Noradrenaline Aguettant (Concentrate) Instructions for Use

ATC Code

C01CA03 (Norepinephrine)

Active Substance

Norepinephrine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Alpha-, beta-adrenergic agonist

Pharmacotherapeutic Group

Alpha-adrenomimetic

Pharmacological Action

Adrenomimetic. It has a pronounced direct effect on alpha-adrenergic receptors, as well as a weak effect on beta₁-adrenergic receptors and a minor effect on beta₂-adrenergic receptors.

The predominance of alpha-adrenomimetic action leads to vasoconstriction, an increase in systemic vascular resistance and systemic blood pressure; central venous pressure also increases.

Since the stimulating effect on the heart (on beta₁-adrenergic receptors of the myocardium) is very weak, compensatory mechanisms associated with vagus nerve excitation in response to increased blood pressure prevail, which ultimately leads to a decrease in heart rate and the development of bradycardia.

However, despite the decrease in heart rate, the positive inotropic effect on the heart persists, so the cardiac output decreases slightly.

Under the influence of norepinephrine, blood flow in the renal and mesenteric vessels also decreases.

It has a minor effect on myocardial oxygen consumption; therefore, it has a less pronounced arrhythmogenic effect than epinephrine.

Unlike epinephrine, it has a stronger (1.5 times) vasoconstrictor and pressor effect, a less pronounced stimulating effect on heart contractions, a weak bronchodilator effect, and a very weak (more than 20 times) hyperglycemic effect.

Pharmacokinetics

Plasma protein binding is 50%.

It is intensively metabolized in adrenergic neurons and in the liver with the participation of monoamine oxidase by oxidative deamination. It is a metabolic substrate for catechol-O-methyltransferase, which methylates the cyclic part of the molecule in the ortho-position. Inactive metabolites partially form conjugated compounds with glucuronic or sulfuric acid and are excreted by the kidneys in this form.

After administration of norepinephrine, the following most important compounds are detected in the urine: norepinephrine-4 – 24%, normetanephrine (o-methyl-norepinephrine) – 21-25%, o-methyl-glycol-derivative – 20-23%, vanillylmandelic acid – 32-35%. Normally, 5 mg/day of vanillylmandelic acid is excreted in the urine (higher levels should raise suspicion of pheochromocytoma).

Norepinephrine does not cross the blood-brain barrier; it crosses the placental barrier.

Indications

Rapid restoration of blood pressure during acute hypotension.

ICD codes

Dosage Regimen

Administer intravenously as a continuous infusion after dilution. Do not administer as a direct intravenous bolus.

Prepare the infusion solution by adding the concentrate to a compatible infusion fluid, typically 5% Dextrose Injection or 5% Dextrose and Sodium Chloride Injection. Do not use 0.9% Sodium Chloride Injection as the sole diluent.

The initial dosage for adults is 0.1-0.2 mcg/kg/minute. Titrate the infusion rate to achieve and maintain the desired blood pressure response.

Adjust the rate of administration in increments of 0.05-0.1 mcg/kg/minute every 2-4 minutes based on blood pressure and clinical status. The usual maintenance dose range is 0.05-0.2 mcg/kg/minute.

In severely ill patients, higher doses up to 0.5-1 mcg/kg/minute may be required. Continuously monitor heart rate, blood pressure, and ECG during infusion.

Use a central venous catheter for administration to minimize the risk of extravasation and severe local tissue necrosis. Frequently inspect the infusion site for signs of infiltration.

Gradually reduce the infusion rate when discontinuing therapy. Avoid abrupt withdrawal, as this may cause severe rebound hypotension.

Adverse Reactions

With rapid administration, headache, chills, cold extremities, tachycardia are possible.

From the cardiovascular system: arterial hypertension and tissue hypoxia; ischemic disorders, tachycardia, bradycardia, arrhythmia, palpitations, increased contractility of the heart muscle as a result of the beta-adrenergic effect on the heart, acute heart failure.

From the nervous system: anxiety, insomnia, headache, mental disorders, weakness, tremor, confusion, decreased attention.

From the digestive system: nausea, vomiting, anorexia.

From the respiratory system: shortness of breath, pain in the sternum and mediastinum, difficulty breathing, respiratory failure.

From the urinary system: urinary retention.

From the organ of vision: acute glaucoma.

From the immune system: allergic reactions and difficulty breathing are possible.

Local reactions: irritation at the injection site, development of necrosis.

Contraindications

Hypersensitivity to norepinephrine; arterial hypotension caused by hypovolemia (except when Norepinephrine is used to maintain cerebral and coronary blood flow until the completion of therapy aimed at replenishing circulating blood volume); anesthesia with cyclopropane or halothane (risk of arrhythmias); severe hypoxia and hypercapnia.

With caution: severe left ventricular failure, acute heart failure, recent myocardial infarction, Prinzmetal’s angina, thrombosis of coronary, mesenteric or peripheral vessels (risk of worsening ischemia and increasing the infarction zone), insufficient circulation, heart rhythm disturbance during infusion, hyperthyroidism, diabetes mellitus; elderly age.

Use in Pregnancy and Lactation

Norepinephrine should not be used during pregnancy due to the risk of fetal hypoxia. It is believed that use is possible only for vital indications (including collapse, myocardial infarction). It should be used with caution during lactation (breastfeeding).

Geriatric Use

It should be used with caution in elderly patients – careful monitoring of blood pressure is necessary in this category of patients.

Special Precautions

Before starting or during therapy, correction of hypovolemia, hypoxia, acidosis, hypercapnia is necessary.

Norepinephrine should be used simultaneously with adequate replenishment of circulating blood volume.

During the infusion of norepinephrine, blood pressure and the rate of administration should be checked frequently every 2 minutes until the desired blood pressure is reached, and then every 5 minutes throughout the entire infusion time.

The patient should not be left unattended during the use of norepinephrine. Headache may be a symptom of arterial hypertension due to an overdose of norepinephrine.

Long-term administration of any potent vasopressor (including Norepinephrine) can lead to a decrease in plasma volume, which must be continuously corrected by appropriate administration of fluids and electrolytes.

If the plasma volume is not corrected, then after stopping the infusion of norepinephrine, arterial hypotension may develop again, or maintaining blood pressure may be associated with the risk of severe peripheral and visceral vasoconstriction with reduced blood flow and tissue perfusion (for example, decreased renal perfusion) with subsequent tissue hypoxia, lactic acidosis and possible ischemic tissue damage.

Elderly patients may be especially sensitive to the effects of norepinephrine. If cardiac arrhythmias occur during the infusion, the dose should be reduced.

Therapy with norepinephrine should be reduced gradually, as abrupt withdrawal can lead to acute arterial hypotension.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, patients are prohibited from driving any vehicles and engaging in other activities that require high concentration and speed of psychomotor reactions.

Drug Interactions

With simultaneous use with monoamine oxidase inhibitors, a slight increase in the pressor effects of norepinephrine is possible.

Alpha-blockers (doxazosin, labetalol, phenoxybenzamine, prazosin, terazosin) and other drugs with alpha-blocking activity (haloperidol, loxapine, phenothiazines, thioxanthenes) reduce the vasoconstrictor effect of norepinephrine.

With simultaneous use of agents for inhalational general anesthesia (chloroform, enflurane, halothane, cyclopropane, isoflurane and methoxyflurane), the risk of ventricular arrhythmias increases. Halothane and cyclopropane increase the autonomic excitability of the heart and, thus, can increase the sensitivity of the myocardium to the effects of intravenously administered sympathomimetics, such as epinephrine or Norepinephrine.

When using norepinephrine simultaneously with cardiac glycosides, quinidine, tricyclic antidepressants, the risk of arrhythmias increases.

With simultaneous use with antihypertensive drugs and diuretics, a decrease in the effectiveness of norepinephrine is possible.

With simultaneous use with adrenergic blockers, mutual weakening of the action occurs.

With simultaneous use with cocaine, doxapram, mutual enhancement of the hypertensive action occurs.

With simultaneous use of monoamine oxidase inhibitors (linezolid, furazolidone, procarbazine, selegiline), prolongation and enhancement of the pressor effect are possible.

With simultaneous use of nitrates, a weakening of the antianginal effect is possible.

With simultaneous use of ergot alkaloids or oxytocin, vasopressor and vasoconstrictor effects may be enhanced.

With simultaneous use of thyroid hormones, the risk of coronary insufficiency against the background of angina pectoris increases.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.