Levophed™ 1:1000

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Noradrenaline acid tartrate monohydrate 2 mg/mL equivalent to Noradrenaline base 1 mg/mL
Available from:
Pfizer New Zealand Limited
INN (International Name):
Noradrenaline acid tartrate monohydrate 2 mg/mL (equivalent to Noradrenaline base 1 mg/mL)
Dosage:
1 mg/mL
Pharmaceutical form:
Concentrate for injection
Composition:
Active: Noradrenaline acid tartrate monohydrate 2 mg/mL equivalent to Noradrenaline base 1 mg/mL Excipient: Sodium chloride Sodium metabisulfite Water for injection
Prescription type:
Prescription
Manufactured by:
Cambrex Profarmaco Milano Srl
Therapeutic indications:
For the restoration of blood pressure in certain acute hypotensive states (e.g. phaeochromocytomectomy, sympathectomy, poliomyelitis, spinal anaesthesia, myocardial infarction, septicaemia, blood transfusions and drug reactions). As an adjunct in the treatment of cardiac arrest. To restore and maintain an adequate blood pressure after an effective heartbeat and ventilation have been established by other means.
Product summary:
Package - Contents - Shelf Life: Vial, glass, Type 1 amber glass with rubber stopper & aluminium seal 4mL - 10 dose units - 18 months from date of manufacture stored at or below 25°C protect from light. Do not freeze.
Authorization number:
TT50-5603a
Authorization date:
2013-12-04

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NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

LEVOPHED

1:1000 Concentrate for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ampoule contains noradrenaline 2 mg in 2 mL (1:1000), present as 4 mg of noradrenaline

acid tartrate in 2 mL.

Each vial contains noradrenaline 4 mg in 4 mL (1:1000), present as 8 mg of noradrenaline acid

tartrate in 4 mL.

Excipient(s) with known effects:

Sodium metabisulfite

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

LEVOPHED

1:1000 is a sterile colourless (or practically colourless), concentrated solution for

injection. It has a pH of 3.0 to 4.5.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

restoration

blood

pressure

certain

acute

hypotensive

states

(e.g.

phaeochromocytomectomy,

sympathectomy,

poliomyelitis,

spinal

anaesthesia,

myocardial

infarction, septicaemia, blood transfusion, and drug reactions).

As an adjunct in the treatment of cardiac arrest. To restore and maintain an adequate blood

pressure after an effective heartbeat and ventilation have been established by other means.

4.2 Dose and method of administration

LEVOPHED

1:1000 contains noradrenaline as the acid tartrate. It is a concentrated, potent

injection which must be diluted in dextrose containing solutions prior to infusion. An infusion of

noradrenaline should be given into a large vein (see Section 4.4).

LEVOPHED

1:1000 contains no antimicrobial preservative. It is for single use in one patient

only. Discard any residue.

Parenteral drug products should be inspected visually for particulate matter and discolouration

prior to use, whenever solution and container permit.

Discoloured solutions or those containing a precipitate should not be used.

Avoid contact with iron salts, alkalis, or oxidising agents.

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Restoration of Blood Pressure in Acute Hypotensive States

Blood volume depletion should always be corrected as fully as possible before any vasopressor

is administered. When, as an emergency measure, intra-aortic pressures must be maintained to

prevent cerebral or coronary artery ischaemia, noradrenaline can be administered before and

concurrently with blood volume replacement.

Diluent

LEVOPHED

1:1000 should be diluted in five percent (5%) dextrose injection or five percent

(5%)

dextrose

sodium

chloride

injections.

These

dextrose

containing

fluids

provide

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 a Y-tube and individual containers if given

simultaneously).

Average Dosage

Ampoules: Add two, 2 mL ampoules (4mL) of LEVOPHED

1:1000 (4 mg of noradrenaline)

to 1,000 mL of a 5% dextrose containing solution

Vials: Add one, 4 mL vial of LEVOPHED

1:1000 (4 mg of noradrenaline) to 1,000 mL of a

5% dextrose containing solution

Each 1 mL of this dilution contains 4 micrograms of the base of noradrenaline (or 8 micrograms

of the acid tartrate). Give this solution by intravenous infusion. Insert a plastic intravenous

catheter through a suitable bore needle well advanced centrally into the vein and securely fixed

with adhesive tape, avoiding, if possible, a catheter tie-in technique as this promotes stasis. An

I.V. 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 2 mL to 3 mL (from 8 micrograms to 12

micrograms of base) per minute, adjust the rate of flow to establish and maintain a low normal

blood pressure (usually 80 mmHg to 100 mmHg 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 mmHg below the pre-existing systolic pressure. The average

maintenance dose ranges from 0.5 mL to 1 mL per minute (from 2 micrograms to 4 micrograms

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 noradrenaline 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 34

ampoules) 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 a flow rate that would involve an excessive dose of the pressor agent per

unit of time, a solution more dilute than 4 micrograms per mL should be used. On the other hand,

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when large volumes of fluid are clinically undesirable, a concentration greater than 4 micrograms

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 noradrenaline 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 Arrest

Infusions of noradrenaline 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. [Noradrenaline's 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, noradrenaline is

used in the same manner as described under Restoration of Blood Pressure in Acute Hypotensive

States.

Use in the elderly

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 therapy.

Noradrenaline infusions should not be administered into the veins in the leg in elderly patients

(see Section 4.4, Site of Infusion).

Paediatric population

Safety and effectiveness in paediatric patients has not been established.

4.3 Contraindications

Noradrenaline 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 noradrenaline 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.

Noradrenaline should also not be given to patients with mesenteric or peripheral vascular

thrombosis (because of the risk of increasing ischaemia and extending the area of infarction)

unless, in the opinion of the attending physician, the administration of noradrenaline is necessary

as a life-saving procedure.

Cyclopropane and halothane anaesthetics increase cardiac autonomic irritability and therefore

seem to sensitise the myocardium to the action of intravenously administered adrenaline or

noradrenaline. Hence, the use of noradrenaline during cyclopropane and halothane anaesthesia is

generally considered contraindicated because of the risk of producing ventricular tachycardia or

fibrillation.

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The same type of cardiac arrhythmias may result from the use of noradrenaline in patients with

profound hypoxia or hypercarbia.

Hypersensitivity to noradrenaline or any of the excipients.

4.4

Special warnings and precautions for use

Warnings

LEVOPHED

1:1000 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

1:1000 contains sodium metabisulphite, which may cause allergic-type reactions

including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain

susceptible people. The overall prevalence of sulphite sensitivity in the general population is

unknown and probably low. Sulphite sensitivity is seen more frequently in asthmatic than non-

asthmatic people.

Precautions

General

Avoid Hypertension

Because of the potency of noradrenaline 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 noradrenaline. Headache may be a symptom of hypertension due to overdosage.

Similar caution should be observed in patients with hypotension following myocardial infarction,

in patients with Prinzmetal’s variant angina, and in patients with diabetes, hypertension or

hyperthyroidism.

Noradrenaline should only be administered by healthcare professionals who are familiar with its

use.

Hypersensitivity

Certain patients may be hypersensitive to the effects of LEVOPHED

1:1000, e.g. patients with

hyperthyroidism (see Section 4.8).

Site of Infusion

Whenever possible, infusions of noradrenaline should be given into a 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. A 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 noradrenaline. Occlusive vascular diseases (for example,

atherosclerosis, arteriosclerosis, diabetic endarteritis, Buerger's 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 a lower

extremity when infusions of noradrenaline were given in an ankle vein.

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Extravasation

The infusion site should be checked frequently for free flow. Care should be taken to avoid

extravasation

noradrenaline

into

tissues,

local

necrosis

might

ensue

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 changing the infusion site at intervals to allow the effects of local vasoconstriction to

subside.

IMPORTANT -- Antidote for Extravasation Ischaemia

The antidote for extravasation ischaemia is phentolamine. 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 5 mg to 10 mg of phentolamine, an

adrenergic blocking agent. A syringe with a fine hypodermic needle should be used, with the

solution being infiltrated liberally throughout the area, which is easily identified by its cold, hard,

pallid

appearance.

Sympathetic

blockade

with

phentolamine

causes

immediate

conspicuous local hyperaemic changes if the area is infiltrated within 12 hours. Therefore,

phentolamine should be given as soon as possible after the extravasation is noted.

Paediatric population

Safety and effectiveness in paediatric patients has not been established.

Use in the elderly

Clinical studies of noradrenaline did not include sufficient numbers of subjects aged 65 and over

to determine whether they respond differently from younger subjects. In general, dose selection

for an elderly patient should be cautious, usually starting at the low end of the dosing range,

reflecting

greater

frequency

decreased

hepatic,

renal,

cardiac

function,

concomitant disease or other therapy.

Noradrenaline infusions should not be administered into the veins in the leg in elderly patients

(see Section 4.4, Site of Infusion).

4.5 Interaction with other medicines and other forms of interaction

Cyclopropane and halothane anaesthetics increase cardiac autonomic irritability and therefore

seem to sensitise the myocardium to the action of intravenously administered adrenaline or

noradrenaline. Hence, the use of noradrenaline during cyclopropane and halothane anaesthesia 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 noradrenaline in

patients with profound hypoxia or hypercarbia.

Noradrenaline should be used with extreme caution in patients receiving monoamine oxidase

inhibitors (MAOI) or tricyclic antidepressants of the triptyline or imipramine types, because

severe, prolonged hypertension may result. Linezolid, adrenergic-serotoninergic drugs, or any

other cardiac sensitizing agents are not recommended as severe prolonged hypertension and

possible arrhythmias may result.

Guanethidine

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The effects of noradrenaline may be enhanced by guanethidine.

4.6 Fertility, pregnancy and lactation

Fertility

Studies have not been performed.

Pregnancy

Category B3

LEVOPHED

1:1000 should be given to a pregnant woman only if clearly needed.

Animal

studies

indicate

noradrenaline

impair

placental

perfusion

induce

foetal

bradycardia. It may also exert a contractile effect on the pregnant uterus and lead to foetal

asphyxia in late pregnancy. However, the clinical significance of these changes to a human

foetus is unknown. These possible risks to the foetus should therefore be weighed against the

potential benefit to the mother.

Lactation

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 noradrenaline is administered to a nursing

woman.

4.7 Effects on ability to drive and use machinery

The effects of this medicine on a person’s ability to drive and use machines were not assessed as

part of its registration.

4.8 Undesirable effects

The following reactions can occur:

Body as a Whole

Ischaemic injury due to potent vasoconstrictor action and tissue hypoxia.

Cardiovascular System

Bradycardia, probably as a reflex of a rise in blood pressure, cardiogenic shock, arrhythmias and

stress cardiomyopathy.

Peripheral ischaemia, gangrene, hypertension, plasma depletion

Nervous System

Anxiety, transient headache.

Respiratory System

Respiratory difficulty, dyspnoea.

Skin and Appendages

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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 noradrenaline is discontinued,

blood

pressure

maintained

risk

severe

peripheral

visceral

vasoconstriction (e.g. decreased renal perfusion) with diminution in blood flow and tissue

perfusion with subsequent tissue hypoxia and lactic acidosis and possible ischaemic injury.

Gangrene of extremities has been rarely reported. Bradycardia sometimes occurs, probably as a

reflex result of a rise in blood pressure.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are

asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

Overdosage with noradrenaline may result in headache, severe hypertension, reflex bradycardia,

marked increase in peripheral resistance, and decreased cardiac output. Headache may indicate

severe hypertension.. Pulmonary oedema, photophobia, retrosternal pain, pallor, intense sweating

and vomiting may occur. In the event of overdose, treatment with noradrenaline should be

withdrawn and appropriate corrective measures initiated.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Noradrenaline

(sometimes

referred

norepinephrine

l-arterenol/levarterenol),

sympathomimetic amine which differs from adrenaline by the absence of a methyl group on the

nitrogen atom.

Noradrenaline functions as a peripheral vasoconstrictor (alpha-adrenergic action) and as an

inotropic stimulator of the heart and dilator of coronary arteries (beta-adrenergic action).

These actions result in an increase in systemic blood pressure and coronary artery blood flow. In

myocardial infarction accompanied by hypertension, LEVOPHED

1:1000 usually increases

aortic blood pressure, coronary artery blood flow, and myocardial oxygenation, thereby helping

to limit the area of myocardial ischaemia and infarction. Venous return is increased and the heart

tends to resume a more normal rate and rhythm than in the hypotensive state. In hypotension that

persists after correction of blood volume deficits, LEVOPHED

1:1000 helps raise the blood

pressure to an optimal level and establish a more adequate circulation.

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5.2 Pharmacokinetic properties

Absorption

Orally ingested noradrenaline is destroyed in the GI tract, and the drug is poorly absorbed after

subcutaneous injection. After IV administration, a pressor response occurs rapidly. The drug has

a short duration of action, and the pressor action stops within 1-2 minutes after the infusion is

discontinued.

Distribution

Noradrenaline localises mainly in sympathetic nervous tissue. The drug crosses the placenta but

not the blood-brain barrier.

Biotransformation

The pharmacologic actions of noradrenaline are terminated primarily by uptake and metabolism

in sympathetic nerve endings. The drug is metabolised in the liver and other tissues by a

combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and

monoamine oxidase (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-mthoxy-4-hydroxyphenylglycol, 3,4-dihydroxymandelic acid, and 3,4-

dihydroxyphenylglycol.

Elimination

Noradrenaline metabolites are excreted in urine primarily as the sulfate conjuges and, to a lesser

extent, as the glucuronide conjugates. Only small quantities of noradrenaline are excreted

unchanged.

5.3 Preclinical safety data

Genotoxicity

Studies have not been performed.

Carcinogenicity

Studies have not been performed.

6.

PHARMACEUTICAL PARTICUALRS

6.1 List of excipients

Sodium metabisulfite

Sodium chloride

Water for injections

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6.2 Incompatibilities

LEVOPHED

1:1000 infusion solutions should not be mixed with other medicines. Infusion

solutions containing noradrenaline acid tartrate have been reported to be incompatible with iron

salts, alkalis and oxidising agents, barbituates, chlorpheniramine, chlorothiazide, nitrofurantoin,

phenytoin, sodium bicarbonate, sodium iodide, streptomycin, sulfadiazine and sulfafurazole.

6.3 Shelf life

Vials - 18 months

Ampoules – 24 months

6.4

Special precautions for storage

Store below 25°C. Do not freeze. Protect from light.

Keep out of reach of children.

6.5 Nature and contents of container

LEVOPHED

1:1000 is available as a single use glass ampoule, 2 mg/2 mL and single use

glass vial (4 mg/4 mL). It is supplied in packs of 5 ampoules per carton or packs of 10 vials per

carton.

Each ampoule contains the equivalent of 2 mg of noradrenaline, as the acid tartrate.

Each vial contains the equivalent of 4 mg of noradrenaline, as the acid tartrate.

6.6 Special precautions for disposal

Any unused medicine

or waste material should be disposed of in accordance with local

requirements.

7.

MEDICINE SCHEDULE

Prescription Medicine

8.

SPONSOR

Pfizer New Zealand Limited,

PO Box 3998

Auckland, New Zealand, 1140

Toll Free Number: 0800 736 363

9.

DATE OF FIRST APPROVAL

Vials - 18 September 2014

Ampoules – 31 December 1969

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10. DATE OF REVISION OF THE TEXT

22 July 2020

Summary table of changes

Section changed

Summary of new information

Throughout

Minor text changes to correct grammar and spelling

Additional contraindication added

Addition of preacution information:

General

Addition of further interactions

Undesirable effects updated to include additional

Examples of signs of overdose updated

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