can decrease insulin sensitivity and raise blood glucose. Monitor glucose and consider dosage adjustment of antidiabetic drugs.. 7.4Halogenated 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.

GERIATRIC USE SECTION.

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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Risk of Tissue DamageAdvise the patient, family, or caregiver to report signs of extravasation urgently [see Warnings and Precautions (5.1)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis, mutagenesis, and fertility studies have not been performed.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

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, pressor response occurs rapidly and reaches steady state within 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing initiation of intravenous infusion, the steady state plasma concentration is achieved in min.. DistributionPlasma protein binding of norepinephrine is approximately 25%. It is mainly bound to plasma albumin and to smaller extent to prealbumin and alpha 1-acid glycoprotein. The volume of distribution is 8.8 L. Norepinephrine localizes mainly in sympathetic nervous tissue. It crosses the placenta but not the blood-brain barrier.. EliminationThe mean half-life of norepinephrine is approximately 2.4 min. The average metabolic clearance is 3.1 L/min.. MetabolismNorepinephrine is metabolized in the liver and other tissues by combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and 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.. ExcretionNoradrenaline metabolites are excreted in urine primarily as sulphate conjugates and, to lesser extent, as glucuronide conjugates. Only small quantities of norepinephrine are excreted unchanged.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLimited published data consisting of 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 times the maximum recommended dose on mg/m3 basis for four days during organogenesis (see Data ).The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 the clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskHypotension 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 DataA study in pregnant sheep receiving high doses of intravenous norepinephrine (40 mcg/min, at approximately 10 times the average maintenance dose of 2-4 mcg/min in human, on mg/kg basis) exhibited 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 times the maximum recommended intramuscular or subcutaneous dose (on mg/m2 basis at maternal subcutaneous dose of 0.5 mg/kg/day from Gestation Day 7-10).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Tissue Ischemia: Avoid extravasation of LEVOPHED into the tissues, as local necrosis might ensue due to the vasoconstrictive action of the drug. Infuse LEVOPHED into large vein. 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 mg to 10 mg of an adrenergic blocking agent. (5.1)Hypotension After Abrupt Discontinuation: Sudden cessation of the infusion rate may result in marked hypotension. Reduce the LEVOPHED infusion rate gradually. (5.2)Cardiac Arrhythmias: LEVOPHED may cause arrhythmias. Monitor cardiac function in patients with underlying heart disease. (5.3)Allergic Reactions with Sulfite: LEVOPHED contains sodium metabisulfite. Sulfite may cause allergic-type-reactions. (5.4). Tissue Ischemia: Avoid extravasation of LEVOPHED into the tissues, as local necrosis might ensue due to the vasoconstrictive action of the drug. Infuse LEVOPHED into large vein. 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 mg to 10 mg of an adrenergic blocking agent. (5.1). Hypotension After Abrupt Discontinuation: Sudden cessation of the infusion rate may result in marked hypotension. Reduce the LEVOPHED infusion rate gradually. (5.2). Cardiac Arrhythmias: LEVOPHED may cause arrhythmias. Monitor cardiac function in patients with underlying heart disease. (5.3). Allergic Reactions with Sulfite: LEVOPHED contains sodium metabisulfite. Sulfite may cause allergic-type-reactions. (5.4). 5.1Tissue 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 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 ExtravasationTo prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using syringe with fine hypodermic needle with to 10 mg of phentolamine mesylate 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.. 5.2Hypotension 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.. 5.3Cardiac 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.. 5.4Allergic Reactions Associated with Sulfite. LEVOPHED contains sodium metabisulfite, 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.