NORADRENALINE (NOREPINEPHRINE) 1 MG / ML CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance: NORADRENALINE TARTRATE

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Noradrenaline
(norepinephrine)
1 mg/ml, concentrate for
solution for infusion

000000 MM/AA

PACKAGE LEAFLET:
INFORMATION FOR THE USER

Noradrenaline (Norepinephrine) 1 mg/ml
concentrate for solution for infusion
Read all of this leaflet carefully before you start using this medicine.
• Keep this leaflet. You may need to read it again.
• If you have further questions, please ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as
yours.
• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

The name of this medicinal product is NORADRENALINE (NOREPINEPHRINE) 1 mg/ml Concentrate for solution for infusion, but will be
referred as Noradrenaline (Norepinephrine) Concentrate throughout the whole leaflet.
In this leaflet
1. What Noradrenaline (Norepinephrine) Concentrate is and what it is used for
2. Before you are given Noradrenaline (Norepinephrine) Concentrate
3. How you are given Noradrenaline (Norepinephrine) Concentrate
4. Possible side effects
5. How to store Noradrenaline (Norepinephrine) Concentrate
6. Further information

1. WHAT NORADRENALINE (NOREPINEPHRINE) CONCENTRATE IS AND WHAT IT IS USED FOR

Noradrenaline (Norepinephrine) Concentrate is a drug that belongs to the group of adrenergic and dopaminergic agent.
Noradrenaline (Norepinephrine) Concentrate is indicated for the emergency restoration of blood pressure in cases of acute hypotension.

2. BEFORE YOU ARE GIVEN NORADRENALINE (NOREPINEPHRINE) CONCENTRATE
Do not use Noradrenaline (Norepinephrine) Concentrate:
• if you are hypersensitive to noradrenaline or to any of the excipients ;
• if you are hypotensive (have low blood pressure) that has been caused by hypovolaemia (low blood volume) ;
• if you are taking some anaesthetics such as halothane or cyclopropane (this may increase the risk of irregular heart beat).
Take special care with Noradrenaline (Norepinephrine) Concentrate (and inform your doctor):
• if you have extravasation risk ;
• if you have major left ventricular dysfunction (a heart condition) ;
• if you have coronary, mesenteric or peripheral vascular thrombosis ;
• if you have hypotension following myocardial infarction ;
• if you have Prinzmetal’s variant angina ;
• if you have heart rhythm disorders during your treatment – you will need a reduced dose ;
• if you have hyperthyroidism or diabetes mellitus ;
• if you are elderly.
Your blood pressure and heart rate will be checked frequently during your treatment to avoid hypertension.
Taking other medicines
Tell your doctor or pharmacist if you are taking, or have recently taken, any other medicines, including medicines obtained without a
prescription as they may interact with Noradrenaline (Norepinephrine) Concentrate. This is especially important of the following medicines:
• Halothane, cyclopropane: these medicines are anaesthetics, they cause insensibility to pain and are used before some operations. If you are
taking these medicines as well as Noradrenaline this may increase the risk of irregular heart beat.
• Amitriptiline, Imipramine, Trimipramine, Moclobemide, Iproniazide, Phenelzine, Fluoxetine, Sertraline: these medicines are used for
treatment of depression. Taking any of these medicines together with Noradrenaline can dangerously increase its concentration in the blood
and therefore its pressor action.
• Linezolid, an antibiotic (drug used to treat infections caused by bacteria and other microorganisms), can dangerously increase
Noradrenaline concentration in the blood and therefore its pressor action, when taken together.
• Alpha and beta-blockers: if you are taking these medicines as well as Noradrenaline this may increase the risk of severe hypertension.
• Thyroid hormones, Cardiac glycosides, Anti-arrhythmics: if you are taking these medicines as well as Noradrenaline this may cause
increased cardiac effects.
• Ergot alkaloids or oxytocin may enhance the vasopressor and vasoconstrictive effects.
Pregnancy and breast-feeding
Please tell your doctor if you are pregnant, think you may be pregnant or are breast-feeding and your doctor will decide if Noradrenaline is
appropriate for you. Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Since Noradrenaline will be given to you in a hospital, your doctor will inform you when you will be able to drive or use machines.

Important information about some of the ingredients of Noradrenaline (Norepinephrine) Concentrate:
This product contains 13.2 mg of sodium per one 4 ml ampoule.
This product contains 26.4 mg of sodium per one 8 ml ampoule.
Please tell your doctor if you are on a low sodium diet.

3. HOW YOU ARE GIVEN NORADRENALINE (NOREPINEPHRINE) CONCENTRATE
Noradrenaline (Norepinephrine) Concentrate will be given to you in a hospital by a doctor or nurse.

Dosage
The dose of Noradrenaline depends on the condition of the patient. Your doctor will know the best dose to use. Noradrenaline is first diluted
and then usually infused into a vein. The dose can then be adjusted using a pump according to the response to treatment, with the aim to
establish a normal blood pressure. The initial dose is 0.4 to 0.8 milligrams per hour of Noradrenaline (Norepinephrine) base.
If you have any questions on the use of this product, ask your doctor.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Noradrenaline (Norepinephrine) Concentrate can cause side effects, although not everybody gets them.
The following side effects have been reported:
• skin necrosis (death) if the infusion is not given directly into the vein,
• anxiety, insomnia, confusion, headaches, psychotic state, weakness, tremor, lower vigilance, anorexia, nauseas, vomiting,
• difficulty in breathing, fast or slow heart rate, pain in the chest or throat,
• retention of urine,
• pallor (loss of skin colour), sweating, sensitivity to light.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE NORADRENALINE (NOREPINEPHRINE) CONCENTRATE
Dot not store above 25°C. Store in the original package to protect from light.

After dilution:
The physicochemical stability of diluted product (in 5% dextrose or in an isotonic dextrose saline) has been demonstrated for 48 hours at
25°C.
However, from a microbiological point of view, the diluted product should be used immediately. If the product is not used immediately, the
duration and conditions of use are the sole responsibility of the user.
Do not use if you notice any type of coloration.

6. FURTHER INFORMATION
What Noradrenaline (Norepinephrine) Concentrate contains
The active substance is Noradrenaline tartrate 2 mg, equivalent to Noradrenaline base 1 mg.
The other ingredients are: sodium chloride, sodium hydroxide or hydrochloric acid and water for injections.
What Noradrenaline (Norepinephrine) Concentrate looks like and contents of the pack
Clear and colourless liquid of pH 3 to 4.0 packaged in a clear glass ampoule of 4 ml or 8 ml.
Each ml of concentrate for solution for infusion contains 2 mg Noradrenaline tartrate equivalent to 1 mg Noradrenaline base.
Each 4 ml ampoule contains 8 mg Noradrenaline tartrate equivalent to 4 mg Noradrenaline base.
Each 8 ml ampoule contains 16 mg Noradrenaline tartrate equivalent to 8 mg Noradrenaline base.
Boxes of 10, 50 or 100 ampoules.
Marketing Authorisation Holder - Manufacturer
Laboratoire AGUETTANT
1, rue Alexander Fleming
69007 LYON
France
Manufacturer
DELPHARM Tours
Rue Paul Langevin
37 170 CHAMBRAY-LÈS-TOURS
France
Distributed by:
AGUETTANT LTD
N°1, Farleigh House - Flax Bourton
BRISTOL - BS48 1UR - United Kingdom
This medicinal product is authorised in the Member States of the EEA under the following names:
Belgium: Noradrenaline (norepinephrine) Aguettant 1 mg/ml solution à diluer pour perfusion
United Kingdom: Noradrenaline (norepinephrine) 1 mg/ml concentrate for solution for infusion
This leaflet was last revised in September 2013.

THE FOLLOWING INFORMATION IS INTENDED
FOR MEDICAL OR HEALTHCARE PROFESSIONAL ONLY

1. NAME OF THE MEDICINAL PRODUCT

NORADRENALINE ( NOREPINEPHRINE) 1 mg / ml
Concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of concentrate for solution for infusion contains 2 mg Noradrenaline
tartrate, equivalent to 1 mg Noradrenaline base.
Each 4ml ampoule contains 8 mg Noradrenaline tartrate equivalent to 4 mg
Noradrenaline base.
Each 8ml ampoule contains 16 mg Noradrenaline tartrate equivalent to 8 mg
Noradrenaline base.
This medicinal product contains sodium.
Each ml of concentrate for solution for infusion contains 3.3 mg equivalent to
0.14 mmol of sodium
Each 4ml ampoule contains 13.2 mg equivalent to 0.57 mmol of sodium.
Each 8ml ampoule contains 26.4 mg equivalent to 1.14 mmol of sodium.
To be taken into consideration by patients on a controlled sodium diet.
For full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear, colourless liquid.
pH = 3.0 to 4.0

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Noradrenaline is indicated for the emergency restoration of blood pressure in
cases of acute hypotension.
4.2 Posology and method of administration
Posology
Adults:
Initial rate of infusion: The initial rate of infusion should be between 10 ml/hour
and 20 ml/hour (0.16 ml/min to 0.33 ml/min). This is equivalent to 0.8 mg/hr to
1.6 mg/hr noradrenaline tartrate (or 0.4 mg/hr to 0.8 mg/hr noradrenaline base).
Titration of dose: Once an infusion of noradrenaline has been established
the dose should be titrated according to the pressor effect observed. There
is great individual variation in the dose required to attain and maintain
normotension. The aim should be to establish a low normal systolic
blood pressure (100-120 mm Hg) or to achieve an adequate mean arterial
blood pressure (greater than 65 to 80 mm Hg – depending on the patient’s
condition).
Noradrenaline tartrate Infusion
solution at 80 mg/L
Patient’s
Weight
60 kg

Posology (µg/kg/min)
Tartrate

Posology (mg/h)
Tartrate

Infusion rate (ml/h)

0.2
0.5
1
2

0.72
1.8
3.6
7.2

9
22.5
45
90

70 kg

0.2

0.84

10.75

0.5
1
2

2.1
4.2
8.4

26.25
52.5
105

0.2

0.96

12

0.5
1

2.4
4.8

30
60

2

9.6

120

80 kg

h: hour
If other dilutions are used check the calculation carefully before starting
treatment.
Duration of Treatment and Monitoring: Noradrenaline should be continued
for as long as vasoactive drug support is indicated. The patient should be
monitored carefully for the duration of noradrenaline therapy.
The infusion must not be stopped suddenly but should be gradually withdrawn
to avoid disastrous falls in blood pressure.
Elderly: As for adults but see Precautions.
Children: Not recommended.
Method of administration
For intravenous use only.
Noradrenaline should be administered through central venous devices to
minimize the risk of extravasation and subsequent tissue necrosis.
Noradrenaline 1 mg/ml concentrate should be diluted prior to intravenous
infusion, either with dextrose 5%, or with isotonic dextrose saline. It should
not be mixed with other medicines.

The final concentration of the infusion solution should be 80 mg/litre
noradrenaline tartrate, which is equivalent to 40 mg/litre noradrenaline base. If
other dilutions are used, check the calculation carefully before starting treatment.
Dilution instructions: Either add 2 ml of Noradrenaline 1 mg/ml to 48 ml 5%
dextrose (or isotonic dextrose saline) for administration by syringe pump,
or add 20 ml of Noradrenaline 1 mg/ml to 480 ml 5% dextrose (or isotonic
dextrose saline) for administration by drip counter.
In the both cases the final concentration of the infusion solution is 80 mg/litre
noradrenaline tartrate, which is equivalent to 40 mg/litre noradrenaline base. If
other dilutions are used check the calculation carefully before starting treatment.
Blood pressure control: Measure blood pressure every two minutes at the
beginning of the infusion until the desired blood pressure is obtained. Then every
five minutes when desired the blood pressure is obtained, if the administration has
to be continued. The infusion should be at a control rate and the patient should be
monitored carefully for the duration of noradrenaline (norepinephrine) therapy.
4.3 Contraindications
Use of Noradrenaline 1 mg/ml concentrate for solution for infusion is
contraindicated in patients with known hypersensitivity to noradrenaline or to
any of the excipients.
Hypotension due to blood volume deficit (Hypovolaemia).
The use of pressor amines during cyclopropane or halothane anaesthesia may
cause serious cardiac arrhythmias. Because of the possibility of increasing the
risk of ventricular fibrillation, norepinephrine should be used with caution in
patients receiving these or any other cardiac sensitising agent or who exhibit
profound hypoxia or hypercarbia.
4.4 Special warnings and precautions for use
Warning:
• Noradrenaline should be used only in conjunction with appropriate blood
volume replacement
• When infusing noradrenaline, the blood pressure and rate of flow should be
checked frequently to avoid hypertension.
• The products administrated by injection must always be visually inspected
and cannot be used if the presence of particles or a change of colouring is
noted.
• Extravasation risk:
The infusion site should be checked frequently for free flow. Care should
be taken to avoid extravasation that would cause a necrosis of the tissues
surrounding the vein used for the injection. Because of the vasoconstriction
of the vein wall with increased permeability, there might be some leakage
of noradrenaline in the tissues surrounding the infused vein causing a
blanching of the tissues which is not due to an obvious extravasation. Hence
if blanching occurs, consideration should be given to changing the infusion
site to allow the effects of local vasoconstriction to subside.
Treatment of the ischemia due to extravasation :
During an extravascular leak of the product or an injection besides the vein,
a tissue destruction can appear resulting from the vasoconstrictive action of
the drug on the blood vessels. The injection zone must be then irrigated as
quickly as possible with 10 to 15ml of physiological salt solution containing
5 to 10 mg of phentolamine mesilate. For this purpose, it is necessary to use
a syringe provided with a fine needle and to inject locally.
Precautions for use:
Caution and respect of the strict indication must be retained in case of:
• major left ventricular dysfunction associated with acute hypotension,
a careful evaluation of patient’s blood pressure is needed. Supportive
therapy should be initiated simultaneously with diagnostic evaluation.
Noradrenaline should be reserved for patients with cardiogenic shock
and refractory hypotension, in particular those without elevated systemic
vascular resistance. It should be started at a dosage of 2 to 4 µg/min and
titrated upwards and titrated as necessary. If systemic perfusion or systolic
pressure cannot be maintained at > 90 mmHg with a dosage of 15 µg/min, it
is unlikely that a further increase will be beneficial.
• Particular caution should be observed in patients with coronary, mesenteric
or peripheral vascular thrombosis because noradrenaline may increase
the ischaemia and extend the area of infarction. Similar caution should be
observed in patients with hypotension following myocardial infarction and
in patients with Prinzmetal’s variant angina.
• Occurrence of heart rhythm disorders during the treatment must lead to a
reduction in the dosage.
• Caution is advised in patients with hyperthyroidism or diabetes mellitus.
• The elderly may be especially sensitive to the effects of noradrenaline.
This medicinal product contains sodium.
To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of
interaction
Inadvisable combinations
+ Volatile halogen anaesthetics: severe ventricular arrhythmia (increase in
cardiac excitability).
+ Imipramine antidepressants: paroxysmal hypertension with the possibility
of arrhythmia (inhibition of the entry of sympathomimetics into sympathetic
fibers).
+ Serotoninergic-adrenergic antidepressants: paroxysmal hypertension with
the possibility of arrhythmia (inhibition of the entry of sympathomimetics
into sympathetic fibers).

Combinations requiring precautions for use
+ Non-selective MAO inhibitors: increase in the pressor action of the
sympathomimetic which is usually moderate. Should only be used under
close medical supervision.
+ Selective MAO-A inhibitors: by extrapolation from non-selective MAO
inhibitors, risk of increase in the pressor action. Should only be used under
close medical supervision.
+ Linezolid: by extrapolation from non-selective MAO inhibitors: risk of
increase in the pressor action. Should only be used under close medical
supervision.
Caution is required when using Noradrenaline with alpha and beta blockers as
severe hypertension may result.
Caution is required when using Noradrenaline with the following drugs as they
may cause increased cardiac effects : Thyroid hormones, Cardiac glycosides,
Anti-arrhythmics.
Ergot alkaloids or oxytocin may enhance the vasopressor and vasoconstrictive
effects.
4.6 Fertility, pregnancy and lactation
Pregnancy
Noradrenaline may impair placental perfusion and induce fetal bradycardia.
It may also exert a contractile effect on the pregnant uterus and lead to fetal
asphyxia in late pregnancy.
These possible risks to the fetus should therefore be weighed against the
potential benefit to the mother.
Breastfeeding
No information is available on the use of noradrenaline in lactation.
4.7 Effects on ability to drive and use machines
Not applicable.
4.8 Undesirable effects
- Vascular system: arterial hypertension and tissue hypoxia; ischemic injury
due to potent vasoconstrictor action may result in coldness and paleness of
the members and the face.
- Cardiac system: tachycardia, bradycardia (probably as a reflex result of blood
pressure rising), arrhythmias, palpitations, increase in the contractility of the
cardiac muscle resulting from the ß adrenergic effect on the heart (inotrope
and chronotrope), acute cardiac insufficiency.
- Central nervous system: anxiety, insomnia, confusion, headaches, psychotic
state, weakness, tremor, lower vigilance, anorexia, nauseas and vomiting.
- Urinary system: retention of urine.
- Respiratory system: respiratory insufficiency or difficulty, dyspnoea.
- Locally: possibility of irritation and necrosis at the injection site.
- Eyes: acute glaucoma; very frequent in patients anatomically predisposed
with the closing of the iridocorn angle.
The continuous administration of vasopressor to maintain blood pressure in
absence of blood volume replacement may cause the following symptoms:
- severe peripheral and visceral vasoconstriction
- decrease in renal blood flow
- decrease in urine production
- hypoxia
- increase in lactate serum levels.
In case of hypersensitivity or overdose, the following effects may appear more
frequently : hypertension, photophobia, retrosternal pain, pharyngeal pain,
pallor, intense sweating and vomiting.
The vasopressor effect (resulting from the adrenergic action on the vessels)
can be reduced by the concomitant administration of an α-blocking agent
(phentolamine mesilate) whereas the administration of a ß-blocking agent
(propranolol) may result in a reduction of the stimulating effect of the product
on the heart and in an increase of the hypertensor effect (through reduction of
arteriolar dilatation), resulting from ß1 adrenergic stimulation.
Prolonged administration of any potent vasopressor may result in plasma
volume depletion which should be continuously corrected by appropriate water
and electrolyte replacement therapy. If plasma volumes are not corrected,
hypotension may recur when the noradrenaline infusion is discontinued,
or blood pressure may be maintained with the risk of severe peripheral and
visceral vasoconstriction with diminution in blood flow.
4.9 Overdose
In the event of overdose, the following may be observed: cutaneous
vasoconstriction, bed sores, circulatory collapse, hypertension.
In the event of adverse reactions linked to an excessive dosage, it is
recommended to reduce the dosage if possible.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Adrenergic and Dopaminergic Agent
ATC Code: C01CA03 (C: Cardiovascular system)
Noradrenaline has a very potent action on alpha receptors and a more moderate
effect on beta-1 receptors. NORADRENALINE (NOREPINEPHRINE)
1 mg/ml causes generalised vasoconstriction, except for the coronary vessels
which it dilates indirectly by increasing the oxygen consumption. This results
in an increase in the force (and in the absence of vagal inhibition) in the rate
of myocardial contraction. Peripheral resistance increases and diastolic and

systolic pressures are raised.
5.2 Pharmacokinetic properties
Two stereoisomers of Noradrenaline exist, the biologically active L-isomer is
the one present in Noradrenaline (Norepinephrine) 1mg/ml Concentrate for
solution for infusion.
Absorption
• Subcutaneous: Poor
• Oral: Noradrenaline is rapidly inactivated in the gastro-intestinal tract
following oral administration.
• After intravenous administration Noradrenaline has a plasmatic half-life of
about 1 to 2 minutes.
Distribution
• Noradrenaline is rapidly cleared from plasma by a combination of cellular
reuptake and metabolism. It does not readily cross the blood-brain barrier.
Biotransformation
• Methylation by catechol-o-methyltransferase
• Deamination by manoamine oxydase (MAO)
• Ultimate metabolites from both is 4- hydroxy-3-methoxymandelic acid
• Intermediate metabolites include normetanephrine and 3,4dihydroxymandelic acid.
Elimination
• Noradrenaline is mainly eliminated as glucuronide or sulphate conjugates of
the metabolites in the urine.
5.3 Preclinical safety data
Most of the adverse effects attributable to sympathomimetics result from
excessive stimulation of the sympathetic nervous system via the different
adrenergic receptors.
Noradrenaline may impair placental perfusion and induce fetal bradycardia.
It may also exert a contractile effect on the pregnant uterus and lead to fetal
asphyxia in late pregnancy.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Sodium chloride, hydrochloric acid or sodium hydroxide (qs pH 3.0 to 4.0)
and water for injections
6.2 Incompatibilities
This medicine must not be mixed with other medicinal products except those
mentioned in the section 6.6.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package to protect from light.
After dilution: The physicochemical stability of diluted product (in 5%
dextrose or isotonic dextrose saline) has been demonstrated for 48 hours at
25°C.
However, from a microbiological point of view, the diluted product should
be used immediately. If the product is not used immediately, the duration and
conditions of use are the sole responsibility of the user.
6.5 Nature and contents of container
4 ml and 8 ml clear glass ampoules packed in boxes of 10, 50 or 100
ampoules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
- Dilute in 5% dextrose or isotonic dextrose saline. Please refer to section 4.2
“Posology and method of administration”.
- Do not use an opened ampoule.
- Do not used if you notice any type of coloration
- Any unused product or waste material should be disposed of in accordance
with local requirements.

7. MARKETING AUTHORISATION HOLDER
Laboratoire AGUETTANT
1, rue Alexander Fleming
69007 LYON - France

8. MARKETING AUTHORISATION NUMBER(S)
PL 14434/0017

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION : First MA 02/03/2010
10. DATE OF REVISION OF THE TEXT : September 2013
11. DOSIMETRY : Not applicable.
12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS : Not applicable.

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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