NOREPINEPHRINE BITARTRATE injection, solution, concentrate

NOREPINEPHRINE BITARTRATE by

Drug Labeling and Warnings

NOREPINEPHRINE BITARTRATE by is a Prescription medication manufactured, distributed, or labeled by Sun Pharmaceutical Industries, Inc., Gland Pharma Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    Norepinephrine bitartrate injection is indicated to raise blood pressure in adult patients with severe, acute hypotension.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Important Dosage and Administration Instructions


    Correct Hypovolemia
    Address hypovolemia before initiation of norepinephrine bitartrate injection therapy. If the patient does not respond to therapy, suspect occult hypovolemia [see Warnings and Precautions (5.1)].


    Administration
    Dilute norepinephrine bitartrate injection prior to use [see Dosage and Administration (2.3)].


    Infuse norepinephrine bitartrate injection into a large vein. Avoid infusions into the veins of the leg in the elderly or in patients with occlusive vascular disease of the legs [see Warnings and Precautions (5.1)]. Avoid using a catheter-tie-in technique.


    Discontinuation
    When discontinuing the infusion, reduce the flow rate gradually. Avoid abrupt withdrawal.

    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 norepinephrine bitartrate injection 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 norepinephrine bitartrate injection vial (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 norepinephrine bitartrate injection 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.

  • 3 DOSAGE FORMS AND STRENGTHS

    Injection: 4 mg/4 mL (1 mg/mL norepinephrine base) sterile, clear colorless to slightly yellow colored solution in a single-dose amber glass vial.

  • 4 CONTRAINDICATIONS

    None.

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Tissue Ischemia


    Administration of norepinephrine bitartrate 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 injection [see Dosage and Administration (2.1)]. Avoid norepinephrine bitartrate 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 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 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.

    5.2 Hypotension after Abrupt Discontinuation

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

    5.3 Cardiac Arrhythmias

    Norepinephrine bitartrate 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

    Norepinephrine bitartrate injection 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.

  • 6 ADVERSE REACTIONS


    The following 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)]

    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

  • 7 DRUG INTERACTIONS

    7.1 MAO-Inhibiting Drugs


    Coadministration of norepinephrine bitartrate 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 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

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

    7.3 Antidiabetics

    Norepinephrine bitartrate 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 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.

  • 8 USE IN SPECIFIC POPULATIONS

    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/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 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 the clinically recognized pregnancies is 2 to 4% and 15 to 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 to 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/m2 basis at a maternal subcutaneous dose of 0.5 mg/kg/day from Gestation Day 7 to 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 bitartrate injection 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 injection into the veins in the leg in elderly patients [see Warnings and Precautions (5.1)].

  • 10 OVERDOSAGE


    Overdosage with norepinephrine bitartrate injection may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output.


    In case of overdosage, discontinue norepinephrine bitartrate injection until the condition of the patient stabilizes.

  • 11 DESCRIPTION


    Norepinephrine (sometimes referred to as l-arterenol/Levarterenol or l-norepinephrine) is a sympathomimetic amine which differs from epinephrine by the absence of a methyl group on the nitrogen atom.


    Norepinephrine bitartrate USP is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate (molecular weight 337.3 g/mol) and has the following structural formula:


    spl-norepinephrine-structure


    Norepinephrine bitartrate injection USP is supplied in a sterile aqueous solution in the form of the bitartrate salt to be administered by intravenous infusion. Norepinephrine is freely soluble in water, slightly soluble in alcohol and practically insoluble in ether. Each mL contains 1 mg of norepinephrine base (equivalent to 1.89 mg of norepinephrine bitartrate, anhydrous basis), sodium chloride for isotonicity, not more than 0.2 mg of sodium metabisulfite as an antioxidant. It has a pH of 3.0 to 4.5. The air in the vials has been displaced by nitrogen gas.


  • 12 CLINICAL PHARMACOLOGY

    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 to 2 minutes after the infusion is discontinued.

    12.3 Pharmacokinetics


    Absorption
    Following initiation of intravenous infusion, the steady state plasma concentration is achieved in 5 min. 


    Distribution
    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 volume of distribution is 8.8 L. Norepinephrine localizes mainly in sympathetic nervous tissue. It crosses the placenta but not the blood-brain barrier.


    Elimination


    The mean half-life of norepinephrine is approximately 2.4 min. The average metabolic clearance is 3.1 L/min.


    Metabolism
    Norepinephrine is metabolized in the liver and other tissues by a 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.


    Excretion
    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.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

  • 16 HOW SUPPLIED/STORAGE AND HANDLING


    Norepinephrine bitartrate injection, USP, is a sterile, clear colorless to slightly yellow colored solution for injection intended for intravenous use. It contains the equivalent of 1 mg of norepinephrine base per 1 mL (4 mg/4 mL). It is available as 4 mg/4 mL in single-dose amber glass vials. Supplied as:


    4 mg/4 mL (1 mg/mL):
    10 x 4 mL Single-Dose Vials in a Carton: NDC: 47335-615-44


    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.

  • 17 PATIENT COUNSELING INFORMATION


    Risk of Tissue Damage
    Advise the patient, family, or caregiver to report signs of extravasation urgently [see Warnings and Precautions (5.1)].
     
    Distributed by:
    Sun Pharmaceutical Industries, Inc.
    Cranbury, NJ 08512


    Manufactured by:
    Gland Pharma Limited
    Hyderabad-502307 India
     
    ISS. 11/2020

  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - Vial

    NDC: 47335-615-40
    Norepinephrine Bitartrate Injection, USP
    4 mg/4 mL (1 mg/mL)
    For INTRAVENOUS INFUSION ONLY
    Warning: Contains Sulfites.
    Rx only
    4 mL Single-dose Fliptop Vial



    spl-norepinephrine-vial
  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - Carton

    NDC: 47335-615-44
    Sterile Injection
    Norepinephrine Bitartrate Injection, USP
    4 mg/4 mL (1 mg/mL)
    Warning: Contains Sulfites.
    For Intravenous Infusion Only

    Warning: This is a potent drug. Dosage should be controlled by frequent determination of blood pressure. Do not leave patient unattended during administration. Avoid extravasation. Read Prescribing Information carefully.

    DILUTE BEFORE USE. DISCARD UNUSED PORTION.
    PROTECT FROM LIGHT.

    Rx only
    10 x 4 mL Single-dose Fliptop Vials
    SUN PHARMA


    spl-norepinephrine-carton

    spl-norepinephrine-carton1
  • INGREDIENTS AND APPEARANCE
    NOREPINEPHRINE BITARTRATE 
    norepinephrine bitartrate injection, solution, concentrate
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 47335-615
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    NOREPINEPHRINE BITARTRATE (UNII: IFY5PE3ZRW) (NOREPINEPHRINE - UNII:X4W3ENH1CV) NOREPINEPHRINE1 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM CHLORIDE (UNII: 451W47IQ8X)  
    SODIUM METABISULFITE (UNII: 4VON5FNS3C)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 47335-615-4410 in 1 CARTON07/01/2021
    14 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21198007/01/2021
    Labeler - Sun Pharmaceutical Industries, Inc. (146974886)
    Establishment
    NameAddressID/FEIBusiness Operations
    Gland Pharma Limited858971074ANALYSIS(47335-615) , MANUFACTURE(47335-615) , PACK(47335-615)
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