NOREPINEPHRINE BITARTRATE (Page 2 of 2)

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
(click image for full-size original)

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
(click image for full-size original)

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
(click image for full-size original)
spl-norepinephrine-carton1
(click image for full-size original)
NOREPINEPHRINE BITARTRATE norepinephrine bitartrate injection, solution, concentrate
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:47335-615
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
NOREPINEPHRINE BITARTRATE (NOREPINEPHRINE) NOREPINEPHRINE 1 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
SODIUM CHLORIDE
SODIUM METABISULFITE
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:47335-615-44 10 VIAL, SINGLE-DOSE in 1 CARTON contains a VIAL, SINGLE-DOSE
1 4 mL in 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (47335-615-44)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA211980 07/01/2021
Labeler — Sun Pharmaceutical Industries, Inc. (146974886)
Establishment
Name Address ID/FEI Operations
Gland Pharma Limited 858971074 ANALYSIS (47335-615), MANUFACTURE (47335-615), PACK (47335-615)

Revised: 07/2021 Sun Pharmaceutical Industries, Inc.

Page 2 of 2 1 2

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2021. All Rights Reserved.