Noradrenaline (Norepinephrine) 0.08 mg/ml, solution for infusion

Noradrenaline (Norepinephrine) is indicated in adults weighing over 50kg for the treatment of hypotensive emergencies.

For intravenous use only.

Noradrenaline (Norepinephrine) should only be administered as an intravenous infusion via a central venous catheter to minimize the risk of extravasation and subsequent tissue necrosis. Noradrenaline (Norepinephrine) should be infused at a controlled rate using an infusion pump or a syringe pump.

Noradrenaline (Norepinephrine) should not be diluted before use: it is supplied ready to use. It should not be mixed with other medicines.

Blood pressure control:

Blood pressure should be monitored carefully for the duration of therapy, and preferably controlled by arterial blood pressure monitoring. The patient should be monitored carefully for the duration of noradrenaline (norepinephrine) therapy.

Posology

Initial dose:

The initial dose of noradrenaline base is usually between 0.05-0.15 micrograms/kg/min.

Maintenance dose range:

The recommended maintenance range of noradrenaline base is between 0.05-1.5 micrograms/kg/min.

Titration of dose:

Noradrenaline (Norepinephrine) should be used with a suitable infusion pump or syringe pump capable of accurately and consistently delivering the minimum specified volume at a strictly controlled rate of infusion in line with the dose titration instructions.

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

Manual bolus for priming when initiating an infusion is not recommended. Caution is required during infusion relay to avoid hemodynamic instability.

Continuous noradrenaline infusion through a double pump system and an extension set reducing dead-space volume should be encouraged.

h: hour

Duration of Treatment:

The treatment should be continued until high-dose vasoactive drug support is no longer indicated, at which point, the infusion should be gradually decreased, then switched to an infusion of lower concentration. Abrupt withdrawal can result in acute hypotension.

Elderly patients

See section 4.4 Special warnings and precautions for use.

Paediatric population

Noradrenaline (Norepinephrine) is indicated for adults only.

The efficacy and safety of Noradrenaline (Norepinephrine) in 50 ml ready to use solution for infusion in children and adolescents has not been established.

Patients with renal- and hepatic impairment.

There is no experience of treatment in patients with renal- and hepatic impairment.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Do not use with cyclopropane and halothane anaesthetics as this may cause serious cardiac arrhythmias including ventricular fibrillation. For interactions see section 4.5.

- Administration via peripheral cannula and/or peripheral vein.

Warning:

Noradrenaline is contraindicated in hypotensive patients in whom circulatory collapse is associated with hypovolaemia except as an emergency measure to maintain supply to the coronary and cerebral arteries until blood volume replacement therapy can be instituted.

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 (e.g. decreased renal perfusion) with diminution in blood flow and tissue perfusion with subsequent tissue hypoxia and lactic acidosis and possible ischemic injury. Gangrene of extremities has been rarely reported.

Noradrenaline (Norepinephrine) is intended for infusion via a central venous catheter only.

The patients receiving noradrenaline should be closely monitored in order to identify early symptoms of vasopressor-induced limb ischaemia and implement the appropriate measures (e.g. elevation of the extremity, splinting, warming of affected limb with ad hoc device, use of vasodilating agents) to prevent progression and minimize the risks associated with necrosis of the extremities.

♦ 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 beside the vein, tissue destruction can appear resulting from the vasoconstrictive action of the drug on the blood vessels. The area should be infiltrated as quickly as possible with 10 to 15ml of a physiological salt solution containing 5 to 10 mg of phentolamine mesilate, an adrenergic blocking agent. For this purpose, it is necessary to use a syringe provided with a fine needle and to inject locally throughout the area, which is easily identified by its cold, hard and pallid appearance. Sympathetic blockade with phentolamine causes immediate conspicuous local hyperaemic changes if the area is infiltrated within 12 hours. Phentolamine should be given as soon as possible after the extravasation is noted and infusion should be stopped.

Precautions for use:

In general, cautious evaluation is recommended in the following cases of hypotension and hypoperfusion, in which a reduction in the dose of noradrenaline may be required:

- Major left ventricular dysfunction associated with acute hypotension. . 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.

- -Hypotensive patients diagnosed with coronary, mesenteric or peripheral vascular thrombosis, myocardial infarction or Prinzmetal's variant angina. Particular caution should be observed as noradrenaline may increase the associated ischaemia and extend the area of infarction.

- Occurrence of heart rhythm disorders during noradrenaline therapy.

- Caution is advised in patients with hyperthyroidism or diabetes mellitus.

In cases where it is necessary to administer noradrenaline at the same time as total blood or plasma, the latter must be administered in a separate drip.

This medicinal product contains sodium.

This medicinal product contains 177.3 mg sodium per vial, equivalent to 8.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Contraindicated combinations

- Volatile halogen anaesthetics

Severe ventricular arrhythmia (increase in cardiac excitability).

Inadvisable combinations

- Tricyclic antidepressants (particularly imipramine type)

Paroxysmal hypertension with the possibility of arrhythmia (inhibition of the entry of sympathomimetics into sympathetic fibres).

- Serotoninergic-adrenergic antidepressants

Paroxysmal hypertension with the possibility of arrhythmia (inhibition of the entry of sympathomimetics into sympathetic fibres).

- Digitalis glycosides

May occasionally cause arrhythmia.

- Levodopa

May enhance the effects of noradrenaline.

Combinations requiring precautions for use

- Non-selective MAO inhibitors (or within 14 days of cessation of such therapy)

Increase in the pressor action of the sympathomimetic which is usually moderate. Should only be used under close medical supervision.

- Selective MAO-A inhibitors, Linezolid and Methylene Blue

By extrapolation from non-selective MAO inhibitors, risk of increase in the pressor action. Should only be used under close medical supervision.

- Alpha 1 agonists (e.g. midodrine)

Caution is required as pronounced hypertension may result.

- Alpha 1 blockers (e.g. prazosine, terazosine or doxazosine)

May reduce the pressure action of norepinephrine.

- Beta blockers

Caution is required as severe hypertension may result.

- Thyroid hormones,

Caution is required as they may cause increased cardiac effects.

- Ergot alkaloids, specifically those with relevant alpha1-agonistic action (e.g. ergotamine, dihydroergotamine, methylergometrine)

May enhance the vasopressor and vasoconstrictive effects.

- Lithium

Decreases the effect of noradrenaline

- Reserpine, amphetamine

May enhance the effects of noradrenaline.

Pregnancy

Because of its indications, noradrenaline may be administered if necessary during pregnancy.

However, pharmacodynamics properties of the substance have to be considered. Indeed 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.

Breast-feeding

No information is available on the use of noradrenaline in breast-feeding.

Noradrenaline has no influence on the ability to drive and use machines.

Very common: ≥1/10 ; Common : ≥1/100, <1/10 ; Uncommon: ≥1/1,000, <1/100 ; Rare: ≥1/10,000, <1/1,000; Very rare: <1/10,000; Not known: cannot be estimated from the available data.

In case of hypersensitivity or overdose, the following effects may appear more frequently: hypertension, photophobia, retrosternal pain, pharyngeal pain, pallor, intense sweating and vomiting.

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 the national reporting system:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

♦ Symptoms

Overdosage may result in headache, severe hypertension, reflex bradycardia, and decreased cardiac output.

These may be accompanied by violent headache, photophobia, retrosternal pain, pallor, fever, intense sweating, pulmonary oedema and vomiting.

The following may also be observed: cutaneous vasoconstriction, bed sores.

♦ Treatment

In case of accidental overdose, as evidenced by excessive blood pressure elevation, discontinue the drug until the condition of the patient stabilizes.

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

Noradrenaline provides a strong stimulation of alpha receptors in blood vessels at which these are counter-extracted. Noradrenaline also has an effect on beta-1 receptors in the heart leading to a positive inotropic and initially positive chronotropic effect. The increase in blood pressure may cause a reflex reduction in heart rate.

Vasoconstriction may lead to decreased blood flow in the kidneys, liver, skin and smooth muscle. Local constriction of the vessels may cause hemostasis and/or necrosis.

The pressor effect disappears 1-2 min after termination of infusion. Development of tolerance to the effects of noradrenaline may occur.

Two stereoisomers of noradrenaline exist, the biologically active L-isomer is the one present in Noradrenaline (Norepinephrine).

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 monoamine oxydase (MAO),

• Ultimate metabolites from both is 4- hydroxy-3-methoxymandelic acid,

• Intermediate metabolites include normetanephrine and 3,4-dihydroxymandelic acid.

Elimination:

• Noradrenaline is mainly eliminated as glucuronide or sulphate conjugates of the metabolites in the urine.

Most of the undesirable effects can be derived from sympathomimetic results from excessive stimulation of the sympathetic nervous system through the various adrenergic receptors.

Noradrenaline may impair placental perfusion and induce fatal fetal bradycardia. It may also exert a contractile effect on the pregnant uterus and lead to fatal fetal asphyxia in late pregnancy.

Sodium chloride

Disodium edetate

Hydrochloric acid or Sodium hydroxide (pH adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products.

18 months.

After the first opening, the product should be used immediately.

Do not store above 25° C. Keep the vial in the outer carton in order to protect from light.

Clear type II glass vial closed with a type I bromobutyl stopper and an aluminum cap containing 50 mL of solution for infusion in pack size of 1, 10, and 25 vials.

Not all pack sizes may be marketed.

For single use only. Discard any unused contents.

Noradrenaline (Norepinephrine) is already diluted and ready to use. It should be used without prior dilution. It should be used with a suitable infusion pump or syringe pump capable of accurately and consistently delivering the minimum specified volume at a strictly controlled rate of infusion in line with the dose titration instructions specified in Section 4.2. This medicine should not be used if the solution is darker than slightly yellow or pink in colour or if it contains a precipitate.

The sterile solution should not be used if it is not clear and contains particles, or if the tamper evident sealed vial is not intact.

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