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 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 may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output.

In case of overdosage, discontinue norepinephrine 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 is (-)-α-(aminomethyl)-3,4-dihydroxybenzyl alcohol tartrate (1:1) (salt) monohydrate (molecular weight 337.28 g/mol) and has the following structural formula:

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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 bitartrate, USP is freely soluble in water, slightly soluble in alcohol and practically insoluble in chloroform and 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 pH of 3.0 to 4.5. The air in the containers 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, colorless or practically colorless to slightly yellow color 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 70121-1576-7

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° 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)].

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.amneal.com.

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd.

Parenteral Unit

Ahmedabad 382213, INDIA

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 08-2020-01

PRINCIPAL DISPLAY PANEL

NDC 70121-1576-1
Norepinephrine bitartrate injection, USP
4 mg/4 mL (1 mg/mL)
Rx only
Vial Label
Amneal Pharmaceuticals LLC

1
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NDC 70121-1576-7
Norepinephrine bitartrate injection, USP
4 mg/4 mL (1 mg/mL)
Rx only
Carton Label (10 vials in carton)
Amneal Pharmaceuticals LLC

1
(click image for full-size original)

NOREPINEPHRINE BITARTRATE
norepinephrine bitartrate injection, solution, concentrate
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70121-1576
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:70121-1576-7 10 VIAL in 1 CARTON contains a VIAL (70121-1576-1)
1 NDC:70121-1576-1 4 mL in 1 VIAL This package is contained within the CARTON (70121-1576-7)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA210839 12/17/2018
Labeler — Amneal Pharmaceuticals LLC (827748190)

Revised: 08/2020 Amneal Pharmaceuticals LLC

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