Noradrenaline Tartrate

Registered South African indications:

• Indicated in adults for use as an emergency measure in the restoration of blood pressure in cases of acute hypotension (4mg/4ml)
• Indicated in adults weighing over 50kg for the on-going treatment of hypotensive emergencies (0.16mg/ml)

Registered South African contraindications

• Hypersensitivity to noradrenaline or to any of the excipients
• Hypotension due to blood volume deficit (hypovolaemia)
• The use of pressor amines during inhalational anaesthesia with halogenated anaesthetics may cause serious cardiac dysrhythmias. Because of the possibility of increasing risk of ventricular fibrillation, noradrenaline solution for infusion should be used with caution in patients receiving these or any other cardiac sensitising medicine or who exhibit profound hypoxia or hypercarbia

Contraindications registered in other jurisdictions

4mg/4ml concentrate for solution for infusion

• Hypersensitivity to the active substance or to any of the excipients

0.16mg/ml solution for infusion

• Hypersensitivity to noradrenaline or to any of the excipients
• Administration via peripheral cannula and/or peripheral vein
• Noradrenaline is contraindicated in hypotensive patients in whom circulatory collapse is associated with hypovolaemia
  except as an emergency measure (See Warnings and Precautions for additional precautions for 0.16mg/ml solution for infusion) 

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Hyperthyroidism
• Diabetes mellitus

Administration

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

Hypotensive patients

• Noradrenaline is contraindicated in hypotensive patients due to hypovolemia, but may be considered as a short-term emergency measure to support blood supply to coronary and cerebral arteries until general blood or solution infusion can be initiated

Blood volume replacement

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

Monitoring

• When infusing noradrenaline, blood pressure and rate of flow should be checked frequently to avoid hypertension
• Perfusion of noradrenaline must be performed with continuous monitoring of blood pressure and cardiac frequency

Visual inspection

• Noradrenaline administered 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 to avoid extravasation, which can cause necrosis of the surrounding tissues. If blanching occurs, consider changing the infusion site to allow the effects of local vasoconstriction to subside

 Treatment of ischaemia due to extravasation

• During an extravascular leak or injection besides the vein, tissue destruction can result from the vasoconstrictive action of noradrenaline on blood vessels. The injection zone should be irrigated as quickly as possible with 10-15ml of physiological salt solution containing 5-10 mg phentolamine mesilate. Use a syringe with a fine needle to inject locally

Major left ventricular dysfunction

• Caution and respect of the strict indication must be retained in cases of 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, particularly those without elevated systemic vascular resistance

Vascular thrombosis

• Particular caution should be observed in patients with coronary, mesenteric, or peripheral vascular thrombosis because noradrenaline may increase 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

Heart rhythm disorders

• The occurrence of heart rhythm disorders during treatment must lead to a reduction in the dosage

Plasma volume depletion

• 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 diminished blood flow and tissue perfusion, leading to tissue hypoxia, lactic acidosis, and possible ischaemic injury

Alpha and beta-blocking medicines

• The vasopressor effect (resulting from the adrenergic action in the vessels) can be reduced by the concomitant administration of an alpha-blocking medicine, whereas the administration of a beta-blocking medicine may result in a reduction of the stimulating effect of the product on the heart and an increase in the hypertensive effect (through reduction of arteriolar dilatation) resulting from beta-1-adrenergic stimulation

Administration with blood or plasma

• 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

Sodium content

• 4mg/4ml: Contains less than 1 mmol sodium (23mg) per ml, which is essentially ‘sodium-free’
• 0.16mg/ml: Contains 165.3 mg sodium per 50ml vial, equivalent to 8.3 % of the WHO recommended maximum daily intake of 2g sodium for an adult

Ability to drive and use machines

• None stated

Recommendations in other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Hyperthyroidism
• Diabetes mellitus
• Hypertension
• Patients who exhibit profound hypoxia or hypercarbia

Administration

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

Coronary, mesenteric, or peripheral vascular thrombosis

• 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

Hypotensive patients

• Caution should be observed in patients with hypotension following myocardial infarction, in patients with Prinzmetal's variant angina as noradrenaline may increase the associated ischaemia and extend the area of infarction

Blood volume replacement

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

Monitoring

• When infusing noradrenaline, blood pressure and rate of flow should be checked frequently to avoid hypertension

Extravasation management

• 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 vasopressors

• 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 ischemic injury

Sodium content

• 4mg/4ml: Contains less than 1 mmol sodium (23mg) per ampoule, which is essentially 'sodium-free'. Patients on low sodium diets can be informed of this. This medicinal product may be diluted with sodium-containing solutions. This should be considered in relation to the total sodium from all sources that will be administered to the patient
• 0.16mg/ml: Contains 177.3mg sodium per vial, equivalent to 8.9% of the WHO recommended maximum
  daily intake of 2g sodium for an adult

Ability to drive and use machines

• None stated

Additional precautions for 0.16mg/ml solution for infusion

Hypotensive patients 

• Noradrenaline 0.16mg/ml solution for infusion 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

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

Forms avail. in SA and covered in this monograph: inf

South African registered indications and dosages

Indicated in adults for use as an emergency measure in the restoration of blood pressure in cases of acute hypotension

4mg/4ml concentrate for solution for infusion

• IV: Upon dilution (see Additional prescribing points  - Dilution instructions): Initial rate of infusion, at a body weight of 70kg: Should be between 10-20ml/hr  (0.16 to 0.33ml/min); This is equivalent to 0.4-0.8mg/hr noradrenaline base (0.8-1.6mg/hr noradrenaline tartrate); Some clinicians may start at a lower initial infusion rate of 5ml/hour (0.08ml/min), equivalent to 0.2mg/hr noradrenaline base (0.4mg/hr noradrenaline tartrate); Once an infusion has been established: Titrate in steps of 0.05-0.1µg/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; Aim should be to establish a low normal systolic blood pressure (100-120mmHg) or to achieve an adequate mean arterial blood pressure (greater than 65-80mmHg - depending on the patient's condition)

Noradrenaline solution for infusion 40mg/litre (40µg/ml) noradrenaline base
Patient weight - 50kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.15	3.75
0.1	0.3	7.5
0.25	0.75	18.75
0.5	1.5	37.5
1	3	75
Patient weight - 60kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.18	4.5
0.1	0.36	9
0.25	0.9	22.5
0.5	1.8	45
1	3.6	90
Patient weight - 70kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.21	5.25
0.1	0.42	10.5
0.25	1.05	26.25
0.5	2.1	52.5
1	4.2	105
Patient weight - 80kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.24	6
0.1	0.48	12
0.25	1.2	30
0.5	2.4	60
1	4.8	120
Patient weight - 90kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.27	6.75
0.1	0.54	13.5
0.25	1.35	33.75
0.5	2.7	67.5
1	5.4	135

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

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Indicated in adults weighing over 50kg for the on-going treatment of hypotensive emergencies

0.16mg/ml solution for infusion

• IV: Usual initial dose of noradrenaline base: 0.05-0.15µg/kg/min; This initial posology should be administered using a less concentrated noradrenaline solution that permits better titration by 0.05 and 0.1µg/kg/min steps; Maintenance dose range: 0.05-1µg/kg/min; Determine infusion rates and relative adjustments according to the required posology as detailed in table below; Titration: Once an infusion of noradrenaline has been established the dose should be titrated in steps of 0.05 and 0.1 micrograms/kg/min of noradrenaline base according to the pressor effect observed (See 'Titration of dose' in red notes below); Duration of treatment: Continue 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

Noradrenaline 0.16mg/ml solution for infusion 50ml vial containing 8mg of noradrenaline base
Patient weight - 50kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.15	1.0
0.1	0.3	1.9
0.25	0.75	4.7
0.5	1.5	9.4
1	3	18.8
Patient weight - 60kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.18	1.2
0.1	0.36	2.3
0.25	0.9	5.7
0.5	1.8	11.3
1	3.6	22.5
Patient weight - 70kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.21	1.3
0.1	0.42	2.7
0.25	1.05	6.6
0.5	2.1	13.2
1	4.2	26.3
Patient weight - 80kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.24	1.5
0.1	0.48	3.0
0.25	1.2	7.5
0.5	2.4	15.0
1	4.8	30.0
Patient weight - 90kg
Posology (µg/kg/min) noradrenaline base	Posology (mg/hr) noradrenaline base	Infusion rate (ml/hr)
0.05	0.27	1.7
0.1	0.54	3.4
0.25	1.35	8.5
0.5	2.7	16.9
1	5.4	33.8

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

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Noradrenaline 0.16mg/ml solution for infusion should not be used for initiating vasopressor treatment. It may be considered for use in patients already established on noradrenaline therapy, whose dose requirements are clinically confirmed to be escalating, such that noradrenaline 0.16mg/ml, solution for infusion may be commenced at a flow rate of 0.75ml/hr.

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Titration of dose
Noradrenaline solution for infusion, should be used with a suitable 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 and 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 - 120mmHg) or to achieve an adequate mean arterial blood pressure (greater than 65mmHg – depending on the patient’s condition). Manual bolus for priming when initiating an infusion is not recommended
Caution is required during syringe relay (replacement of the used syringe with a new one) to avoid haemodynamic instability
Continuous noradrenaline infusion through a double pump system and an extension set reducing dead-space volume should be encouraged

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Method of administration
For intravenous use only. Noradrenaline solution for infusion is administered intravenously
To avoid ischemic necrosis (skin, extremities) noradrenaline solution for infusion should be infused via a cannula placed in a central vein. Noradrenaline solution for infusion should be infused at a controlled rate using a syringe pump. Noradrenaline solution for infusion should not be diluted before use: it is supplied ready to use
It should not be mixed with other medicines (See Additional Prescribing Points)

Not established for use in children

Pregnancy

South African recommendations

• Caution
• Safety in pregnancy has not been established. 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

Recommendations in other jurisdictions

• Caution
• 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

South African recommendations

• Caution
• The safety of noradrenaline during breastfeeding has not been established
• No information is available on the use of noradrenaline during lactation

Recommendations in other jurisdictions

• Caution
• No information is available on the use of noradrenaline in lactation

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• No information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended
  Elderly patients may be especially sensitive to the effects of noradrenaline

Psychiatric Disorders

• Anxiety
• Insomnia
• Confusion
• Weakness
• Psychotic state

Nervous System Disorders

• Headache
• Tremor

Eye Disorders

• Acute glaucoma (very frequent in patients anatomically predisposed with the closing of the iridocorneal angle)

Cardiac Disorders

• Tachycardia
• Bradycardia (probably as a reflex result of blood pressure rising)
• Arrhythmias (when used in conjunction with cardiac sensitising agents)
• Palpitations
• Increase in the contractility of the cardiac muscle resulting from the beta-adrenergic effect on the heart (inotrope and chronotrope)
• Acute cardiac insufficiency
• Stress cardiomyopathy

Vascular Disorders

• Arterial hypertension and tissue hypoxia
• Ischaemic injury (including gangrene of the extremities) due to potent vasoconstrictor action, may result in coldness and paleness of the members and the face

Respiratory, Thoracic and Mediastinal Disorders

• Respiratory insufficiency or difficulty
• Dyspnoea

Gastrointestinal Disorders

• Nausea
• Vomiting

Renal and Urinary Disorders

• Retention of urine

General Disorders and Administration Site Conditions

• Possibility of irritation, sloughing, and necrosis at the injection site

Hypersensitivity Disorders

• Hypertension
• Photophobia
• Retrosternal pain
• Pharyngeal pain
• Pallor
• Intense sweating and vomiting

Other

• 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 serum lactate levels

• Volatile halogenated anaesthetic agents
• Monoamine oxidase (MAO) inhibitors
  - Non-selective MAO inhibitors
  - Selective MAO-A inhibitors
• Linezolid
• Tricyclic antidepressants
• Alpha- and beta-blockers
• Serotoninergic-adrenergic antidepressants
• Thyroid hormones
• Cardiac glycosides
• Antidysrhythmic medicines
• Ergot alkaloids
• Oxytocin
• Other cardiac sensitising agents

• Blood pressure (or mean arterial pressure)
• Heart rate
• Cardiac output (as appropriate)
• Intravascular volume status
• Pulmonary capillary wedge pressure (as appropriate)
• Urine output
• Peripheral perfusion

Additional observations

• Closely monitor infusion site

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.