Noradrenaline (Norepinephrine) 1 mg/ml Concentrate for Solution for Infusion – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Noradrenaline (Norepinephrine) 1 mg/ml Concentrate for Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml concentrate for solution for infusion contains 2 mg noradrenaline tartrate equivalent to 1 mg noradrenaline base.

One ampoule of 4 ml contains 8 mg noradrenaline tartrate equivalent to 4 mg noradrenaline base.

Excipient(s) with known effect

Noradrenaline (Norepinephrine) 1 mg/ml concentrate for solution for infusion contains 13.3 mg of sodium in each 4 ml ampoule.

One ampoule of 10 ml contains 20 mg noradrenaline tartrate equivalent to 10 mg noradrenaline base.

Excipient(s) with known effect

Noradrenaline (Norepinephrine) 1 mg/ml concentrate for solution for infusion contains 33.3 mg of sodium in each 10 ml ampoule.

When diluted as recommended, each ml contains 80 micrograms noradrenaline tartrate equivalent to 40 micrograms noradrenaline base.

For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Sterile, clear, colourless to yellowish concentrate for solution for infusion, free of any visible

particles.

The solution has a pH ranging between 3.0 and 4.0 and osmolarity approx. 280 mOsm/l.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Noradrenaline is indicated for use as an emergency measure in the restoration of blood

pressure in cases of acute hypotension

4.2 Posology and method of administration

Posology

Adults

Initial rate of infusion:

When diluted as recommended in section 6.6 (the concentration of the prepared infusion is 40 mg/l norepinephrine base (80 mg/l norepinephrine tartrate)) the initial rate of infusion, at a body weight of 70 kg, should be between 10 ml/hour and 20 ml/hour (0.16 to 0.33 ml/min). This is equivalent to 0.4 mg/hour to 0.8 mg/hour noradrenaline base (0.8 mg/hour to 1.6 mg/hour noradrenaline tartrate). Some clinicians may wish to start at a lower initial infusion rate of 5 ml/hour (0.08 ml/min), equivalent to 0.2 mg/hour noradrenaline base (0.4 mg/hour noradrenaline tartrate).

Titration of dose:

Once an infusion of noradrenaline has been established the dose should be titrated in steps of 0.05 -0.1 µg/kg/min of noradrenaline base 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 - 80 mm Hg – depending on the patient's condition).

Some clinicians may prefer to dilute to other concentrations. If dilutions other than 40 mg/l are used, check the infusion rate calculation carefully before starting treatment.

Renal or hepatic impairment:

There is no experience in treatment of renally or hepatically impaired patients

Elderly:

As for adults but see section 4.4.

Paediatric population

Not recommended.

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 therapy. Blood pressure should be carefully monitored for the duration of therapy.

Withdrawal of Therapy:

The noradrenaline infusion should be gradually decreased since abrupt withdrawal can result in acute hypotension.

Route of Administration:

For intravenous use.

Method of administration:

Administer as a diluted solution via a central venous catheter.

The infusion should be at a controlled rate using either a syringe pump or an infusion pump or a drip counter.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to noradrenaline tartrate or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

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

Elderly patients may be especially sensitive to the effects of noradrenaline.

Particular caution should be observed in patients with coronary, mesenteric or peripheral vascular thrombosis because noradrenaline may increase the ischemia and extend the area of infarction. 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 be used with caution in patients who exhibit profound hypoxia or hypercarbia.

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.

Extravasation of the solution may cause local tissue necrosis. The infusion site should be checked frequently. If extravasation occurs, the infusion should be stopped and the area should be infiltrated with phentolamine without delay.

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 the infusion is discontinued, or blood pressure may be maintained at the risk of severe peripheral and 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.

Excipients

Norepinephrine contains 13.3 mg of sodium in each 4 ml, equivalent to 0.7% of the WHO

recommended maximum daily intake of 2 g sodium for an adult. Norepinephrine contains 33.3 mg of sodium in each 10 ml, equivalent to 1.7% of the WHO

recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

The use of noradrenaline with volatile halogenated anaesthetic agents, monoamine oxidase inhibitors, linezolid, tricyclic antidepressants, adrenergic-serotoninergic drugs or any other cardiac sensitising agents is not recommended because severe, prolonged hypertension and possible arrhythmias may result.

The effects of noradrenaline may be enhanced by guanethidine.

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

None stated.

4.8 Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Overdosage may result in severe hypertension, reflex bradycardia, marked increase in peripheral resistance and decreased cardiac output. These may be accompanied by violent headache, pulmonary oedema, photophobia, retrosternal pain, pallor, intense sweating and vomiting. In the event of overdosage, treatment should be withdrawn and appropriate corrective treatment initiated.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Adrenergic and dopaminergic agents, ATC code: C01CA03

The vascular effects in the doses normally used clinically result from the simultaneous stimulation of alpha and beta adrenergic receptors in the heart and vascular system. Except in the heart, its action is predominantly on the alpha receptors. 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.

The increase in blood pressure may cause a reflex decrease in heart rate. Vasoconstriction may result in decreased blood flow in kidneys, liver, skin and smooth muscles. Local vasoconstriction may cause haemostasis and/or necrosis.

The effect on blood pressure disappears 1-2 minutes after stopping the infusion.

5.2 Pharmacokinetic properties

Up to 16% of an intravenous dose is excreted unchanged in the urine with methylated and deaminated metabolites in free and conjugated forms.

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

Disodium edetate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

6.2 Incompatibilities

This medicine must not be mixed with other medicinal products except those mentioned in the section 6.6.

Infusion solutions containing noradrenaline tartrate have been reported to be incompatible with the following substances: alkalis and oxidising agents, barbiturates, chlorpheniramine, chlorothiazide, nitrofurantoin, novobiocin, phenytoin, sodium bicarbonate, sodium iodide, streptomycin.

For compatibility with infusion bags see section 6.6.

6.3 Shelf life

Unopened ampoule

2 years

After opening

The concentrate for solution for infusion after opening should be used immediately.

After dilution

Chemical and physical in-use stability has been demonstrated for 48 h at 22 ± 2 °C exposed to daily

light cycles and 30 °C for diluted concentrate in glucose 5% (w/v), sodium chloride 0.9% (w/v) and

sodium chloride 0.45% (w/v) with glucose 5% (w/v).

From a microbiological point of view, the diluted product should be used immediately. If not used

immediately, in-use storage times and conditions prior to use are the responsibility of the user and

would normally not be longer than 24 h at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

Any unused contents remaining in the ampoule should be discarded.

6.4 Special precautions for storage

Store below 25 °C. Keep ampoules in outer carton in order to protect from light.

For storage conditions after dilution, see section 6.3.

6.5 Nature and contents of container

Clear glass ampoules of hydrolytic class No. I with OPC breaking-off containing 4 ml or 10 ml,

molded plastic tray, paper folding box.

Pack sizes: 5, 10 or 50 ampoules containing 4 ml and 10 ampoules containing 10 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

For single use only.

Discard any unused contents.

This medicinal product should not be used if the solution is not colourless to yellowish colour or if it is cloudy or contains visible particles/solids.

Dilute before use with one of these solutions (diluents): glucose 5% (w/v) solution, sodium chloride

0.9% (w/v) solution or sodium chloride 0.45% (w/v) with glucose 5% (w/v) solution.

Dilution rations (e.g.):

Add 2 ml of concentrate to 48 ml of solution (diluent).

Add 4 ml of concentrate to 96 ml of solution (diluent).

Add 10 ml of concentrate to 240 ml of solution (diluent). Add 20 ml of concentrate to 480 ml of solution (diluent).

In all cases the final concentration of the infusion solution is 40 mg/l norepinephrine(which is

equivalent to 80 mg/l norepinephrine tartrate). Dilutions other than 40 mg/l norepinephrine may also

be used (see section 4.2). If dilutions other than 40 mg/l norepinephrine are used, check the infusion

rate calculation carefully before starting treatment.

Appearance of diluted solution has to be clear, colourless and free of visible particles. For stability data of diluted solution, see section 6.3.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Zentiva Pharma UK Limited

12 New Fetter Lane

London

EC4A 1JP

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 17780/1339

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

24/06/2025

10 DATE OF REVISION OF THE TEXT

24/06/2025