Noradrenaline (Norepinephrine) 1 mg/ml concentrate for solution for infusion

Noradrenaline (Norepinephrine) 1 mg/ml concentrate for solution for infusion is recommended in adults for use as an emergency measure in the restoration of blood pressure in cases of acute hypotension.

Posology

Adults

Add 2 ml of Noradrenaline (Norepinephrine) 1 mg/ml concentrate for solution for infusion to 48 ml 50 mg/ml (5%) glucose (or other in section 6.6 mentioned solutions for dilution) for administration by syringe pump. The final concentration of the infusion solution is 80 mg/litre noradrenaline (norepinephrine) tartrate, which is equivalent to 40 mg/litre noradrenaline. If other dilutions are used check the calculation carefully before starting treatment.

Initial rate of infusion

The initial rate of infusion should be between 10 ml/hour and 20 ml/hour (0.16 ml/min to 0.32 ml/min). This is equivalent to 0.8 mg/hour to 1.6 mg/hour noradrenaline (norepinephrine) tartrate (or 0.4 mg/hour to 0.8 mg/hour noradrenaline).

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 65-80 mm Hg – depending on the patient's condition).

Table 1 Dose titration of noradrenaline solution for infusion

Duration of treatment and monitoring

Noradrenaline should be continued until adequate blood pressure and tissue perfusion are maintained without therapy. The patient should be monitored carefully for the duration of noradrenaline therapy.

Noradrenaline should only be administered by healthcare professionals who are familiar with its use and have appropriate facilities to adequately monitor the patient.

Withdrawal of therapy

Infusions should be reduced gradually, avoiding abrupt withdrawal which can result in acute hypotension.

Hepatic/renal impairment

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

Elderly

In general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range as to reflect the greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy.

Paediatric population

The safety and efficacy of noradrenaline in children less than 18 years of age has not yet been established. No data are available.

Method of administration

Route of administration

Intravenous use after dilution.

Noradrenaline (Norepinephrine) 1 mg/ml concentrate for solution for infusion should be diluted and should be administered 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.

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

Hypotension due to blood volume deficit (hypovolaemia).

Do not use with cyclopropane and halothane anaesthetics. For interactions see section 4.5.

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, noradrenaline should be used with caution in patients receiving these or any other cardiac sensitising agent or who exhibit profound hypoxia or hypercarbia.

The administration in the veins of the lower limbs of the elderly and patients with occlusive diseases due to possible vasoconstriction should be avoided (see section 4.4).

Do not use undiluted.

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.

Noradrenaline should be used only in conjunction with appropriate blood volume replacement.

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 lactic acidosis. Blood volume replacement can be administered before and/or concurrently with this agent; however, if whole blood or blood plasma is indicated to increase blood volume, administer separately (e.g. if given simultaneously, use Y-tubing and individual containers).

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 or the 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 ischemic injury; gangrene of extremities has been rarely reported.

When infusing noradrenaline, the blood pressure and rate of flow should be checked frequently to avoid hypertension, which may be associated with bradycardia as well as headache and peripheral ischemia, including rarely gangrene of the extremities. Extravasation may cause local tissue necrosis (see section 'Extravasation' below).

Caution is advised in patients with 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.

Occurrence of heart rhythm disorders during the treatment must lead to a reduction in the dosage.

Cardiac arrhythmias may arise when noradrenaline is used in conjunction with cardiac sensitizing agents, and may be more likely in patients with hypoxia or hypercarbia.

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, unless in the opinion of the attending physician, the administration of noradrenaline is necessary as a life-saving procedure. Similar caution should be observed in patients with hypotension following myocardial infarction and in patients with angina, particularly Prinzmetal's variant angina, diabetes, hypertension or hyperthyroidism (see section 4.8).

Special caution should be used for patients with liver failure, severe renal dysfunction, ischemic heart diseases and elevated intracranial pressure. Overdoses or conventional doses in hypersensitive persons (e.g. hyperthyroid patients) may cause severe hypertension with violent headache, photophobia, stabbing retrosternal pain, pallor, intense sweating and vomiting. Hypertension may eventually lead to acute pulmonary oedema, arrhythmia or cardiac arrest.

Care should be taken in diabetics as it increases the level of blood glucose (due to the glycogenolytic action in the liver and the inhibition of insulin release from the pancreas).

The elderly may be especially sensitive to the effects of noradrenaline due to the greater frequency of hepatic, renal or cardiac dysfunction and concomitant disease or other drug therapy.

The use of noradrenaline in children is not recommended (see sections 4.2 and 5.2).

Noradrenaline should only be used by doctors familiar with the selective indications for its use.

Where indicated, appropriate replacement therapy of blood or fluid together with adoption of the supine position with elevation of the legs, must be instituted and maintained prior to and/or during therapy with this product. When infusing noradrenaline, the blood pressure and rate of flow should be checked frequently to avoid hypertension. Therefore, it is desirable to record the blood pressure every two minutes from the time the administration started until the desired blood pressure is obtained and then every five minutes thereafter, if the administration is to be continued. The rate of flow must be watched constantly and the patient should never be left unattended while receiving noradrenaline. Hypertension may eventually lead to acute pulmonary oedema, arrhythmia or cardiac arrest.

The infusion of noradrenaline should be stopped gradually as sudden cessation may produce a catastrophic fall in blood pressure.

Extravasation

The infusion site should be checked frequently for free flow. Care should be taken to avoid extravasation of noradrenaline into the tissues, as local necrosis might ensue due to the 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. On rare occasions this may progress to superficial slough, particularly during infusion into leg veins in elderly patients or in those suffering from obliterative vascular disease. 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

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 and pallid appearance. Sympathetic blockade with phentolamine causes immediate and 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.

Excipients

Ampoules containing 1 ml, 2 ml, 4 ml or 5 ml of concentrate for solution for infusion contains less than 1 mmol sodium (23 mg) per ampoule, that is to say essentially 'sodium-free'.

Each ampoule containing 8 ml of concentrate for solution for infusion contains 26.4 mg (1.12 mmol) sodium, equivalent to 1.32 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Each ampoule containing 10 ml of concentrate for solution for infusion contains 33 mg (1.40 mmol) sodium, equivalent to 1.65 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Inadvisable combinations

- Volatile halogenated 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 fibres).

- Serotoninergic-adrenergic antidepressants: paroxysmal hypertension with the possibility of arrhythmia (inhibition of the entry of sympathomimetics into sympathetic fibres).

- Digitalis glycosides.

- Levodopa.

- Chlorpheniramine hydrochloride, tripelennamine hydrochloride and desipramine: significantly increase the toxicity of noradrenaline.

- Antihistamines, as some may block the intake of catecholamines by peripheral tissues and increase the toxicity of injected noradrenaline.

The use of pressor amines with cyclopropane, halothane, chloroform, enflurane or other halogenated anaesthetics may cause serious cardiac arrhythmias, because of the possibility of increasing the risk of ventricular fibrillation, noradrenaline should be used with caution in patients receiving these or any other cardiac sensitising agent or who exhibit profound hypoxia or hypercarbia.

Combinations requiring precautions for use

- Non-selective monoamine oxidase (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.

Noradrenaline should be used with extreme caution in patients receiving MAO inhibitors or within 14 days of cessation of such therapy.

The effects of noradrenaline may be enhanced by guanethidine, guanadrel, reserpine, methyldopa or tricyclic antidepressants, amphetamine, doxapram, mazindol, rauwolfia alkaloids.

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, antiarrhythmic.

Ergot alkaloids (ergoloid mesylates, ergotamine, dihydroergotamine, ergometrine, methylergometrine, and methysergide) or oxytocin may enhance the vasopressor and vasoconstrictive effects.

Concomitant administration of propofol and noradrenaline may lead to propofol infusion syndrome (PRIS).

Desmopressin or vasopressin: its antidiuretic effect is diminished.

Lithium decreases the effect of noradrenaline.

Noradrenaline infusion solutions should not be mixed with other medications (except those mentioned in section 6.6).

Pregnancy

Noradrenaline may impair placental perfusion and induce foetal bradycardia. It may also exert a contractile effect on the pregnant uterus and lead to foetal asphyxia in late pregnancy. These possible risks to the foetus should therefore be weighed against the potential benefit to the mother.

Breast-feeding

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.

Fertility

No studies have been performed to collect fertility data for noradrenaline.

No information is available. Therefore, driving or operating machinery is not recommended.

Table 2 lists adverse reactions that have been experienced following treatment with noradrenaline. This data has largely been collected from spontaneous reporting, and due to the problems in calculating reporting frequencies from spontaneous reporting, the frequency of the listed adverse reactions is 'not known' (cannot be estimated from the available data). The adverse reactions are reported in decreasing order of frequency within each system order class (SOC).

Table 2 Adverse reactions reported with noradrenaline through spontaneous reporting

¹ Bradycardia, probably as a reflex result of a rise in blood pressure

² Ischaemia, due to potent vasoconstrictor action and tissue hypoxia

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 alpha blocking agent (phentolamine mesilate) whereas the administration of a beta 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 beta-1 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.

Hypertension may occur, which may be associated with bradycardia as well as headache and peripheral ischemia, including gangrene of the extremities.

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 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, marked increase in peripheral resistance, and decreased cardiac output. These may be accompanied by violent headache, cerebral haemorrhage, photophobia, retrosternal pain, pallor, fever, intense sweating, pulmonary oedema and vomiting.

Treatment

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

Pharmacotherapeutic group: cardiac therapy, adrenergic and dopaminergic agents, ATC code: C01CA03

Noradrenaline has a very potent action on alpha receptors and a more moderate effect on beta-1 receptors. Noradrenaline 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.

The vascular effects of noradrenaline in the doses usually 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.

Two stereoisomers of noradrenaline exist, the biologically active L-isomer is the one present in Noradrenaline (Norepinephrine) 1 mg/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 monoamine oxydase (MAO)

- Ultimate metabolite 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.

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

Paediatric population

No data on experience of pharmacokinetic studies in paediatric age groups is available.

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.

Sodium chloride

Hydrochloric acid (for pH adjustment)

Water for injections

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

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

Unopened

1 ml, 2 ml: 18 months

4 ml, 5 ml, 8 ml, 10 ml: 2 years

Shelf life after opening the ampoule

Once opened, the diluted solution should be prepared immediately.

Shelf life after dilution

Chemical and physical in-use stability has been demonstrated for 48 hours at 25 ° C and 2-8 ° C when diluted to 4 mg/litre and 40 mg/litre noradrenaline in sodium chloride 9 mg/ml (0.9%) solution or glucose 50 mg/ml (5%) solution, or sodium chloride 9 mg/ml (0.9%) with glucose 50 mg/ml (5%) solution.

From a microbiological point of view, the diluted solution 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 hours at 2 to 8 ° C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not store above 25 ° C.

Keep the ampoules in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

1 ml, 2 ml, 4 ml, 5 ml, 8 ml or 10 ml of solution filled in colourless glass ampoules with one point cut. The ampoules are packed in liner and placed into carton box.

Pack sizes: 5 or 10 ampoules

Not all pack sizes may be marketed.

For single use only. Discard any unused contents.

The solution should be visually inspected prior to use. The solution should not be used if it contains any visible particles/solids.

Do not use the solution for infusion if it has a brown colour.

Dilute before use with:

– glucose 50 mg/ml (5%) solution or

– sodium chloride 9 mg/ml (0.9%) solution or

– sodium chloride 9 mg/ml (0.9%) with glucose 50 mg/ml (5%) solution.

Either add 2 ml concentrate to 48 ml glucose 50 mg/ml (5%) solution (or any of the other above mentioned solutions for dilution) for administration by syringe pump, or add 20 ml of concentrate to 480 ml glucose 50 mg/ml (5%) solution (or any of the other above mentioned solutions for dilution) for administration by drip counter. In both cases the final concentration of the infusion solution is 40 mg/litre noradrenaline (which is equivalent to 80 mg/litre noradrenaline (norepinephrine) tartrate). Dilutions other than 40 mg/litre noradrenaline may also be used (see section 4.2). If dilutions other than 40 mg/litre noradrenaline are used, check the infusion rate calculation carefully before starting treatment.

The product is compatible with polyvinyl chloride (PVC), ethyl vinyl acetate (EVA) or polyethylene (PE) infusion bags.

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