Norfine

Clear and colourless aqueous solution.
Each mL contains: Norepinephrine (as bitartrate), BP 1 mg.

Adrenergic and Dopaminergic Agent.
Pharmacology: Pharmacodynamics: Norepinephrine has a very potent action on alpha receptors and a more moderate effect on beta-1 receptors. Norepinephrine causes generalized vasoconstriction, except for the coronary vessels, which it dilates indirectly by increasing 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 norepinephrine 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.
Pharmacokinetics: Two stereoisomers of Norepinephrine exist, the biologically active L-isomer is the one present in Norepinephrine 1 mg/mL concentrate for solution for infusion.
Absorption: Subcutaneous: Poor.
Oral: Norepinephrine is rapidly inactivated in the gastro-intestinal tract following oral administration.
After intravenous administration Norepinephrine has a plasmatic half-life of about 1 to 2 minutes.
Distribution: Norepinephrine 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: Norepinephrine 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.

Norepinephrine is used for the emergency restoration of blood pressure in acute hypotensive states such as shock. Locally applied solutions have been used to control bleeding in upper gastrointestinal haemorrhage and similar disorders.

Posology: Adults: Add 2 mL of Norepinephrine 1 mg/mL concentrate for solution for infusion to 48 mL 50 mg/mL (5%) glucose (or other solutions for dilution mentioned in Special precautions for disposal and other handling under Cautions for Usage) for administration by syringe pump. The final concentration of the infusion solution is 80 mg/litre Norepinephrine, which is equivalent to 40 mg/litre Norepinephrine. 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 Norepinephrine (or 0.4 mg/hour to 0.8 mg/hour Norepinephrine).
Titration of Dose: Once an infusion of Norepinephrine 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). (See Table 1.)

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Duration of Treatment and Monitoring: Norepinephrine should be continued until adequate blood pressure and tissue perfusion are maintained without therapy. The patient should be monitored carefully for the duration of Norepinephrine therapy.
Norepinephrine 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 Norepinephrine 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.
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.

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.

Use of Norepinephrine 1 mg/mL concentrate for solution for infusion is contraindicated in patients with known hypersensitivity to Norepinephrine 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.

Do not use undiluted.
Norepinephrine 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.
Norepinephrine should be used only in conjunction with appropriate blood volume replacement.
If Norepinephrine 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 Norepinephrine 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 Norepinephrine, 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' under Precautions).

Caution is advised in patients with major left ventricular dysfunction associated with acute hypotension. Supportive therapy should be initiated simultaneously with diagnostic evaluation. Norepinephrine 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 Norepinephrine 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 Norepinephrine may increase the ischemia and extend the area of infarction, unless in the opinion of the attending physician, the administration of Norepinephrine 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.
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 Norepinephrine due to the greater frequency of hepatic, renal or cardiac dysfunction and concomitant disease or other drug therapy.
The use of Norepinephrine in children is not recommended.
Norepinephrine 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 Norepinephrine, 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 Norepinephrine. Hypertension may eventually lead to acute pulmonary oedema, arrhythmia or cardiac arrest.
The infusion of Norepinephrine 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 Norepinephrine 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.
Effects on Ability to Drive and Use of Machines: No information is available.

Pregnancy: Norepinephrine 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 Norepinephrine is administered to a nursing woman.
Fertility: No studies have been performed to collect fertility data for Norepinephrine.

Table 2 lists adverse reactions that have been experienced following treatment with Norepinephrine. 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). (See Table 2.)

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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 Norepinephrine 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.

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 Norepinephrine.
Antihistamines, as some may block the intake of atecholamines by peripheral tissues and increase the toxicity of injected Norepinephrine.
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, Norepinephrine 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.
Norepinephrine should be used with extreme caution in patients receiving MAO inhibitors or within 14 days of cessation of such therapy.
The effects of Norepinephrine may be enhanced by guanethidine, guanadrel, reserpine, methyldopa or tricyclic antidepressants, amphetamine, doxapram, mazindol, rauwolfia alkaloids.
Caution is required when using Norepinephrine with alpha and beta blockers as severe hypertension may result.
Caution is required when using Norepinephrine 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 Norepinephrine may lead to propofol infusion syndrome (PRIS).
Desmopressin or Vasopressin: its antidiuretic effect is diminished.
Lithium decreases the effect of Norepinephrine.
Norepinephrine infusion solutions should not be mixed with other medications (except those mentioned in Special Precautions for Disposal and Other Handling under Cautions for Usage).

Special Precautions for Disposal and Other Handling: 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 previously 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 previously mentioned solutions for dilution) for administration by drip counter. In both cases the final concentration of the infusion solution is 40 mg/litre Norepinephrine (which is equivalent to 80 mg/litre Norepinephrine. Dilutions other than 40 mg/litre Norepinephrine may also be used. If dilutions other than 40 mg/litre Norepinephrine 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.
Instructions and Special Precautions for Handling and Disposal: Do not use if injection is not clear.
Discard unused portion. Must be diluted.

Store at temperatures not exceeding 30°C.
Shelf Life: 36 months.

Vasoconstrictors

C01CA03 - norepinephrine ; Belongs to the class of adrenergic and dopaminergic cardiac stimulants excluding glycosides. Used in the treatment of hypotension.

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