Norepinephrine tartrate agetan 2 mg/ml (without sulfites)

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NORADRENALINE TARTRATE AGUETTANT 2 MG/ML (SULPHITE-FREE) (NORADRENALINE TARTRATE AGUETTANT 2MG/ML (SULPHITE-FREE))

Composition:

Active substance: noradrenaline;

1 ml of concentrate contains 2 mg of noradrenaline tartrate;

1 ampoule (4 ml) contains 8 mg of noradrenaline tartrate, equivalent to 4 mg of noradrenaline base;

1 ampoule (8 ml) contains 16 mg of noradrenaline tartrate, equivalent to 8 mg of noradrenaline base;

Excipients: sodium chloride, sodium hydroxide or hydrochloric acid, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colourless or slightly yellow liquid.

Pharmacotherapeutic group. Agents acting on the cardiovascular system. Non-glycoside cardiotonic agents. Adrenergic and dopaminergic agents.

ATC code C01CA03.

Pharmacological properties.

Pharmacodynamics.

Norepinephrine exerts a very strong effect on alpha-receptors and a more moderate effect on beta-1 receptors. Norepinephrine (noradrenaline) 1 mg/mL causes generalized vasoconstriction, except for coronary vessels, which it indirectly dilates due to increased oxygen consumption. As a result, there is an increase in the force (and, in the absence of vagal inhibition, frequency) of myocardial contractions. Peripheral vascular resistance increases, and both diastolic and systolic blood pressure rise.

Pharmacokinetics.

There are two stereoisomers of norepinephrine; the biologically active L-isomer is the one present in the norepinephrine (noradrenaline) 1 mg/mL concentrate for preparation of infusion solution.

Absorption

• Subcutaneous: weak.
• Oral: norepinephrine is rapidly inactivated in the gastrointestinal tract following oral administration.
• After intravenous administration, norepinephrine has a plasma half-life of approximately 1 to 2 minutes.

Distribution

• Norepinephrine is rapidly removed from plasma by a combination of cellular uptake and metabolism. Norepinephrine crosses the blood-brain barrier slowly.

Biological transformation

• Methylation by catechol-O-methyltransferase (COMT).
• Deamination by monoamine oxidase (MAO).
• The end metabolites of both pathways are 4-hydroxy-3-methoxybenzoic acid.
• Intermediate metabolites include normetanephrine and 3,4-dihydroxybenzoic acid.

Elimination

• Norepinephrine is primarily eliminated from the body mainly as glucuronide or sulfate conjugates of metabolites in urine.

Clinical characteristics.

Indications.

Norepinephrine is indicated for emergency (immediate) restoration of arterial pressure in cases of acute hypotension.

Contraindications.

The use of norepinephrine concentrate 1 mg/mL for preparation of infusion solution is contraindicated in patients with known hypersensitivity (allergic reaction) to norepinephrine or to any of the excipients.

Arterial hypotension due to insufficient blood volume (hypovolemia, reduced circulating blood volume).

The use of pressor amines during cyclopropane or halothane anesthesia may cause severe cardiac arrhythmia. Due to the possible increased risk of ventricular fibrillation, norepinephrine should be used with caution in patients receiving these or any other cardiac sensitizing agents, or in patients with increased hypoxia (oxygen deficiency) or hypercapnia (elevated carbon dioxide levels in blood or tissues).

Interaction with other medicinal products and other forms of interaction.

Unwanted combinations

Halogenated anesthetic agents (e.g., halothane): severe ventricular arrhythmia (increased cardiac excitability).

Tricyclic antidepressants: paroxysmal arterial hypertension with possible arrhythmia (inhibition of uptake of sympathomimetics into sympathetic nerve fibers).

Serotonin-norepinephrine reuptake inhibitors (SNRIs): paroxysmal arterial hypertension with possible arrhythmia (inhibition of uptake of sympathomimetics into sympathetic nerve fibers).

Combinations requiring precautions during use

Non-selective MAO inhibitors: enhanced pressor effect of sympathomimetics, usually moderate. Should be used only under strict medical supervision.

Selective MAO-A inhibitors: by extrapolation from non-selective MAO inhibitors – risk of enhanced pressor effect. Should be used only under strict medical supervision.

Linezolid: by extrapolation from non-selective MAO inhibitors – risk of enhanced pressor effect. Should be used only under strict medical supervision.

Caution is required when administering norepinephrine with alpha- and beta-blockers, as this may result in severe arterial hypertension.

Caution should be exercised when using norepinephrine with medicinal products that may cause enhanced cardiac effects, such as thyroid hormones, cardiac glycosides, and antiarrhythmic agents.

Ergot alkaloids or oxytocin may potentiate the vasopressor and vasoconstrictor effects.

Special precautions for use.

Warning

Norepinephrine should only be used concomitantly with restoration of appropriate circulating blood volume.

During infusion of norepinephrine, arterial pressure and infusion rate must be frequently monitored to avoid the development of arterial hypertension.

Parenterally administered medicinal products must always be visually inspected; they should not be used if particulate matter is observed or if they have a different color.

Risk of extravasation (leakage of drug from the vessel into surrounding tissues)

The administration site should be frequently checked for free flow of the drug. Care must be taken to avoid extravasation, which may lead to necrosis of the tissues surrounding the vein used for injection. Due to vasoconstriction, leakage of some amount of norepinephrine into the surrounding tissues may occur from veins with increased permeability, resulting in tissue pallor unrelated to obvious extravasation. Therefore, if pallor occurs, changes at the injection site should be considered and taken into account to alleviate (reduce) the impact of local vasoconstriction.

Treatment of extravasation consequences

In case of extravascular leakage or paravenous administration, tissue damage may occur due to the vasoconstrictive effect of the drug on blood vessels. In such cases, the injection site should be flushed as soon as possible with 10–15 mL of physiological saline solution containing 5 to 10 mg of phentolamine mesylate. This should be done by local injection using a syringe equipped with a fine needle.

Precautions for use

Caution and clear indication are required in patients with significant left ventricular dysfunction associated with acute hypotension. In such circumstances, careful assessment of the patient's arterial pressure is necessary. Supportive therapy should be initiated simultaneously with diagnostic evaluation. Adequate supplies of norepinephrine should be available for patients with cardiogenic shock and persistent arterial hypotension, particularly in patients without elevated systemic vascular resistance. Therapy should be initiated at a dose of 2–4 mcg/min, which can then be increased as needed. If systemic perfusion or systolic arterial pressure cannot be maintained at a level > 90 mm Hg with a dose of 15 mcg/min, further dose escalation is unlikely to be effective.

Particular caution is required when treating patients with thrombosis of coronary, mesenteric, or peripheral vessels, as norepinephrine may exacerbate ischemic disease and extend the area of myocardial infarction. Similar caution should be exercised when treating patients with arterial hypotension following myocardial infarction and in patients with vasospastic variant angina.

If cardiac arrhythmias occur during treatment, the dose should be reduced.

Caution is recommended when treating patients with hyperthyroidism or diabetes mellitus.

Elderly patients may be especially sensitive to the effects of norepinephrine.

This medicinal product contains sodium.

This should be taken into account for patients on a controlled sodium diet.

1 mL of concentrate for preparation of infusion solution contains 3.3 mg of sodium, equivalent to 0.14 mmol of sodium.

One 4 mL ampoule contains 13.2 mg of sodium, equivalent to 0.57 mmol of sodium.

One 8 mL ampoule contains 26.4 mg of sodium, equivalent to 1.14 mmol of sodium.

This medicinal product contains 26.4 mg of sodium per 8 mL ampoule, which corresponds to 1.3% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

Use during pregnancy or breastfeeding.

Pregnancy

Norepinephrine may adversely affect placental blood flow and cause fetal bradycardia. It may also affect uterine contractions in pregnant women and lead to fetal asphyxia in late pregnancy.

Therefore, the anticipated benefit to the mother should be carefully weighed against the potential risk to the fetus.

Breastfeeding

There is no information available on the use of norepinephrine during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Data are lacking.

Method of Administration and Dosage

Doses

Adult Patients

Initial infusion rate (intravenous administration):

The initial infusion rate should be from 10 ml/h to 20 ml/h (from 0.16 ml/min to 0.33 ml/min). This is equivalent to 0.8 mg/h to 1.6 mg/h of norepinephrine tartrate (or 0.4 mg/h to 0.8 mg/h of norepinephrine base).

Dose Titration

Immediately after starting norepinephrine infusion, the dose should be titrated according to the observed pressor effect. There is considerable variation in the dose required to achieve and maintain normal arterial pressure in patients. The main goal is to establish a low normal systolic arterial pressure (100–120 mm Hg) or to achieve an appropriate mean arterial pressure (greater than 65–80 mm Hg—depending on the patient's condition).

If other solutions are used, the dose must be carefully calculated before starting treatment.

Duration of treatment and monitoring

Treatment with noradrenaline should be continued as long as vasopressor support is indicated. The patient must be under close surveillance throughout the entire period of noradrenaline treatment.

Infusion must not be stopped abruptly; it should be tapered gradually to avoid a sudden drop in blood pressure.

Elderly patients

Elderly patients may be particularly sensitive to the effects of noradrenaline.

Method of administration

For intravenous use only.

Noradrenaline should be administered using central venous access devices to minimize the risk of extravasation (leakage of the drug from the vessel into surrounding tissues) and subsequent tissue necrosis.

The noradrenaline concentrate 1 mg/mL must be diluted before intravenous administration with 5% dextrose or isotonic dextrose solution. It should not be mixed with other medicinal products.

The final concentration of the infusion solution should be 80 mg/L of noradrenaline tartrate, equivalent to 40 mg/L of noradrenaline base. If other solutions are used, the dose must be carefully calculated before starting treatment.

Instructions for dilution

Add 2 mL of noradrenaline 1 mg/mL to 48 mL of 5% dextrose (or isotonic dextrose solution) for administration via syringe infusion pump, or add 20 mL of noradrenaline 1 mg/mL to 480 mL of 5% dextrose (or isotonic dextrose solution) for administration via infusion drip.

In both cases, the final concentration of the infusion solution is 80 mg/L of noradrenaline tartrate, equivalent to 40 mg/L of noradrenaline base. If other solutions are used, the dose must be carefully calculated before starting treatment.

Blood pressure monitoring

Blood pressure should be measured every 2 minutes at the beginning of the infusion until the desired blood pressure is achieved. Once the desired blood pressure is reached, blood pressure should be measured every 5 minutes as needed during continued infusion. The infusion rate should be closely monitored, and the patient should be carefully observed throughout the entire period of noradrenaline (norepinephrine) treatment.

Children

Not recommended.

Overdose

In case of overdose, the following may occur: skin vasoconstriction, pressure ulcers, vascular insufficiency, and arterial hypertension.

In the event of adverse reactions related to excessive dosing, it is recommended to reduce the dose, if possible.

Side effects.

Cardiovascular system: arterial hypertension and tissue hypoxia; ischemic lesions due to pronounced vasoconstrictive action may result in coldness and pallor of extremities and face, and may lead to gangrene of extremities.

Cardiac side effects: tachycardia, bradycardia (possibly as a reflex response to increased blood pressure), arrhythmia, palpitations, increased myocardial contractility due to β-adrenergic stimulation of the heart (inotropic and chronotropic effects), acute heart failure, stress-induced cardiomyopathy.

Central nervous system: anxiety (restlessness), sleep disturbances (insomnia), confusion (clouding of consciousness), headache, psychotic state, weakness, tremor, impaired attention and alertness, anorexia, nausea, and vomiting.

Urinary system: urinary retention.

Respiratory system: respiratory failure or labored breathing, dyspnea (shortness of breath).

Local reactions: possible irritation and necrosis at the site of drug administration.

Eyes: acute glaucoma; very frequently occurs in patients anatomically predisposed to closure of the iridocorneal angle (anterior chamber angle of the eyeball).

With prolonged use of vasopressors (vasoconstrictive agents) to maintain arterial pressure in the absence of adequate restoration of circulating blood volume, the following symptoms may occur:

• marked constriction of peripheral and visceral vessels;
• reduced renal blood flow;
• decreased urine output;
• hypoxia (oxygen deficiency);
• increased serum lactate levels.

In cases of hypersensitivity (allergic reaction) or overdose, the following symptoms may occur more frequently: arterial hypertension, photophobia, substernal pain, throat pain, pallor, excessive sweating, and vomiting.

The vasopressor effect (resulting from adrenergic action on blood vessels) may be counteracted by concomitant administration of an α-blocker (phentolamine mesylate), whereas administration of a β-blocker (propranolol) may reduce the drug's stimulatory effect on the heart and increase the pressor effect (due to reduced arteriolar dilation) resulting from β1-adrenergic stimulation.

Prolonged use of any potent vasopressor may lead to a reduction in plasma volume, which must be continuously corrected with appropriate fluid and electrolyte replacement therapy. If plasma volume is not adequately restored, arterial hypotension may recur once norepinephrine infusion is discontinued, or arterial pressure may be maintained at the risk of severe constriction of peripheral and visceral vessels, resulting in reduced blood flow.

Shelf life. 2 years.

After dilution

Physical and chemical stability of the diluted preparation (in 5% dextrose solution or isotonic dextrose solution) has been demonstrated for 48 hours at 25°C.

However, from a microbiological standpoint, the diluted preparation should be used immediately. If not used immediately, responsibility for storage duration and conditions lies solely with the user.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C. Keep out of reach of children.

For information on storage conditions of the medicinal product after dilution, see the section "Shelf life".

Incompatibilities.

The preparation must not be mixed with other medicinal products except 5% dextrose or isotonic dextrose solution; refer to the section "Dosage and administration".

Do not reuse an opened ampoule.

This preparation should be visually inspected before administration.

Use only clear, colorless or slightly yellowish solution free from particles or precipitate.

Solutions that are pinkish in color, darker than pale yellow, or contain precipitate must not be used.

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

Packaging.

4 ml or 8 ml in an ampoule; 5 ampoules in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Laboratoire Aguettant, France.

Manufacturer's address.

1, rue Alexander Fleming, Lyon, 69007, France.